Whole Body Health Sale

Abstracts

Cancer Adjuvant Therapy
Updated: 08/26/2004

ABSTRACTS

Prognostic value and expression of p21(waf1/cip1) protein in prostate cancer.

Aaltomaa S, Lipponen P, Eskelinen M, et al.

Prostate. 1999 Apr 1; 39(1):8-15.

BACKGROUND: p21(waf1/cip1) protein is a cyclin-dependent kinase inhibitor able to arrest the cell cycle at the G1 phase by inhibiting DNA replication. The expression of p21(waf1/cip1) and its prognostic value in prostate cancer are largely unexplored. METHODS: We used immunohistochemistry to analyze the expression of p21(waf1/cip1) in 213 prostate cancer cases, and the results were related to other known prognostic factors and patient survival during a long-term follow-up. RESULTS: The expression of p21 (waf1/cip1) protein was significantly associated with high Gleason score (P = 0.001), DNA aneuploidy (P = 0.013), high S-phase fraction (P = 0.019), and expression of Ki-67 (P = 0.021) and bcl-2 (P = 0.001) as well as cyclin A (P = 0.035) and D proteins (P<0.001). In univariate survival analysis the signal of p21(waf1/cip1) was significantly related to unfavorable prognosis (P = "0.010)" both in the entire cohort and in local tumors (P = "0.034)." In multivariate analysis, M-category, clinical T-category, Gleason score, and patient age were independent prognostic factors. In local tumors the expression of p21(waf1/cip1) together with clinical T-category and S-phase fraction were significant independent predictors of cancer related survival. CONCLUSIONS: The results suggest that the expression of p21(waf1/cip1) protein is associated both with cell proliferation and patient survival in prostate cancer

Breast Cancer Blues.

ABC News.

2000

Garlic revisited: therapeutic for the major diseases of our times?

Abdullah TH, Kandil O, Elkadi A, et al.

J Natl Med Assoc. 1988 Apr; 80(4):439-45.

Enhancement of natural killer cell activity in AIDS with garlic.

Abdullah TH.

Dtsch Z Onkol. 1989; 21

Immunosuppressive effect of tetrahydrocannabinol plus cyclophosphamide.

Ader R, Grota LJ.

N Engl J Med. 1981 Aug 20; 305(8):463.

Phytoestrogens: epidemiology and a possible role in cancer protection.

Adlercreutz H.

Environ Health Perspect. 1995 Oct; 103 Suppl 7:103-12.

Because many diseases of the Western Hemisphere are hormone-dependent cancers, we have postulated that the Western diet, compared to a vegetarian or semivegetarian diet, may alter hormone production, metabolism, or action at the cellular level by some biochemical mechanisms. Recently, our interest has been mainly focused on the cancer-protective role of some hormonelike diphenolic phytoestrogens of dietary origin, the lignans and the isoflavonoids. The precursors of the biologically active compounds originate in soybean products (mainly isoflavonoids), whole grain cereal food, seeds, and probably berries and nuts (mainly lignans). The plant lignan and isoflavonoid glycosides are converted by intestinal bacteria to hormonelike compounds with weak estrogenic but also antioxidative activity; they have now been shown to influence not only sex hormone metabolism and biological activity but also intracellular enzymes, protein synthesis, growth factor action, malignant cell proliferation, differentiation, and angiogenesis in a way that makes them strong candidates for a role as natural cancer-protective compounds. Epidemiologic investigations strongly support this hypothesis because the highest levels of these compounds in the diet are found in countries or regions with low cancer incidence. This report is a review on recent results suggesting that the diphenolic isoflavonoids and lignans are natural cancer-protective compounds

Phytoestrogens and breast cancer.

Adlercreutz H.

J Steroid Biochem Mol Biol. 2002 Dec; 83(1-5):113-8.

The role of phytoestrogens and consumption of phytoestrogen-rich foods such as soy containing isoflavones and whole grain products with lignans for the prevention of breast cancer is reviewed. It is concluded that soy-containing diet in adult women is not or only slightly protective with regard to breast cancer, but that it may be beneficial if consumed in early life before puberty or during adolescence supporting results of immigrant and epidemiological studies. No negative effects of soy on breast cancer have been observed. On the other hand, a diet low in lignans, resulting in a low plasma enterolactone concentration, increases risk both in a case-control and a prospective study, but some controversial results have also been obtained. Some of these results may be explained by the fact that the determinants of plasma or urinary enterolactone concentration are very different in different countries. In Scandinavia, the main determinants are whole grain cereal food, vegetables and berries. Whether the protective effect is caused by the phytoestrogens in the diet or whether they are only biomarkers of a healthy diet has not been established

all-trans retinoic acid enhances cisplatin-induced apoptosis in human ovarian adenocarcinoma and in squamous head and neck cancer cells.

Aebi S, Kroning R, Cenni B, et al.

Clin Cancer Res. 1997 Nov; 3(11):2033-8.

Cisplatin exerts its cytotoxicity by inducing apoptosis. Similarly, all-trans retinoic acid (ATRA) causes apoptosis in certain cells. We studied the interaction of cisplatin and ATRA in human ovarian adenocarcinoma cells 2008, in human head and neck squamous carcinoma cells UMSCC10b, and in their respective cisplatin-resistant sub-lines. ATRA enhanced the cytotoxicity of cisplatin. The interaction of the drugs was synergistic in combination index-isobologram analyses (combination index >0.5 at 50% cell survival) in all of the cell lines tested. ATRA inhibited the cellular accumulation of the cisplatin analogue [3H] cis-dichloroethylenediamineplatinum(II) by 22-33% in three of four cell lines tested but did not alter the cellular content of reduced glutathione. The expression of Bcl-2 relative to Bax decreased more after combined treatment with cisplatin and ATRA than after either drug alone. The apoptotic mechanism of cell death was confirmed by demonstrating cleavage of poly(ADP-ribose)polymerase and by morphological analysis. The combined treatment with ATRA and cisplatin induced apoptosis in significantly more cells than either drug alone. We conclude that ATRA enhances the cytotoxicity of cisplatin by facilitating apoptosis in ovarian and head and neck carcinoma cells

Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac.

Agarwal B, Rao CV, Bhendwal S, et al.

Gastroenterology. 1999 Oct; 117(4):838-47.

BACKGROUND & AIMS: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (HRIs) were found incidentally to reduce new cases of colon cancer in 2 large clinical trials evaluating coronary events, although most patients in both treatment and control group were taking nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are associated with reduced colon cancer incidence, predominantly by increasing apoptosis. We showed previously that lovastatin induces apoptosis in colon cancer cells. In the present study we evaluated the potential of combining lovastatin with sulindac for colon cancer chemoprevention. RESULTS: Lovastatin, 10-30 micromol/L, augmented sulindac-induced apoptosis up to 5-fold in 3 colon cancer cell lines. This was prevented by mevalonate (100 micromol/L) or geranylgeranylpyrophosphate (10 micromol/L) but not farnesylpyrophosphate (100 micromol/L), suggesting inhibition of geranylgeranylation of target protein(s) as the predominant mechanism. In an azoxymethane rat model of chemical-induced carcinogenesis, the total number of colonic aberrant crypt foci per animal (control, 161 +/- 11) and the number of foci with 4+ crypts (control, 40 +/- 4.5) decreased to 142 +/- 14 (NS) and 43 +/- 2.9 (NS), respectively, with 50 ppm lovastatin alone; to 137 +/- 5.4 (P = 0.053) and 36 +/- 2.1 (NS) with 80 ppm sulindac alone; and to 116 +/- 8.1 (P = 0.004) and 28 +/- 3.4 (P = 0.02) when 50 ppm lovastatin and 80 ppm sulindac were combined. CONCLUSIONS: Addition of an HRI such as lovastatin may augment chemopreventive effects of NSAIDs or/and may allow lower, less toxic doses of these drugs to be used

Anticarcinogenic effect of a polyphenolic fraction isolated from grape seeds in human prostate carcinoma DU145 cells: modulation of mitogenic signaling and cell-cycle regulators and induction of G1 arrest and apoptosis.

Agarwal C, Sharma Y, Agarwal R.

Mol Carcinog. 2000 Jul; 28(3):129-38.

There is an increasing interest in identifying potent cancer preventive and therapeutic agents against prostate cancer (PCA). In a recent study, we showed that a polyphenolic fraction isolated from grape seeds (hereafter referred to as GSP) that is substantially rich in antioxidant procyanidins exerts exceptionally high preventive effects against tumorigenesis in a murine skin model. In the present study, we investigated the anticarcinogenic effect of GSP against PCA by employing DU145 human prostate carcinoma cells. GSP treatment (10-100 microg/mL doses for 2-6 d) of cells resulted in a highly significant (P < 0.01-0.001) inhibition of cell growth in both dose- and time-dependent manner. Compared with the vehicle, 2 d of GSP treatment resulted in 27, 39, and 76% growth inhibition at 50, 75, and 100 microg/mL doses, respectively, whereas 28-97% and 12-98% inhibition was evident at 10-100 microg/mL doses of GSP after 4 and 6 d of treatment, respectively. These doses of GSP also resulted in dose- and time-dependent cell death (6-50%, P <0.1-0. 001) that was later characterized as apoptotic death. In molecular mechanistic studies, treatment of DU145 cells with GSP at 25-75 microg/mL doses for 24, 48, and 72 h resulted in 77-88%, 65-93%, and 38-98% reduction, respectively (P < 0.001), in phospho-extracellular signal-regulated protein kinase (ERK) 1 and 78%, 19-76%, and 63-71% reduction (P < 0.1-0.001) in phospho-ERK2 levels, respectively. In other studies, similar doses of GSP showed up to 1.9-fold increases in Cip1/p21 and a significant (P < 0.001) decrease in cyclin-dependent kinase (CDK) 4 (up to 90% decrease), CDK2 (up to 50% decrease), and cyclin E (up to 60% decrease). GSP treatment of DU145 cells also resulted in a significant (P < 0.001) G1 arrest in cell-cycle progression in a dose-dependent manner. The growth-inhibitory and cell-death effects of GSP were also observed in another human PCA line, LNCaP. Together, these results suggest that GSP may exert strong anticarcinogenic effect against PCA and that this effect possibly involves modulation of mitogenic signaling and cell-cycle regulators and induction of G1 arrest, cell-growth inhibition, and apoptotic death. Mol. Carcinog. 28:129-138, 2000

Tomato lycopene and its role in human health and chronic diseases.

Agarwal S, Rao AV.

CMAJ. 2000 Sep 19; 163(6):739-44.

Lycopene is a carotenoid that is present in tomatoes, processed tomato products and other fruits. It is one of the most potent antioxidants among dietary carotenoids. Dietary intake of tomatoes and tomato products containing lycopene has been shown to be associated with a decreased risk of chronic diseases, such as cancer and cardiovascular disease. Serum and tissue lycopene levels have been found to be inversely related to the incidence of several types of cancer, including breast cancer and prostate cancer. Although the antioxidant properties of lycopene are thought to be primarily responsible for its beneficial effects, evidence is accumulating to suggest that other mechanisms may also be involved. In this article we outline the possible mechanisms of action of lycopene and review the current understanding of its role in human health and disease prevention

Histamine dihydrochloride: inhibiting oxidants and synergising IL-2-mediated immune activation in the tumour microenvironment.

Agarwala SS, Sabbagh MH.

Expert Opin Biol Ther. 2001 Sep; 1(5):869-79.

The potential role of histamine in cancer immunotherapy has been a subject of interest for more than a decade. A significant body of research has elucidated the action of histamine in a model system that mimics the tumour microenvironment. In vitro evidence indicates that histamine inhibits the generation and release of reactive oxygen species (ROS) by monocytes/macrophages (MO) during respiratory burst. Since ROS have been shown to abrogate peritumoural and intratumoural cytokine activation of natural killer (NK) and T-cells and induce apoptosis of these cells in vitro, inhibition of ROS may enable cytokines to activate NK and T-cells and restore their antineoplastic, cytotoxic capabilities. Experimental data indicate that histamine and interleukin-2 (IL-2) act synergistically to activate NK cell cytotoxicity (NKCC). Although IL-2, a regulator of immune responses, has been shown to promote NKCC in monotherapy for metastatic melanoma (MM), renal cell carcinoma (RCC) and acute myeloid leukaemia (AML), objective responses occur in a minority of patients and survival is not significantly extended, except for a minority of patients with MM using high-dose regimens which have not been widely adopted. In vitro findings suggest that the addition of histamine to IL-2 therapy might improve response rates and disease-free survival by protecting the cells of the immune system from oxidative stress and inducing natural endogenous immune cytotoxicity. An IL-2/histamine Phase III trial is in progress in a population of AML patients. A recently completed Phase III trial of IL-2 vs. IL-2/histamine in patients with MM demonstrated a trend towards a superior survival benefit from IL-2/histamine for all patients entered, and a statistically significant survival benefit for patients with hepatic metastases

Green tea polyphenol epigallocatechin-3-gallate differentially modulates nuclear factor kappaB in cancer cells versus normal cells.

Ahmad N, Gupta S, Mukhtar H.

Arch Biochem Biophys. 2000 Apr 15; 376(2):338-46.

Green tea has shown remarkable anti-inflammatory and cancer chemopreventive effects in many animal tumor bioassays, cell culture systems, and epidemiological studies. Many of these biological effects of green tea are mediated by epigallocatechin 3-gallate (EGCG), the major polyphenol present therein. We have earlier shown that EGCG treatment results in apoptosis of several cancer cells, but not of normal cells (J. Natl. Cancer Inst. 89, 1881-1886 (1997)). The mechanism of this differential response of EGCG is not known. In this study, we investigated the involvement of NF-kappaB during these differential responses of EGCG. EGCG treatment resulted in a dose-dependent (i) inhibition of cell growth, (ii) G0/G1-phase arrest of the cell cycle, and (iii) induction of apoptosis in human epidermoid carcinoma (A431) cells, but not in normal human epidermal keratinocytes (NHEK). Electromobility shift assay revealed that EGCG (10-80 microM) treatment results in lowering of NF-kappaB levels in both the cytoplasm and nucleus in a dose-dependent manner in both A431 cells and NHEK, albeit at different concentrations. EGCG treatment was found to result in a dose-based differential inhibition of TNF-alpha- and LPS-mediated activation of NF-kappaB in these cells. The inhibition of NF-kappaB constitutive expression and activation in NHEK was observed only at high concentrations. The immunoblot analysis also demonstrated a similar pattern of inhibition of the constitutive expression as well as activation of NF-kappaB/p65 nuclear protein. This inhibition of TNF-alpha-caused NF-kappaB activation was mediated via the phosphorylative degradation of its inhibitory protein IkappaBalpha. Taken together, EGCG was found to impart differential dose-based NF-kappaB inhibitory response in cancer cells vs normal cells; i.e., EGCG-mediated inhibition of NF-kappaB constitutive expression and activation was found to occur at much higher dose of EGCG in NHEK as compared to A431 cells. This study suggests that EGCG-caused cell cycle deregulation and apoptosis of cancer cells may be mediated through NF-kappaB inhibition

Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin.

Ahsan H, Parveen N, Khan NU, et al.

Chem Biol Interact. 1999 Jul 1; 121(2):161-75.

Curcumin, a naturally occurring phytochemical responsible for the colour of turmeric shows a wide range of pharmacological properties including antioxidant, anti-inflammatory and anti-cancer effects. We have earlier shown that curcumin in the presence of Cu(II) causes strand cleavage in DNA through generation of reactive oxygen species, particularly the hydroxyl radical. Thus, curcumin shows both antioxidant as well as pro-oxidant effects. In order to understand the chemical basis of various biological properties of curcumin, we have studied the structure-activity relationship between curcumin and its two naturally occurring derivatives namely demethoxycurcumin (dmC) and bisdemethoxycurcumin (bdmC). Curcumin was found to be the most effective in the DNA cleavage reaction and a reducer of Cu(II) followed by dmC and bdmC. The rate of formation of hydroxyl radicals by the three curcuminoids also showed a similar pattern. The relative antioxidant activity was examined by studying the effect of these curcuminoids on cleavage of plasmid DNA by Fe(II)-EDTA system (hydroxyl radicals) and the generation of singlet oxygen by riboflavin. The results indicate that curcumin is considerably more active both as an antioxidant as well as an oxidative DNA cleaving agent. The DNA cleavage activity is the consequence of binding of Cu(II) to various sites on the curcumin molecule. Based on the present results, we propose three binding sites for Cu(II). Two of the sites are provided by the phenolic and methoxy groups on the two benzene rings and the third site is due to the presence of 1,3-diketone system between the rings. Furthermore, both the antioxidant as well as pro-oxidant effects of curcuminoids are determined by the same structural moieties

Beneficial effects of sun exposure on cancer mortality.

Ainsleigh HG.

Prev Med. 1993 Jan; 22(1):132-40.

For more than 50 years, there has been documentation in the medical literature suggesting that regular sun exposure is associated with substantial decreases in death rates from certain cancers and a decrease in overall cancer death rates. Recent research suggests that this is a causal relationship that acts through the body's vitamin D metabolic pathways. The studies reviewed here show that (a) sunlight activation is our most effective source of vitamin D; (b) regular sunlight/vitamin D "intake" inhibits growth of breast and colon cancer cells and is associated with substantial decreases in death rates from these cancers; (c) metabolites of vitamin D have induced leukemia and lymphoma cells to differentiate, prolonged survival of leukemic mice, and produced complete and partial clinical responses in lymphoma patients having high vitamin D metabolite receptor levels in tumor tissue; (d) sunlight has a paradoxical relationship with melanoma, in that severe sunburning initiates melanoma whereas long-term regular sun exposure inhibits melanoma; (e) frequent regular sun exposure acts to cause cancers that have a 0.3% death rate with 2,000 U.S. fatalities per year and acts to prevent cancers that have death rates from 20-65% with 138,000 U.S. fatalities per year; (f) there is support in the medical literature to suggest that the 17% increase in breast cancer incidence during the 1991-1992 year may be the result of the past decade of pervasive anti-sun advisories from respected authorities, coinciding with effective sunscreen availability; and (g) trends in the epidemiological literature suggest that approximately 30,000 U.S. cancer deaths yearly would be averted by the widespread public adoption of regular, moderate sunning.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of invasion, gelatinase activity, tumor take and metastasis of malignant cells by N-acetylcysteine.

Albini A, D'Agostini F, Giunciuglio D, et al.

Int J Cancer. 1995 Mar 29; 61(1):121-9.

The thiol N-acetylcysteine (NAC) is currently considered one of the most promising cancer chemopreventive agents by virtue of its multiple and coordinated mechanisms affecting the process of chemical carcinogenesis. Recent studies have shown that an unpaired cysteine residue in the propeptide plays a key role in inactivation of latent metastasis-associated metalloproteinases: the present study was designed to assess whether NAC could also affect tumor take, invasion and metastasis of malignant cells. As assessed by zymographic analysis, NAC completely inhibited the gelatinolytic activity of type-IV collagenases in the cells tested (gelatinases A and B). Moreover, NAC was efficient in inhibiting the chemotactic and invasive activities of tumor cells of human (A2058 melanoma) and murine origin (K1735 and B16-F10 melanoma cells as well as C87 Lewis lung carcinoma cells) in Boyden-chamber assays, which are predictive of the invasive and metastatic properties. Reduced glutathione (GSH) had a similar, although less effective activity. The number of lung metastases decreased sharply when B16-F10 murine melanoma cells, injected i.v. into nude mice, were pre-treated with NAC and resuspended in medium supplemented with 10 mM NAC. In other experiments NAC was given in drinking water, starting 48-72 hr before subcutaneous inoculation of either B16-F10 cells or of their highly metastatic variant B16-BL6, or intramuscular injection of LLC cells. In all experiments NAC treatment decreased the weight of the locally formed primary tumor and produced a dose-related delay in tumor formation. Spontaneous metastasis formation by B16-F10 and B16-BL6 tumors was slightly yet significantly reduced by oral administration of NAC. However, this was not observed for Lewis lung tumors. These data indicate that NAC affects the process of tumor-cell invasion and metastasis, probably due to inhibition of gelatinases by its sulfhydryl group, with the possible contribution of other mechanisms, including the potent antioxidant activity of this thiol

Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dose-dependent manner.

Allred CD, Allred KF, Ju YH, et al.

Cancer Res. 2001 Jul 1; 61(13):5045-50.

We have demonstrated that the isoflavone, genistein, stimulates growth of estrogen-dependent human breast cancer (MCF-7) cells in vivo (C. Y. Hsieh et al., Cancer Res., 58: 3833-3838, 1998). The isoflavones are a group of phytoestrogens that are present in high concentrations in soy. Whether consumption of genistein from soy protein will have similar effects on estrogen-dependent tumor growth as pure genistein has not been investigated in the athymic mouse tumor implant model. Depending on processing, soy protein isolates vary widely in concentrations of genistein. We hypothesize that soy isolates containing different concentrations of genistein will stimulate the growth of estrogen-dependent cells in vivo in a dose-dependent manner. To test this hypothesis we conducted experiments in which these soy protein isolates were fed to athymic mice implanted s.c. with estrogen-dependent tumors. Genistein content (aglycone equivalent) of the soy isolate diets were 15, 150, or 300 ppm. Positive (with 17beta-estradiol pellet implant) and negative (no 17beta-estradiol) control groups received casein-based (isoflavone-free) diets. Tumor size was measured weekly. At completion of the study animals were killed and tumors collected for evaluation of cellular proliferation and estrogen-dependent gene expression. Incorporation of bromodeoxyuridine into cellular DNA was used as an indicator of cell proliferation, and pS2 mRNA was used as an estrogen-responsive gene. Soy protein diets containing varying amounts of genistein increased estrogen-dependent tumor growth in a dose-dependent manner. Cell proliferation was greatest in tumors of animals given estrogen or dietary genistein (150 and 300 ppm). Expression of pS2 was increased in tumors from animals consuming dietary genistein (150 and 300 ppm). Here we present new information that soy protein isolates containing increasing concentrations of genistein stimulate the growth of estrogen-dependent breast cancer cells in vivo in a dose-dependent manner

ACS Monograph 173: Chemical Carcinogens 1976.

American Chemical Society.

1976

Helicobactor pylori Infection 2002.

Analyst.

2002;Mar 2002

Stress and immune responses after surgical treatment for regional breast cancer.

Andersen BL, Farrar WB, Golden-Kreutz D, et al.

J Natl Cancer Inst. 1998 Jan 7; 90(1):30-6.

BACKGROUND: Adults who undergo chronic stress, such as the diagnosis and surgical treatment of breast cancer, often experience adjustment difficulties and important biologic effects. This stress can affect the immune system, possibly reducing the ability of individuals with cancer to resist disease progression and metastatic spread. We examined whether stress influences cellular immune responses in patients following breast cancer diagnosis and surgery. METHODS: We studied 116 patients recently treated surgically for invasive breast cancer. Before beginning their adjuvant therapy, all subjects completed a validated questionnaire assessing the stress of being cancer patients. A 60-mL blood sample taken from each patient was subjected to a panel of natural killer (NK) cell and T-lymphocyte assays. We then developed multiple regression models to test the contribution of psychologic stress in predicting immune function. All regression equations controlled for variables that might exert short- or long-term effects on these responses, and we also ruled out other potentially confounding variables. RESULTS: We found, reproducibly between and within assays, the following: 1) Stress level significantly predicted lower NK cell lysis, 2) stress level significantly predicted diminished response of NK cells to recombinant interferon gamma, and 3) stress level significantly predicted decreased proliferative response of peripheral blood lymphocytes to plant lectins and to a monoclonal antibody directed against the T-cell receptor. CONCLUSIONS: The data show that the physiologic effects of stress inhibit cellular immune responses that are relevant to cancer prognosis, including NK cell toxicity and T-cell responses. Additional, longitudinal studies are needed to determine the duration of these effects, their health consequences, and their biologic and/or behavioral mechanisms

Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy.

Anderson PM, Schroeder G, Skubitz KM.

Cancer. 1998 Oct 1; 83(7):1433-9.

BACKGROUND: Mouth sores and/or difficulty swallowing are common and painful consequences of cytotoxic chemotherapy for cancer. In previous studies oral glutamine was found to protect animals from the effects of whole abdominal radiation and methotrexate-induced enteritis. Glutamine also was found to reduce oral mucositis in a nonrandomized pilot study in humans. Therefore, the authors attempted to determine the efficacy of oral glutamine in a randomized, double blind, crossover trial in cancer patients receiving chemotherapy. METHODS: Twenty-four patients (16 children and 8 adults) received glutamine or placebo (glycine) suspension (2 g amino acid/M2/dose twice daily) to swish and swallow on days of chemotherapy administration and for at least 14 additional days. Patients completed a calendar indicating days of mouth pain associated with each chemotherapy course and the effect of mouth pain on oral intake. RESULTS: Paired data indicated significant amelioration of stomatitis associated with glutamine administration after chemotherapy. The duration of mouth pain was 4.5 days less in chemotherapy courses in which glutamine supplementation was compared with placebo (Wilcoxon's signed rank test, P=0.0005). The severity of oral pain also was reduced significantly when glutamine was provided with chemotherapy (the amount of days mucositis restricted oral intake to soft foods [> or =Grade 2; Modified Eastern Cooperative Oncology Group grading system] was 4 days less with glutamine compared with placebo; Wilcoxon's signed rank test, P=0.002). CONCLUSIONS: Low dose oral glutamine supplementation during and after chemotherapy significantly reduced both the duration and severity of chemotherapy-associated stomatitis. Oral glutamine appears to be a simple and useful measure to increase the comfort of many patients at high risk of developing mouth sores as a consequence of intensive cancer chemotherapy

Migration and prostate cancer: an international perspective.

Angwafo FF.

J Natl Med Assoc. 1998 Nov; 90(11 Suppl):S720-S723.

There are intra- and interracial differences in prostate cancer incidence and mortality rates worldwide. The environment and migration patterns seem to influence the disparities in cancer statistics. The lowest incidence rate is recorded in Chinese, followed by other Asians, South Americans, southern Europeans, and northern Europeans, in ascending order. However, people of African descent have the highest incidence so far. Until recently, African Americans in Alameda County (California) in the United States had the highest reported incidence (160/1000,000). An incidence of 314/100,000 recently was reported in African Caribbeans from Jamaica. These high rates contrast with the low incidence rates reported in continental (Sub-Saharan) Africa. Angwafo et al have reported higher age-adjusted incidence rates in Yaounde, Cameroon (93.8/100,000). They highlighted the importance of diagnostic methodology, availability of and access to diagnostic techniques and trained manpower, and adjustments for the age distribution of populations when comparing incidence rates between regions. The great disparity in cancer statistics over large geographic areas and races has oriented studies toward genes and gene products susceptible to environmental risk factors such as diet, ultraviolet rays, and cadmium, which may be associated with or causative of prostate cancer. Randomized studies on suspected risk factors and promoters of prostate cancer need to be conducted worldwide. However, caution is in order when inferences are made comparing populations with access to health care to those without

Effects of high doses of vitamins C and E against doxorubicin-induced chromosomal damage in Wistar rat bone marrow cells.

Antunes LM, Takahashi CS.

Mutat Res. 1998 Nov 9; 419(1-3):137-43.

Doxorubicin (DXR) is one of the major antitumoral agents available for clinical use. In addition to intercalating into the DNA molecule, this drug generates free radicals. Vitamins C (VC) and E (VE) can protect normal cells from the damage caused by radicals without interfering with the cytotoxicity of DXR against tumors. The objective of the present study was to investigate the possible protective effect of VC and/or VE on mammalian cells treated with DXR in vivo. Animals treated with the lowest doses of VC and/or VE, alone or in combination, plus a single dose of DXR presented a statistically significant reduction in total number of chromosome aberrations and in number of abnormal metaphases. The highest vitamin doses tested caused no changes in the parameters analyzed when compared with control. Under the present experimental conditions, the efficiency of VC and/or VE in protecting against chromosome damage was dependent on the dose used

Estrogen receptor beta mRNA in colon cancer cells: growth effects of estrogen and genistein.

Arai N, Strom A, Rafter JJ, et al.

Biochem Biophys Res Commun. 2000 Apr 13; 270(2):425-31.

Knowledge regarding the expression of the recently cloned estrogen receptor beta (ERbeta) in colonic mucosa is limited. In this study, we demonstrated that five human colon cancer cell lines, HT29, Colo320, Lovo, SW480, and HCT116, expressed ERbeta mRNA, but lacked ERalpha mRNA. Results from a cell growth assay demonstrated that these colon cancer cells were not influenced by estrogen, while genistein possessed slight growth inhibitory effects on HT29, Colo320 and Lovo cells at 10 microM, at which concentration is stimulated the growth of ERalpha-positive human breast cancer MCF-7 cells. Tamoxifen inhibited the growth of HT29 and Colo320 cells, dose-dependently, as well as MCF-7 cells. A transfected reporter plasmid containing a vitellogenin estrogen response element could be activated by estradiol in Colo320 cells. Taken together with previous reports, these data suggest that ERalpha and ERbeta may have different biological functions in colon cells

Curcumin is an in vivo inhibitor of angiogenesis.

Arbiser JL, Klauber N, Rohan R, et al.

Mol Med. 1998 Jun; 4(6):376-83.

BACKGROUND: Curcumin is a small-molecular-weight compound that is isolated from the commonly used spice turmeric. In animal models, curcumin and its derivatives have been shown to inhibit the progression of chemically induced colon and skin cancers. The genetic changes in carcinogenesis in these organs involve different genes, but curcumin is effective in preventing carcinogenesis in both organs. A possible explanation for this finding is that curcumin may inhibit angiogenesis. MATERIALS AND METHODS: Curcumin was tested for its ability to inhibit the proliferation of primary endothelial cells in the presence and absence of basic fibroblast growth factor (bFGF), as well as its ability to inhibit proliferation of an immortalized endothelial cell line. Curcumin and its derivatives were subsequently tested for their ability to inhibit bFGF-induced corneal neovascularization in the mouse cornea. Finally, curcumin was tested for its ability to inhibit phorbol ester-stimulated vascular endothelial growth factor (VEGF) mRNA production. RESULTS: Curcumin effectively inhibited endothelial cell proliferation in a dose-dependent manner. Curcumin and its derivatives demonstrated significant inhibition of bFGF-mediated corneal neovascularization in the mouse. Curcumin had no effect on phorbol ester-stimulated VEGF production. CONCLUSIONS: These results indicate that curcumin has direct antiangiogenic activity in vitro and in vivo. The activity of curcumin in inhibiting carcinogenesis in diverse organs such as the skin and colon may be mediated in part through angiogenesis inhibition

Proliferation of cultured human astrocytoma cells in response to an oxidant and antioxidant.

Arora-Kuruganti P, Lucchesi PA, Wurster RD.

J Neurooncol. 1999; 44(3):213-21.

The role of reactive oxygen species (ROS) in initiation, promotion and progression of several (lung, skin, colon, bladder, breast) tumors is well-documented. Indirect evidence for ROS involvement in tumor proliferation is provided by numerous in vivo and in vitro studies that show antioxidants inhibit tumor proliferation. However, despite strong epidemiological and experimental support for ROS involvement in brain tumor proliferation, to date little is known about the role of ROS in brain tumor promotion at a cellular level. In the present study ROS involvement in proliferation of a cultured, human astrocytoma cell line (U373-MG) was tested by studying effects of an oxidant (hydrogen peroxide, H2O2), and an antioxidant (N-acetylcysteine, NAC) on astrocytoma on proliferation of these cultured cells. Proliferation was assessed by evaluating changes in cell counts and DNA synthesis. Results from these experiments clearly indicate that NAC inhibits tumor cell proliferation and DNA synthesis induced by both serum and H2O2 (10(-5) M). NAC alone did not have any significant effects on the proliferation of serum-starved cells. Thus, ROS are capable of inducing proliferation in cultured astrocytoma cells and antioxidants block ROS- and serum-induced proliferation. Further investigation using primary cultures and animal models will be needed to substantiate the therapeutic potential of antioxidants in future brain tumor therapy

Selenium in the immune system.

Arthur JR, McKenzie RC, Beckett GJ.

J Nutr. 2003 May; 133(5 Suppl 1):1457S-9S.

Selenium as an essential component of selenocysteine-containing protein is involved in most aspects of cell biochemistry and function. As such, there is much potential for selenium to influence the immune system. For example, the antioxidant glutathione peroxidases are likely to protect neutrophils from oxygen-derived radicals that are produced to kill ingested foreign organisms. When the functions of all selenoproteins are described, only then will it be possible to fully understand their role in maintaining optimal immune function

Induction of interferon and activation of NK cells and macrophages in mice by oral administration of Ge-132, an organic germanium compound.

Aso H, Suzuki F, Yamaguchi T, et al.

Microbiol Immunol. 1985; 29(1):65-74.

After oral administration of an organic germanium compound, Ge-132 (300 mg/kg), a significant level of interferon (IFN) activity was detected in the sera of mice at 20 hr and it reached a maximum of 320 U/ml at 24 hr. This IFN activity was lost after heat- or acid-treatment, suggesting that the induced IFN is of gamma-nature. The molecular weight of this IFN was estimated to be 50,000 daltons by gel filtration. The NK activity of spleen cells was increased 24 hr after the oral administration of Ge-132, and cytotoxic macrophages were induced in the peritoneal cavity by 48 hr. In the mice receiving an intraperitoneal (ip) injection of trypan blue or carrageenan 2 days before oral administration of Ge-132, neither induction of IFN nor augmentation of NK activity occurred, and X-ray irradiation of mice also rendered the mice incapable of producing IFN, all indicating that both macrophages and lymphocytes are required for this IFN induction. Both NK and cytotoxic macrophages appeared 18 hr after ip administration of the induced IFN with a titer as low as 20 U/ml. These facts suggest that both the augmentation of NK activity and activation of macrophages in mice after oral administration of Ge-132 are mediated by the induced IFN

Resveratrol, a natural product derived from grapes, is a new inducer of differentiation in human myeloid leukemias.

Asou H, Koshizuka K, Kyo T, et al.

Int J Hematol. 2002 Jun; 75(5):528-33.

A natural product, resveratrol (3,4,40-trihydroxy-trans-stilbene), a phytoalexin found in grapes and other food products, is known as a cancer chemopreventive agent. We studied the in vitro biological activity of this compound by examining its effect on proliferation and differentiation in myeloid leukemia cell lines (HL-60, NB4, U937,THP-1, ML-1, Kasumi-1) and fresh samples from 17 patients with acute myeloid leukemia. Resveratrol (20 microM, 4 days) alone inhibited the growth in liquid culture of each of the 6 cell lines. Resveratrol (10 microM) enhanced the expression of adhesion molecules (CD11a, CD11b, CD18, CD54) in each of the cell lines except for Kasumi-1. Moreover, resveratrol (25 microM, 4 days) induced 37% of U937 cells to produce superoxide as measured by the ability to reduce nitroblue tetrazolium (NBT). The combination of resveratrol (10 microM) and all-trans-retinoic acid (ATRA) (50 nM, 4 days) induced 95% of the NB4 cells to become NBT-positive, whereas <1% and 12% of the cells became positive for NBT after a similar exposure to either resveratrol or ATRA alone, respectively. In U937 cells exposed to resveratrol (25 microM, 3 days), the binding activity of nuclear factor-kappaB (NFkappaB) protein was suppressed. Eight of 19 samples of fresh acute leukemia cells reduced NBT after exposure to resveratrol (20 microM, 4 days). Taken together, these findings show that resveratrol inhibits proliferation and induces differentiation of myeloid leukemia cells

Ingestion of green tea rapidly decreases prostaglandin E2 levels in rectal mucosa in humans.

August DA, Landau J, Caputo D, et al.

Cancer Epidemiol Biomarkers Prev. 1999 Aug; 8(8):709-13.

The objective of this Phase I/II study was to assess the potential for green tea to be used as a colorectal cancer chemopreventive agent. This study measured the dose-related biological effects of administration of a single dose of green tea on the rectal mucosa of normal volunteers. Volunteers were admitted to the Robert Wood Johnson Medical School Clinical Research Center for 24 h. Baseline blood and rectal biopsy samples were obtained before the volunteers drank 0.6, 1.2, or 1.8 g of green tea solids dissolved in warm water. Blood samples were taken 2, 4, 8, and 24 h after the tea administration. Rectal biopsies were obtained at 4, 8, and 24 h. Prostaglandin E2 (PGE2) levels were analyzed by ELISA. Tea polyphenol levels in the blood, urine, and rectal tissue were measured by high-performance liquid chromatography using a Coulochem electrode array detection system. Statistical comparisons were made using ANOVA. Decreased levels of PGE2 in rectal mucosa were observed at 4 and 8 h after consumption of green tea. There was no correlation between inhibition of PGE2 and tissue or plasma levels of tea polyphenols. Ten of 14 subjects demonstrated a response to green tea, as evidenced by at least a 50% inhibition of PGE2 levels at 4 h. We conclude that green tea constituents have biological activity in inhibiting PGE2 synthesis. Given the 71% "response rate," we believe these data support the study of green tea as a colorectal chemopreventive agent in more long-term Phase II trials

Signal transduction for proliferation of glioma cells in vitro occurs predominantly through a protein kinase C-mediated pathway.

Baltuch GH, Yong VW.

Brain Res. 1996 Feb 26; 710(1-2):143-9.

Previous work has demonstrated that glioma cells have very high protein kinase C (PKC) enzyme activity when compared to non-malignant glia, and that their PKC activity correlates with their proliferation rate. The purpose of this study was to determine whether the elevated PKC activity in glioma is secondary to an autonomously active PKC isoform implying oncogenic transformation, or whether this activity is driven by upstream ligand-receptor tyrosine kinase interactions. We treated established human glioma cell lines A172, U563 or U251 with either the highly selective PKC inhibitor CGP 41 251, or with genistein, a tyrosine kinase inhibitor. The proliferation rate and PKC activity of all the glioma lines was reduced by CGP 41 251; the IC50 values for inhibiting cell proliferation corresponded to the IC50v values for inhibition of PKC activity. Genistein also inhibited cell proliferation, with IC50 proliferation values approximating those for inhibition of tyrosine kinase activity in cell free protein extracts. Importantly, in genistein-treated cells, downstream PKC enzyme activity was dose dependently reduced such that the correlation coefficient for effects of genistein on proliferation rate and PKC activity was 0.92. These findings suggest that upstream tyrosine kinase linked events, rather than an autonomously functioning PKC, result in the high PKC activity observed in glioma. Finally, fetal calf serum (FCS) evoked a strong mitogenic effect on glioma cell lines. This mitogenic activity was completely blocked by CGP 41 251, suggesting that although the many mitogens in FCS for glioma cells signal initially through genistein-inhibitable tyrosine kinases, they ultimately channel through a PKC-dependent pathway. We conclude that proliferative signal transduction in glioma cells occurs through a predominantly PKC-dependent pathway and that selectively targeting this enzyme provides an approach to glioma therapy

Decrease in linoleic acid metabolites as a potential mechanism in cancer risk reduction by conjugated linoleic acid.

Banni S, Angioni E, Casu V, et al.

Carcinogenesis. 1999 Jun; 20(6):1019-24.

Previous research suggested that conjugated linoleic acid (CLA) feeding during the period of pubescent mammary gland development in the rat resulted in diminished mammary epithelial branching which might account for the reduction in mammary cancer risk. Terminal end buds (TEB) are the primary sites for the chemical induction of mammary carcinomas in rodents. One of the objectives of the present study was to investigate the modulation of TEB density by increasing levels of dietary CLA and to determine how this might affect the risk of methylnitrosourea-induced mammary carcinogenesis. The data show a graded and parallel reduction in TEB density and mammary tumor yield produced by 0.5 and 1% CLA. No further decrease in either parameter was observed when CLA in the diet was raised to 1.5 or 2%. Thus, optimal CLA nutrition during pubescence could conceivably control the population of cancer-sensitive target sites in the mammary gland. Since both CLA and linoleic acid are likely to share the same enzyme system for chain desaturation and elongation, it is possible that increased CLA intake may interfere with the further metabolism of linoleic acid. Fatty acid analysis of total lipid showed that CLA and CLA metabolites continued to accumulate in mammary tissue in a dose-dependent manner over the range 0.5-2% CLA. There was no perturbation in tissue linoleic acid, however, linoleic acid metabolites (including 18:3, 20:3 and 20:4) were consistently depressed by up to 1% CLA. Of particular interest was the significant drop in 20:4 (arachidonic acid), which is the substrate for the cyclooxygenase and lipoxygenase pathways of eicosanoid biosynthesis. Thus the CLA dose-response effect on arachidonic acid suppression corresponded closely with the CLA dose-response effect on cancer protection in the mammary gland. This information is critical in providing new insights regarding the biochemical action of CLA

Differential response of estrogen receptor alpha and estrogen receptor beta to partial estrogen agonists/antagonists.

Barkhem T, Carlsson B, Nilsson Y, et al.

Mol Pharmacol. 1998 Jul; 54(1):105-12.

The existence of two rather than one estrogen receptor, today characterized as estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta), indicates that the mechanism of action of 17beta-estradiol and related synthetic drugs is more complex than previously thought. Because the homology of amino acid residues in the ligand-binding domain (LBD) of ERbeta is high compared with those amino acid residues in ERalpha LBD, previously shown to line the ligand binding cavity or to make direct contacts with ligands, it is not surprising that many ligands have a similar affinity for both receptor subtypes. We report that 17alpha-ethynyl, 17beta-estradiol, for example, has an ERalpha-selective agonist potency and that 16beta,17alpha-epiestriol has an ERbeta-selective agonist potency. We also report that genistein has an ERbeta-selective affinity and potency but an ERalpha-selective efficacy. Furthermore, we show that tamoxifen, 4-OH-tamoxifen, raloxifene, and ICI 164,384 have an ERalpha-selective partial agonist/antagonist function but a pure antagonist effect through ERbeta. In addition, raloxifene displayed an ERalpha-selective antagonist potency, in agreement with its ERalpha-selective affinity. However, although ICI 164,384 showed an ERbeta-selective affinity, it had a similar potency to antagonize the effect of 17beta-estradiol in the ERalpha- and ERbeta-specific reporter cell lines, respectively. In conclusion, our data indicate that the ligand binding cavity of ERbeta is probably more different from that of ERalpha than can be anticipated from the primary sequences of the two ER subtypes and that it will be possible to develop receptor-specific ligands that may form the basis of novel pharmaceuticals with better in vivo efficacy and side effect profile than current available drugs

Combined supplementation of vanadium and 1alpha,25-dihydroxyvitamin D(3) inhibit diethylnitrosamine-induced rat liver carcinogenesis.

Basak R, Basu M, Chatterjee M.

Chem Biol Interact. 2000 Aug 15; 128(1):1-18.

A combination of a differentiation-inducing agent like 1alpha, 25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] with a compound that blocks entry of calcium into cells like vanadium (V) may offer a new approach to differentiation therapy and address the problem of hypercalcemia. Initiation of hepatocarcinogenesis was performed by a single intraperitoneal injection of diethylnitrosamine (DEN) (200 mg/kg b.wt.) in male Sprague-Dawley rats. Supplementation of V, 1, 25(OH)(2)D(3), or both V and 1,25(OH)(2)D(3) were started 4 weeks prior to DEN injection and continued thereafter till 20th week. It was observed that supplementation of V (0.5 ppm) in drinking water ad libitum or 1,25(OH)(2)D(3) (3 microg/ml propylene glycol) per os twice weekly for the entire period of the experiment significantly reduces the number and size of hyperplastic nodules while the combination treatment offered an additive effect in reducing it to 37.5% from 83.3%. V-1,25(OH)(2)D(3) combination was also effective in elevating the level of hepatic microsomal cytochrome P-450 (Cyt. P-450) (P<0.001). Moreover, A significant reduced level of cytosolic glutathione (GSH) (P<0.001) and glutathione S-transferase (GST) (P<0.001) activity as well as reduction in the appearance of gamma-glutamyltranspeptidase (GGT)-positive foci (P<0.001) as compared to carcinogen control were observed in V plus 1, 25(OH)(2)D(3) treated group. These results suggest that V may be useful in combination with 1,25(OH)(2)D(3) in the inhibition of experimental rat hepatocarcinogenesis

Inositol-phosphate-induced enhancement of natural killer cell activity correlates with tumor suppression.

Baten A, Ullah A, Tomazic VJ, et al.

Carcinogenesis. 1989 Sep; 10(9):1595-8.

In recent studies, we have demonstrated that inositol hexaphosphate (InsP6) inhibits experimental colon carcinogenesis. Since natural killer (NK) cells are involved in tumor cell destruction, we investigated the effect of InsP6 on murine NK cell activity. We show that; (i) 1,2-dimethylhydrazine (DMH), a colon carcinogen, depresses NK activity; (ii) in vivo treatment of mice with InsP6 enhances baseline NK activity and reverses DMH-induced depressed NK activity with an inverse correlation (r = -0.9811) with tumor incidence, (iii) short-term in vitro treatment of spleen cells and NK-enriched fraction with InsP6 also enhances NK cytotoxicity in a dose-dependent manner, (iv) inositol potentiates the action of InsP6. Our data suggest yet another important role of inositol phosphates in the regulation of cellular activity

Vitamin Protects Against Cancer 2000 Aug 22.

BBC News.

BBC News. 2000;2000 Aug 22

Effect of natural beta-carotene supplementation in children exposed to radiation from the Chernobyl accident.

Ben Amotz A, Yatziv S, Sela M, et al.

Radiat Environ Biophys. 1998 Oct; 37(3):187-93.

Attempts were made to evaluate 709 children (324 boys and 385 girls) who had been exposed long-term to different doses of radiation during and after the Chernobyl accident and had moved to Israel between 1990 and 1994. Upon arrival, all of them underwent a check-up for most common clinical disorders and were then divided into three groups according to their residences (distance from the reactor) and the level of irradiation exposure: no radiation, 5 Ci/m2, respectively. Blood serum analyses for total carotenoids, retinol, alpha-tocopherol and oxidized conjugated dienes in 262 of the children showed increased HPLC levels of conjugated dienes, indicating increased levels of oxidation of in vivo blood lipids in children from the contaminated areas. The levels were higher in girls than in boys. Some 57 boys and 42 girls were given a basal diet with a diurnal supplementation of 40 mg natural 9-cis and all-trans equal isomer mixture beta-carotene in a capsulated powder form of the alga Dunaliella bardawil, for a period of 3 months. Blood serum analyses were regularly conducted before supplementation to determine the baseline effect of radiation exposure to the children, after 1 and 3 months of natural beta-carotene supplementation. After supplementation, the levels of the oxidized conjugated dienes decreased in the children's sera without any significant changes in the level of total carotenoids, retinol or alpha-tocopherol. Other common blood biochemicals were within the normal range for all tests and no statistical differences before or after supplementation of beta-carotene were noted. High pressure liquid chromatography (HPLC) analyses for carotenoids in the blood detected mainly oxycarotenoids, and to a lesser extent, all-trans beta-carotene, alpha-carotene, but not 9-cis beta-carotene. The results suggest that irradiation increases the susceptibility of lipids to oxidation in the Chernobyl children and that natural beta-carotene may act as an in vivo lipophilic antioxidant or radioprotector

Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity.

Ben Eliyahu S, Page GG, Yirmiya R, et al.

Int J Cancer. 1999 Mar 15; 80(6):880-8.

Stress and surgery have been suggested to compromise host resistance to infectious and malignant diseases in experimental and clinical settings. Because stress affects numerous physiological systems, the role of the immune system in mediating such effects is unclear. In the current study, we assessed the degree to which stress-induced alterations in natural killer (NK) cell activity underlie increased susceptibility to tumor development in F344 rats. Two stress paradigms were used: forced swim and abdominal surgery. Host resistance to tumor development was studied using 3 tumor models syngeneic to inbred F344 rats: CRNK-16 leukemia and the MADB106 mammary adenocarcinoma, both sensitive to NK activity, and the NK-insensitive C4047 colon cancer. Swim stress increased CRNK-16-associated mortality and metastatic development of MADB106 but not metastasis of C4047 cells. In both stress paradigms, stress suppressed NK activity (NKA) for a duration that paralleled its metastasis-enhancing effects on the MADB106 tumor. In vivo depletion of large granular lymphocyte/NK cells abolished the metastasis-enhancing effects of swim stress but not of surgical stress. Our findings indicate that stress-induced suppression of NKA is sufficient to cause enhanced tumor development. Under certain stressful conditions, suppression of NKA is the primary mediator of the tumor-enhancing effects of stress, while under other conditions, additional factors play a significant role. Clinical circumstances in which surgical stress may induce enhanced metastatic growth are discussed

Suppression of NK cell activity and of resistance to metastasis by stress: a role for adrenal catecholamines and beta-adrenoceptors.

Ben Eliyahu S, Shakhar G, Page GG, et al.

Neuroimmunomodulation. 2000; 8(3):154-64.

Although acute stress has been reported to suppress natural killer cell activity (NKA) and host resistance to metastasis, it is unclear whether the sympathetic nervous system (SNS) has a role in these effects. The current study in Fischer 344 rats assessed the involvement of adrenal catecholamines and beta(1)- and beta(2)-adrenoceptors in mediating these deleterious effects of swim stress. In addition to assessing the number and activity of NK cells following swim stress, we used a tumor model based on the MADB106 mammary adenocarcinoma line: this syngeneic tumor metastasizes only to the lungs, and its lung tumor retention (LTR) and metastatic colonization are highly sensitive to NKA. The findings indicate that stress increased both LTR, assessed 24 h after inoculation, and the number of lung metastases, counted 3 weeks later. These effects were attenuated or completely abolished by the ganglionic blocker chlorisondamine (3 mg/kg i.p.), by adrenal demedullation, by a selective beta-adrenergic antagonist (nadolol, 0.4 mg/kg), and additively by a selective beta(1)- (atenolol, 1-6 mg/kg) and a selective beta(2)-antagonist (either butoxamine 4-32 mg/kg or ICI-118,551 0.3-8 mg/kg). Stress also suppressed NKA, and adrenal demedullation prevented this suppression. Administration of adrenaline (0.1-1 mg/kg) or of a beta-adrenergic agonist (metaproterenol, 0.8 mg/kg), in physiologically relevant doses, suppressed NKA in a dose-dependent manner, and increased LTR to levels characteristic of swim stress. Taken together, these findings suggest that acute stress, by releasing catecholamines from the adrenal glands and activating beta(1)- and beta(2)-adrenoceptors, suppresses NKA and consequently compromises resistance to NK-sensitive metastasis

The promotion of tumor metastasis by surgery and stress: immunological basis and implications for psychoneuroimmunology.

Ben Eliyahu S.

Brain Behav Immun. 2003 Feb; 17 Suppl 1:S27-S36.

This mini-review emphasizes a psychoneuroimmunology (PNI) perspective of the hypothesis that stress and surgical excision of the primary tumor can promote tumor metastasis. It first establishes the empirical and theoretical basis for control of metastasis by cell-mediated immunity (CMI), as well as the interactive role of non-immunological risk factors. It then describes the various aspects of surgery that suppress CMI, and the neuroendocrine mechanisms mediating suppression by stress and surgery. Last, it briefly reviews the empirical evidence, from animal and human studies, for the promotion of metastasis by stress and surgery, with specific reference to the mediating role of CMI. It is concluded that: (a) Immunological mechanisms most likely play a role in limiting metastasis in patients with solid tumors. (b) Immunosuppression can be deleterious, especially when surgery is conducted early, before the tumor develops insurmountable mechanisms to escape immune destruction. (c) The most sensitive period for the establishment of metastases is the immediate aftermath of surgery. Interventions aiming at reducing stress and immunosuppression should thus strive to start beforehand. (d) 'Psychological and physiological insults activate similar neuroendocrine mechanisms of immunosuppression. Therefore, a multimodal therapeutic approach should be used to prevent tumor metastasis during the perioperative period. (e) Studies employing interventions aimed at reducing the surgical stress response should preferably assess immunological indices with an established clinical relevance, and follow up long-term recurrence provided sample size assure statistical power. (f) The progress toward earlier detection of cancer, and our growing understanding of immunosuppression, continuously improves the chances for successful PNI interventions

New advances in the biology and treatment of myeloma bone disease.

Berenson JR.

Semin Hematol. 2001 Apr; 38(2 Suppl 3):15-20.

The bisphosphonates provide effective therapy for the skeletal complications of multiple myeloma (MM). Although the earliest bisphosphonates had poor bioavailability and relatively low potency, newer compounds such as pamidronate and zoledronic acid have greater potency. Bisphosphonates block the development of monocytes into osteoclasts and are thought to promote apoptosis of osteoclasts. These agents prevent osteoclasts from moving to the bone surface and seem to inhibit the production of bone-resorbing cytokines such as interleukin-6 (IL-6) by bone marrow stromal cells. In addition, bisphosphonates seem to have a direct antimyeloma effect by inducing apoptosis of malignant plasma cells. The beneficial effects of pamidronate have been demonstrated in a clinical trial setting. Patients who failed to respond to chemotherapy had a slight prolongation of survival and better performance status and quality of life. Ongoing clinical trials with ibandronate and zoledronic acid indicate the latter is 100 to 1,000 times more potent than pamidronate. Biochemical effects of zoledronic acid continue for as long as 8 weeks after a single administration. In a new trial comparing pamidronate and zoledronic acid, 90% of the patients who received zoledronic acid were normocalcemic, compared with 69% of those who received pamidronate at 10 days. In addition, the time to relapse or development of hypercalcemia was shorter for patients receiving pamidronate compared with zoledronic acid

[Effect of thioctic acid (alpha-limpoic acid) on the chemotherapeutic efficacy of cyclophosphamide and vincristine sulfate].

Berger M, Habs M, Schmahl D.

Arzneimittelforschung. 1983; 33(9):1286-8.

Pretreatment with thioctic acid has no negative influence on the chemotherapeutic efficacy of cyclophosphamide against i.p. transplanted Yoshida sarcoma and vincristine sulfate against i.p. transplanted Walker carcinosarcoma 256. The toxic side effects of vincristine sulfate are lowered to such a degree that an increase results in median survival time compared to animals treated only with vincristine sulfate. A diminution of the toxic side effects of cyclophosphamide due to adjuvant treatment with thioctic acid could not be proven

Expression of the multidrug resistance-associated protein (MRP) and chemoresistance of human non-small-cell lung cancer cells.

Berger W, Elbling L, Hauptmann E, et al.

Int J Cancer. 1997 Sep 26; 73(1):84-93.

Human non-small-cell lung cancer (NSCLC) is considered to be a chemotherapy-refractory malignancy. The underlying mechanisms remain rather obscure. The multidrug resistance-associated protein (MRP), mediating a multidrug resistance (MDR) phenotype, has been reported to be overexpressed in several drug-selected lung cancer cell lines. A few previous studies have described intrinsic MRP expression in both NSCLC and normal lung tissues. However, the drug-transporting activity as well as the correlation with chemoresistance is unclear. Using 15 unselected cell lines, we show that MRP (mRNA and protein as detected by reverse transcriptase polymerase chain reaction and immunoblot) is frequently expressed intrinsically, with markedly varying intensity, in NSCLC. Two cell lines expressed high MRP levels, one comparable to the drug-selected controls (GLC4/ADR, HL-60/AR) without, however, amplification of the MRP gene (Southern hybridization). Using 3H-daunomycin (3H-DM) and calcein as MRP substrates and probenecid (PRO), genistein (GEN), benzbromarone (BB), N-ethylmaleimide (NEM) and verapamil (VP) as MRP modulators, drug accumulation studies revealed a transporting activity of MRP that correlated significantly with the gene expression data. Moreover, a significant correlation between MRP expression and chemoresistance against daunomycin (DM), doxorubicin (DOX), etoposide (VP-16) and vinblastine (VBL), but not cisplatin (CDDP) and bleomycin (Bleo) (MTT-based survival assay), was detected. Correlations mainly rested on the pronounced chemoresistance of 2 highly MRP-expressing cell lines and did not reach significance when these cell lines were excluded

Resveratrol causes arrest in the S-phase prior to Fas-independent apoptosis in CEM-C7H2 acute leukemia cells.

Bernhard D, Tinhofer I, Tonko M, et al.

Cell Death Differ. 2000 Sep; 7(9):834-42.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), in the concentration range of 20 microM and above, induced arrest in the S-phase and apoptosis in the T cell-derived T-ALL lymphocytic leukemia cell line CEM-C7H2 which is deficient in functional p53 and p16. Expression of transgenic p16/INK4A, which causes arrest in G0/G1, markedly reduced the percentage of apoptotic cells. Antagonist antibodies to Fas or FasL, or constitutive expression of crmA did not diminish the extent of resveratrol-induced apoptosis. Furthermore, a caspase-8-negative, Fas-resistant Jurkat cell line was sensitive to resveratrol-induced apoptosis which could be strongly inhibited in the Jurkat as well as in the CEM cell line by z-VAD-fmk and z-IETD-fmk. The almost complete inhibition by z-IETD-fmk and the lack of inhibition by crmA suggested caspase-6 to be the essential initiator caspase. Western blots revealed the massive conversion of procaspase-6 to its active form, while caspase-3 and caspase-2 were proteolytically activated to a much lesser extent

Adriamycin associated cardiotoxicity: research on prevention with coenzyme Q.

Bertazzoli C, Ghione M.

Pharmacol Res Commun. 1977 Mar; 9(3):235-50.

Inhibition of angiogenesis and induction of endothelial and tumor cell apoptosis by green tea in animal models of human high-grade non-Hodgkin's lymphoma.

Bertolini F, Fusetti L, Rabascio C, et al.

Leukemia. 2000 Aug; 14(8):1477-82.

Recent reports suggest that green tea consumption may prevent or delay the growth of human cancer, possibly by impairing tumor invasion and/or by an anti-angiogenic effect. In NOD/SCID mice transplanted intraperitoneally with human non-Hodgkin's lymphoma (NHL) cell lines, Namalwa, RAP1-EIO and HS-Sultan, green tea prevented 50% of Namalwa tumors (P = 0.0017 by log-rank) and significantly inhibited RAP1-EIO and HS-Sultan tumor growth. Notably, treatment with the chemotherapy drug cyclophosphamide at the maximum tolerable dose was unable to prevent Namalwa tumor occurrence. In the three models evaluated, the frequency of apoptotic endothelial and tumor cells was significantly increased in mice given green tea compared to controls. These results support further trials in NHL to evaluate whether green tea, alone or in combination with chemotherapy, may delay or prevent disease progression

Antioxidants inhibit cytokine production and suppress NF-kappaB activation in CAPAN-1 and CAPAN-2 cell lines.

Blanchard JA, Barve S, Joshi-Barve S, et al.

Dig Dis Sci. 2001 Dec; 46(12):2768-72.

Interleukin (IL) -6 and IL-8 are cytokines that have been shown to play a role in several pancreatic diseases, including acute pancreatitis, chronic pancreatitis, and pancreatic adenocarcinoma. Previously, we have demonstrated that tumor necrosis factor-alpha (TNF-alpha) and gram-negative bacterial lipopolysaccharide stimulate production of IL-6 and IL-8 and activation of the transcription factor NF-kappaB in the well-differentiated pancreatic ductal adenocarcinoma cell lines CAPAN-1 and CAPAN-2. In these studies we have examined the effect of chain-breaking and glutathione-enhancing antioxidants on NF-kappaB activation and production of IL-6 and IL-8 in these cell lines. Generally, suppression of NF-kappaB activation correlated well with inhibition of IL-6 and IL-8 secretion. In the CAPAN-2 cell line, antioxidants inhibited both NF-kappaB activation and IL-6 and IL-8 secretion. In the CAPAN-1 cell line, antioxidants generally failed to suppress both NF-kappaB activation and IL-6 and IL-8 secretion. The single exception was the chain-breaking antioxidant butylated hydroxyanisole (BHA), which markedly inhibited IL-6 and IL-8 secretion, but had no effect on NF-kappaB activation. These findings may have implications for the treatment of acute and chronic pancreatitis and pancreatic cancer

Coenzymes Q: stimulants of the phagocytic activity in rats and immune response in mice.

Bliznakov E, Casey A, Premuzic E.

Experientia. 1970 Sep 26; 26(9):953-4.

Role of transforming growth factor beta in human disease.

Blobe GC, Schiemann WP, Lodish HF.

N Engl J Med. 2000 May 4; 342(18):1350-8.

Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity.

Bokemeyer C, Fels LM, Dunn T, et al.

Br J Cancer. 1996 Dec; 74(12):2036-41.

Cisplatin is one of the most active cytotoxic agents in the treatment of testicular cancer, but its clinical use is associated with side-effects such as ototoxicity, neurotoxicity and nephrotoxicity. Long-term kidney damage from cisplatin particularly affects the proximal tubular apparatus and can be detected by increased urinary excretion of brush-border enzymes, such as L-alanine-aminopeptidase (AAP), and magnesium. In the current study, the flavonoid silibinin was used as a nephroprotectant for cisplatin-induced nephropathy in a rat animal model. Infusion of silibinin before cisplatin results in a significant decrease in glomerular (indicated by creatinine clearance and serum urea level) and tubular kidney toxicity (excretion of brush-border enzymes and magnesium). Silibinin given alone had no effect on renal function. In order to exclude an inhibition of the anti-tumour activity of cisplatin and 4-hydroperoxy-ifosfamide by co-administration of silibinin, in vitro studies were performed in three established human testicular cancer cell lines. Dose-response curves for cisplatin (3-30 000 nmol) combined with non-toxic silibinin doses (7.25 x 10(-6) or 7.25 x 10(-5) mol l-1) did not deviate significantly from those of cisplatin alone as measured by relative cell survival during a 5 day assay using the sulphorhodamine-B staining technique. Also silibinin did not influence the cytotoxic activity of 4-hydroperoxy-ifosfamide (30-10 000 nmol) in vitro. In summary, these in vitro data rule out a significant inhibition of the anti-tumour activity of the major nephrotoxic components, cisplatin and 4-hydroperoxy-ifosfamide, by co-administration of silibinin in a human germ cell tumour cell line model. Together with these demonstrated cytoprotection effects in the rat animal model, these data form the basis for a randomised clinical trial of silibinin for the protection of cisplatin-associated nephrotoxicity in patients with testicular cancer

Toxicological, pharmacokinetic and metabolic studies on acetylcysteine.

Bonanomi L, Gazzaniga A.

Eur J Respir Dis Suppl. 1980; 111:45-51.

Antioxidant-related parameters in patients treated for cancer chemoprevention with N-acetylcysteine.

Bongers V, de Jong J, Steen I, et al.

Eur J Cancer. 1995 Jun; 31A(6):921-3.

N-acetylcysteine (NAC) is an antioxidant, possibly effective in the early steps of carcinogenesis, and is applied to prevent second primary tumours in the upper aerodigestive tract and the lungs. In this study, we evaluated the pharmacodynamic profile of 600 mg NAC treatment, given daily for 3 months. Treatment caused a significant increase of the non-protein-SH concentration in blood plasma (38%) and erythrocytes (31%). Glutathione levels in exfoliated buccal mucosa cells appeared not to be influenced by treatment. The total radical-trapping ability parameter (TRAP) of blood plasma showed no change. In vitro, the addition of glutathione, but not of NAC did increase the TRAP value. In addition, when peroxyl radicals were generated in vitro, NAC was shown to be consumed more rapidly than glutathione. This suggests that NAC prevents early damage, while glutathione functions over a longer time period

Isoflavones inhibit intestinal epithelial cell proliferation and induce apoptosis in vitro.

Booth C, Hargreaves DF, Hadfield JA, et al.

Br J Cancer. 1999 Jul; 80(10):1550-7.

There have been many reports that high soya-based diets reduce the risk of certain types of cancer. This effect may be due to the presence of high levels of isoflavones derived from the soya bean, particularly genistein which has been shown to be a protein tyrosine kinase (PTK) inhibitor and have both oestrogenic and anti-oestrogenic properties. We have examined the effect of genistein and a number of novel synthetic analogues on both normal (IEC6, IEC18) and transformed (SW620, HT29) intestinal epithelial cell lines. Responses were compared to those elicited by oestradiol, the anti-oestrogen tamoxifen, and the tyrosine kinase inhibitor tyrphostin. Genistein and tamoxifen were potent inhibitors of cell proliferation. Of seven novel isoflavones tested, none were more potent inhibitors than genistein, and all displayed similar relative activities across the different cell lines. In addition to inhibiting cell proliferation, cell death via apoptosis was observed when the cells were exposed to the isoflavones and all but one exhibited PTK inhibitory activity. These data suggest that by reducing proliferation and inducing apoptosis, possibly due in part to PTK inhibition, isoflavones may have a role in protecting normal intestinal epithelium from tumour development (reducing the risk) and may reduce colonic tumour growth

Pharmacokinetics of N-acetylcysteine in man.

Borgstrom L, Kagedal B, Paulsen O.

Eur J Clin Pharmacol. 1986; 31(2):217-22.

N-Acetylcysteine was given intravenously and as three fast dissolving and one slow-release formulation, on separate occasions, as a single dose of 600 mg to 10 fasting (5 men and 5 women) healthy volunteers. Blood and urine were sampled for the following 12 h. Renal clearance constituted around 30% of total body clearance, which was 0.21 l/h/kg. Volume of distribution was 0.33 l/kg, consistent with distribution mainly to extracellular water. The late elimination half-life was 2.27 h and the mean residence time 1.62 h. The slow-release tablet resulted in a flattened plasma concentration-time curve typical of slow release formulations, while the other three oral formulations were rapidly absorbed. The oral availability of N-acetylcysteine varied between 6 and 10%, with the slow-release tablet having the lowest and the fast dissolving tablet the highest availability

Bax expression correlates with cellular drug sensitivity to doxorubicin, cyclophosphamide and chlorambucil but not fludarabine, cladribine or corticosteroids in B cell chronic lymphocytic leukemia.

Bosanquet AG, Sturm I, Wieder T, et al.

Leukemia. 2002 Jun; 16(6):1035-44.

In B-CLL, non-proliferating B cells accumulate due to defective apoptosis. Cytotoxic therapies trigger apoptosis and deregulation of apoptotic pathways contributes to chemoresistance. Loss of the apoptosis-promoting Bax has been implicated in resistance to cytotoxic therapy. We therefore evaluated ex vivo drug sensitivity of CLL, producing chemoresponse data which are prognostic indicators for B-CLL, in particular in the case of purine nucleoside analogs. To analyze the underlying mechanisms of drug resistance, we compared endogenous Bax and Bcl-2 expression to ex vivo response to eight drugs, and to survival in 39 B-CLL patients. We found that reduced Bax levels correlated well with ex vivo resistance to traditional B-CLL therapies - anthracyclines, alkylating agents and vincristine (all P 0.5). Mutational analysis of p53 could not explain the loss of Bax protein expression. Levels of Bcl-2 were not associated with sensitivity to any drug. In contrast to the ex vivo data, neither Bax or Bcl-2 expression nor doxorubicin sensitivity were associated with increased survival whereas sensitivity to fludarabine correlated with better overall survival (P = 0.031). These findings suggest that the resistance to purine nucleoside analogs and corticosteroids in B-CLL is due to inactivation of pathways different from those activated by anthracyclines, vinca alkaloids and alkylating agents and may be the molecular rationale for the efficacy of purine analogs in this disease

Vitamin C inhibits NF-kappa B activation by TNF via the activation of p38 mitogen-activated protein kinase.

Bowie AG, O'Neill LA.

J Immunol. 2000 Dec 15; 165(12):7180-8.

The transcription factor NF-kappaB is a central mediator of altered gene expression during inflammation, and is implicated in a number of pathologies, including cancer, atherosclerosis, and viral infection. We report in this study that vitamin C inhibits the activation of NF-kappaB by multiple stimuli, including IL-1 and TNF in the endothelial cell line ECV304 and in primary HUVECs. The induction of a NF-kappaB-dependent gene, IL-8, by TNF was also inhibited. The effect requires millimolar concentrations of vitamin C, which occur intracellularly in vivo, particularly during inflammation. Vitamin C was not toxic to cells, did not inhibit another inducible transcription factor, STAT1, and had no effect on the DNA binding of NF-kappaB. Inhibition by vitamin C was not simply an antioxidant effect, because redox-insensitive pathways to NF-kappaB were also blocked. Vitamin C was shown to block IL-1- and TNF-mediated degradation and phosphorylation of I-kappaBalpha (inhibitory protein that dissociates from NF-kappaB), due to inhibition of I-kappaB kinase (IKK) activation. Inhibition of TNF-driven IKK activation was mediated by p38 mitogen-activated protein kinase, because treatment of cells with vitamin C led to a rapid and sustained activation of p38, and the specific p38 inhibitor SB203580 reversed the inhibitory effect of vitamin C on IKK activity, I-kappaBalpha phosphorylation, and NF-kappaB activation. The results identify p38 as an intracellular target for high dose vitamin C

Differential effects of dietary flavonoids on drug metabolizing and antioxidant enzymes in female rat.

Breinholt V, Lauridsen ST, Dragsted LO.

Xenobiotica. 1999 Dec; 29(12):1227-40.

1. Gavage administration of the natural flavonoids tangeretin, chrysin, apigenin, naringenin, genistein and quercetin for 2 consecutive weeks to the female rat resulted in differential effects on selected phase 1 and 2 enzymes in liver, colon and heart as well as antioxidant enzymes in red blood cells (RBC). 2. Glutathione transferase (GST) activity assayed by use of the substrate 1-chloro-2,4-dinitrobenzene was significantly induced by apigenin, genistein and tangeretin in the heart but not in colon or liver. 3. In RBC chrysin, quercetin and genistein significantly decreased the activity of glutathione reductase (GR), catalase (CAT) and glutathione peroxidase (GPx), whereas superoxide dismutase (SOD) was only significantly decreased by genistein. 4. The oxidative status of the animal, measured as plasma malondialdehyde, revealed that chrysin, quercetin, genistein, and beta-naphthoflavone (BNF) significantly protected against, 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP)-induced oxidative stress. Hepatic PhIP-DNA adduct formation was not affected by any of the administered flavonoids, whereas PhIP-DNA adduct formation in colon was slightly, but significantly, inhibited by quercetin, genistein, tangeretin and BNF. 5. The observed effects of chrysin, quercetin and genistein on antioxidant enzymes, concurrently with a protection against oxidative stress, suggest a feedback mechanism on the antioxidant enzymes triggered by the flavonoid antioxidants. 6. Despite the use of high flavonoid doses, which by far exceed the human exposure levels, the effect on drug metabolizing and antioxidant enzymes was still very minor. The role of singly administered flavonoids in the protection against cancer and heart disease is thus expected to be limited

Vitamin D receptor gene polymorphisms are associated with breast cancer risk in a UK Caucasian population.

Bretherton-Watt D, Given-Wilson R, Mansi JL, et al.

Br J Cancer. 2001 Jul 20; 85(2):171-5.

There is increasing evidence that vitamin D can protect against breast cancer. The actions of vitamin D are mediated via the vitamin D receptor (VDR). We have investigated whether polymorphisms in the VDR gene are associated with altered breast cancer risk in a UK Caucasian population. We recruited 241 women following a negative screening mammogram and 181 women with known breast cancer. The VDR polymorphism Bsm I, an intronic 3' gene variant, was significantly associated with increased breast cancer risk: odds ratio bb vs BB genotype = 2.32 (95% CI, 1.23-4.39). The Bsm I polymorphism was in linkage disequilibrium with a candidate translational control site, the variable length poly (A) sequence in the 3' untranslated region. Thus, the 'L' poly (A) variant was also associated with a similar breast cancer risk. A 5' VDR gene variant, Fok I, was not associated with breast cancer risk. Further investigations into the mechanisms of interactions of the VDR with other environmental and/or genetic influences to alter breast cancer risk may lead to a new understanding of the role of vitamin D in the control of cellular and developmental pathways

Natural cytotoxicity in breast cancer patients receiving neoadjuvant chemotherapy: effects of L-arginine supplementation.

Brittenden J, Heys SD, Ross J, et al.

Eur J Surg Oncol. 1994 Aug; 20(4):467-72.

Certain cytotoxic drugs have been shown to suppress host anti-cancer defence mechanisms. The amino acid L-arginine can significantly enhance natural killer (NK) and lymphokine-activated killer (LAK) cell cytotoxicity in patients with locally advanced breast cancer. In this study, the effect of L-arginine supplementation on natural cytotoxicity was determined in patients with breast cancer receiving CHOP chemotherapy. This cytotoxic regimen caused a transient immunosuppression, maximal on day 14 of each cycle (P < 0.001); this was not cumulative during the four cycles of treatment. Those patients receiving L-arginine supplementation (30 g/day for 3 days prior to each course of chemotherapy) had a smaller and delayed onset of immunosuppression (day 14), compared with those patients who had CHOP only (day 9). L-Arginine was able to repeatedly stimulate NK and LAK cell cytotoxicity in patients who were receiving CHOP chemotherapy (P < 0.003). In conclusion, further studies are required to determine the optimal use of chemotherapeutic agents, alone or in combination with immunostimulators, to avoid inhibition of host anti-cancer defence mechanisms

Plasma selenium level before diagnosis and the risk of prostate cancer development.

Brooks JD, Metter EJ, Chan DW, et al.

J Urol. 2001 Dec; 166(6):2034-8.

PURPOSE: Epidemiological studies and a randomized intervention trial suggest that the risk of prostate cancer may be reduced by selenium intake. We investigated whether plasma selenium level before diagnosis correlated with the risk of later developing prostate cancer. MATERIALS AND METHODS: A case control study was performed on men from the Baltimore Longitudinal Study of Aging registry, including 52 with known prostate cancer and 96 age matched controls with no detectable prostatic disease. Plasma selenium was measured at an average time plus or minus standard deviation of 3.83 +/- 1.85 years before the diagnosis of prostate cancer by graphite furnace atomic absorption spectrophotometry. Adjusted odds ratio and 95% confidence interval were computed with logistic regression. RESULTS: After correcting for years before diagnosis, body mass index, and smoking and alcohol use history, higher selenium was associated with a lower risk of prostate cancer. Compared with the lowest quartile of selenium (range 8.2 to 10.7 microg./dl.), the odds ratios of the second (10.8 to 11.8), third (11.9 to 13.2) and fourth (13.3 to 18.2) quartiles were 0.15 (95% confidence interval 0.05 to 0.50), 0.21 (0.07 to 0.68) and 0.24 (0.08 to 0.77, respectively, p =0.01). Furthermore, plasma selenium decreased significantly with patient age (p <0.001). CONCLUSIONS: Low plasma selenium is associated with a 4 to 5-fold increased risk of prostate cancer. These results support the hypothesis that supplemental selenium may reduce the risk of prostate cancer. Because plasma selenium decreases with patient age, supplementation may be particularly beneficial to older men

Antioxidants may limit key mutations.

Brotzman M.

ScienceNewsOnline. 1999; 155(17)

Diet and nutrition as risk factors for multiple myeloma among blacks and whites in the United States.

Brown LM, Gridley G, Pottern LM, et al.

Cancer Causes Control. 2001 Feb; 12(2):117-25.

OBJECTIVES: To explore whether dietary factors contribute to the risk of multiple myeloma and the two-fold higher incidence among blacks compared to whites in the United States. METHODS: Data from a food-frequency questionnaire were analyzed for 346 white and 193 black subjects with multiple myeloma, and 1086 white and 903 black controls who participated in a population-based case-control study of multiple myeloma in three areas of the United States. RESULTS: Elevated risks were associated with obese vs. normal weight (OR = 1.9, 95% confidence interval (CI) = 1.2-3.1 for whites and OR = 1.5, 95% CI = 0.9-2.4 for blacks), while the frequency of obesity was greater for black than white controls. Reduced risks were related to frequent intake of cruciferous vegetables (OR = 0.7, 95% CI = 0.6-0.99) and fish (OR = 0.7, 95% CI = 0.5-0.9) in both races combined, and to vitamin C supplements in whites (OR = 0.6, 95% CI = 0.5-0.9) and blacks (OR = 0.8, 95% CI = 0.5-1.4), with the frequency of vitamin supplement use being greater for white than black controls. However, frequent intake of vitamin C from food and supplements combined was associated with a protective effect in whites (OR = 0.6, 95% CI = 0.4-0.9), but not blacks (OR = 1.2, 95% CI = 0.8-2.1). CONCLUSIONS: The greater use of vitamin C supplements by whites and the higher frequency of obesity among blacks may explain part of the higher incidence of multiple myeloma among blacks compared to whites in the United States. In addition, the increasing prevalence of obesity may have contributed to the upward trend in the incidence of multiple myeloma during recent decades

Effects of phytoestrogens and synthetic combinatorial libraries on aromatase, estrogen biosynthesis, and metabolism.

Brueggemeier RW, Gu X, Mobley JA, et al.

Ann N Y Acad Sci. 2001 Dec; 948:51-66.

Approximately 60% of breast cancer patients have hormone-dependent breast cancer containing estrogen receptors and requiring estrogen for tumor growth. The extent of estrogen biosynthesis and metabolism in the breast cancer tissue microenvironment influences breast-tumor development and growth, and endogenous and exogenous agents may alter the levels of hormonally active estrogens and their metabolites. Isoflavonoid phytoestrogens such as genistein exhibit numerous biochemical activities; however, their effects on estrogen biosynthesis and metabolism in breast cancer cells have not been fully examined. MCF-7 cells (hormone-dependent) and MBA-MB-231 cells (hormone-independent) were treated with genistein (100 nM) for five days and then incubated with radiolabeled estradiol (100 nM, 2.5 microCi) for 0 to 48 h. Media were extracted with ethyl acetate, and the organic residues analyzed by reverse-phase HPLC with a radioactivity flow detector. The major metabolite formed in all cases is estrone, although differences were observed between the cell lines and the various drug treatments. The formation of estrone in untreated MCF-7 cells (approximately 9.3% of radioactivity at 24 h) is relatively limited, in contrast to untreated MDA-MB-231 cells (approximately 32.0% of radioactivity at 24 h). Treatment of MCF-7 cells with 100 nM genistein increased the conversion of estradiol to estrone up to 19.5% in 24 h. The effect of genistein on estrone formation in MDA-MB-231 cells resulted in 37.7% of the radioactivity being estrone. Thus, genistein treatment of breast cancer cells resulted in increased 17-betahydroxysteroid dehydrogenase activity and elevated formation of estrone. Increased levels of oxidative 17-betahydroxysteroid dehydrogenase activity (Type II) were confirmed by Western blots. Therefore, exposure of breast cancer cells to genistein results in elevated conversion of estradiol to estrogenically weaker or inactive metabolites. The regulation of breast-tissue aromatase by exogenous agents such as drugs and environmental agents is being investigated. The benzopyranone-ring system is a molecular scaffold of considerable interest, and this scaffold is found in flavonoid natural products that have weak aromatase inhibitory activity. Medicinal chemistry efforts focus on diversifying the benzopyranone scaffold and utilizing combinatorial chemistry approaches to construct small benzopyranone libraries as potential aro- matase inhibitors. Several compounds in the initial libraries have demonstrated moderate aromatase inhibitory activity in screening assays

Eicosapentaenoic Acid As a Targeted Therapy for Cancer Cachexia.

Bruera ED.

J Clin Oncol. 2003 21(24):4657-58.

Serologic precursors of cancer: serum micronutrients and the subsequent risk of pancreatic cancer.

Burney PG, Comstock GW, Morris JS.

Am J Clin Nutr. 1989 May; 49(5):895-900.

In a nested case-control study the stored, frozen sera from 22 cases of cancer of the pancreas and 44 matched control subjects were assayed for retinol, retinol-binding protein, total carotenoids, beta-carotene, lycopene, vitamin E (alpha-tocopherol), and selenium. Prediagnostic serum levels of lycopene and Se were lower among cases than among matched control subjects. These differences remained after adjustment was made for possible confounding by smoking, educational level, and the other measured serum levels. Low levels of serum vitamin E appeared to have a protective effect but a chance association between vitamin E and cancer of the pancreas could not reasonably be excluded. The association between cancer of the pancreas and serum Se was significant when the data were analyzed as a whole but its effect was seen principally in men

Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo.

Busse E, Zimmer G, Schopohl B, et al.

Arzneimittelforschung. 1992 Jun; 42(6):829-31.

The influence of alpha-lipoic acid (CAS 62-46-4) on the amount of intracellular glutathione (GSH) was investigated in vitro and in vivo. Using murine neuroblastoma as well as melanoma cell lines in vitro, a dose-dependent increase of GSH content was observed. Dependent on the source of tumor cells the increase was 30-70% compared to untreated controls. Normal lung tissue of mice also revealed about 50% increase in glutathione upon treatment with lipoic acid. This corresponds with protection from irradiation damage in these in vitro studies. Survival rate of irradiated murine neuroblastoma was increased at doses of 100 micrograms lipoic acid/d from 2% to about 10%. In agreement with the in vitro studies, in vivo experiments with whole body irradiation (5 and 8 Gy) in mice revealed that the number of surviving animals was doubled at a dose of 16 mg lipoic acid/kg. Improvement of cell viability and irradiation protection by the physiological compound lipoic acid runs parallel with an increase of intracellular GSH/GSSG ratio

Vitamin D receptor gene polymorphisms in breast cancer.

Buyru N, Tezol A, Yosunkaya-Fenerci E, et al.

Exp Mol Med. 2003 Dec 31; 35(6):550-5.

Breast cancer is the leading cause of cancer death among women around the world and its incidence is annually increasing. The vitamin D receptor (VDR) gene is a member of the nuclear receptor superfamily, which is expressed in breast tissue and known to modulate the rate of cell proliferation. Association between the VDR gene polymorphisms and cancer development has been suggested by several studies. However, the relationship between VDR polymorphisms and breast cancer is controversial and has not been confirmed by all studies. The purpose of this study was to investigate the genotype frequencies and association of the VDR Bsm I and Taq I polymorphisms with breast cancer in Turkish patients. In this study, 78 patients with breast cancer and 27 healthy individuals were enrolled. The prevalence of the VDR Taq I and Bsm I alleles and the genotype frequencies in patients with breast cancer was similar to that in the normal population. Our data indicate that no significant differences exist between the patients and control subjects

Divergent effects of omega-6 and omega-3 fatty acids on mammary tumor development in C3H/Heston mice treated with DMBA.

Cameron E.

Nutr Res. 1989(9):383-93.

Cancer and Vitamin C 1993.

Cameron EPL.

1993;

[Silibinin and acute poisoning with Amanita phalloides].

Carducci R, Armellino MF, Volpe C, et al.

Minerva Anestesiol. 1996 May; 62(5):187-93.

The aim of the present study was to show the therapeutic effect of silibinin dihemisuccinate in a case of intoxication by mushrooms of Amanita gender. We report a clinical case of a 4-person family intoxicated by ingestion of mushrooms Amanita phalloides and admitted to the center for poisoning treatment of the Hospital "A. Cardarelli" in Naples. Although all were treated with standard therapy, there was a worsening of the clinical picture till the third day, when it was decided to add silibinin dihemisuccinate by the intravenous route to the therapy. After the beginning of silibinin administration the patients showed a favourable course with a rapid resolution of the clinical picture, although the prognosis appeared severe on the basis of hematochemical examination results. On day 9 silibinin dihemisuccinate was replaced with silibinin betacyclodextrine per os. All patients were discharged on day 10-13. After two months all hematological parameters are in the normal range also a hepatobiliopancreatic echography does not show any morphological alteration. As in the case of polytherapies and because of the lack of comparative studies, it seems difficult to establish which therapeutic component had the major role in the resolution of the clinical picture. However, on the basis of our experience, and of the literature data, we think that silibinin may play a significant role in protecting hepatic tissue not yet injured. However we believe that other studies are necessary to confirm our hypothesis

Opposite effects of linoleic acid and conjugated linoleic acid on human prostatic cancer in SCID mice.

Cesano A, Visonneau S, Scimeca JA, et al.

Anticancer Res. 1998 May; 18(3A):1429-34.

The relationship between dietary fat intake (level and type) and cancer development is a matter of concern in Western society. The purpose of this study was to determine the effect of three different diets on the local growth and metastatic properties of DU-145 human prostatic carcinoma cells in severe combined immunodeficient (SCID) mice. Animals were fed a standard diet or diets supplemented with 1% LA or 1% CLA for 2 weeks prior to subcutaneous (s.c.) inoculation of DU-145 cells and throughout the study (total of 14 weeks). Mice receiving LA-supplemented diet displayed significantly higher body weight, lower food intake and increased local tumor load as compared to the other two groups of mice. Mice fed the CLA-supplemented diet displayed not only smaller local tumors than the regular diet-fed group, but also a drastic reduction in lung metastases. These results support the view that dietary polyunsaturated fatty acids may influence the prognosis of prostatic cancer patients, thus opening the possibility of new therapeutic options

c-Jun N-terminal kinase activation by hydrogen peroxide in endothelial cells involves SRC-dependent epidermal growth factor receptor transactivation.

Chen K, Vita JA, Berk BC, et al.

J Biol Chem. 2001 May 11; 276(19):16045-50.

The phenotypic properties of the endothelium are subject to modulation by oxidative stress, and the c-Jun N-terminal kinase (JNK) pathway is important in mediating cellular responses to stress, although activation of this pathway in endothelial cells has not been fully characterized. Therefore, we exposed endothelial cells to hydrogen peroxide (H(2)O(2)) and observed rapid activation of JNK within 15 min that involved phosphorylation of JNK and c-Jun and induction of AP-1 DNA binding activity. Inhibition of protein kinase C and phosphoinositide 3-kinase did not effect JNK activation. In contrast, the tyrosine kinase inhibitors, genistein, herbimycin A, and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) significantly attenuated H(2)O(2)-induced JNK activation as did endothelial cell adenoviral transfection with a dominant-negative form of Src, implicating Src as an upstream activator of JNK. Activation of JNK by H(2)O(2) was also inhibited by AG1478 and antisense oligonucleotides directed against the epidermal growth factor receptor (EGFR), implicating the EGFR in this process. Consistent with this observation, H(2)O(2) stimulated EGFR tyrosine phosphorylation and complex formation with Shc-Grb2 that was abolished by PP2, implicating Src in H(2)O(2)-induced EGFR activation. Tyrosine phosphorylation of the EGFR by H(2)O(2) did not involve receptor autophosphorylation at Tyr(1173) as assessed by an autophosphorylation-specific antibody. These data indicate that H(2)O(2)-induced JNK activation in endothelial cells involves the EGFR through an Src-dependent pathway that is distinct from EGFR ligand activation. These data represent one potential pathway for mediating oxidative stress-induced phenotypic changes in the endothelium

Effects of conjugated dienoic derivatives of linoleic acid and beta-carotene in modulating lymphocyte and macrophage function.

Chew BP, Wong TS, Shultz TD, et al.

Anticancer Res. 1997 Mar; 17(2A):1099-106.

The in vitro effects of conjugated dienoic derivatives of linoleic acid (CLA) in combination with beta-carotene on lymphocyte and macrophage function was studied. Porcine blood lymphocytes and murine peritoneal macrophages were incubated with 0 (control), 1.78 x 10(-5), 3.57 x 10(-5) and 7.14 x 10(-5) M CLA and 0 (control), 10(-9), 10(-8) and 10(-7) M beta-carotene. CLA alone stimulated mitogen-induced lymphocyte proliferation, lymphocyte cytotoxic activity and macrophage bactericidal activity. In contrast, CLA inhibited interleukin-2 production by lymphocytes and suppressed the phagocytic activity of macrophages. beta-Carotene alone stimulated the cytotoxicity of lymphocytes and increased superoxide production by peritoneal macrophages. When present together, CLA and beta-carotene interacted in an additive manner to further enhance lymphocyte cytotoxicity and spontaneous lymphocyte proliferation. In addition, beta-carotene was able to negate the inhibitory action of CLA on the phagocytic activity of macrophages. Also, CLA and beta-carotene together seemed to suppress mitogen-induced lymphocyte proliferation. Therefore, CLA and beta-carotene; alone and in concert, act to modulate different aspects of cellular host defense

Modulation of growth of human prostate cancer cells by the N-acetylcysteine conjugate of phenethyl isothiocyanate.

Chiao JW, Chung F, Krzeminski J, et al.

Int J Oncol. 2000 Jun; 16(6):1215-9.

There is growing evidence that thiol conjugates of isothiocyanates present in cruciferous vegetables are effective cancer chemopreventive and potentially active therapeutic agents. The effects of the N-acetylcysteine conjugate of phenethyl isothiocyanate (PEITC-NAC) on tumor cell growth were analyzed in human prostate cancer cell lines LNCaP, androgen-dependent, and DU-145, androgen-independent. Exposure of the cells to PEITC-NAC at high concentrations caused cytolysis, while at lower concentrations PEITC-NAC mediated a dose-dependent growth modulation, with reduction of DNA synthesis and growth rate, inhibition of clonogenicity and induction of apoptosis in both types of prostate cancer cells. PEITC-NAC decreased cells in S and G2M phases of cell cycle, blocking cells entering replicating phases. In parallel, a significant enhancement of cells expressing the cell cycle regulator p21 as well as its intensity was determined using a fluorescent antibody technique. The action of PEITC-NAC was time-dependent, with the magnitude of inhibition increasing to 50-65% after PEITC-NAC exposure for several days. Interaction of tumor cells with dissociation products of PEITC-NAC, PEITC and NAC, are proposed as the mechanism of growth regulation

Indole-3-carbinol (I3C) induced cell growth inhibition, G1 cell cycle arrest and apoptosis in prostate cancer cells.

Chinni SR, Li Y, Upadhyay S, et al.

Oncogene. 2001 May 24; 20(23):2927-36.

Prostate cancer is one of the most common cancers in men and it is the second leading cause of cancer related death in men in the United States. Recent dietary and epidemiological studies have suggested the benefit of dietary intake of fruits and vegetables in lowering the incidence of prostate cancer. A diet rich in fruits and vegetables provides phytochemicals, particularly indole-3-carbinol (I3C), which may be responsible for the prevention of many types of cancer, including hormone-related cancers such as prostate. Studies to elucidate the role and the molecular mechanism(s) of action of I3C in prostate cancer, however, have not been conducted. In the current study, we investigated whether I3C had any effect against prostate cancer cells and, if so, attempts were made to identify the potential molecular mechanism(s) by which I3C elicits its biological effects on prostate cancer cells. Here we report for the first time that I3C inhibits the growth of PC-3 prostate cancer cells. Induction of G1 cell cycle arrest was also observed in PC-3 cells treated with I3C, which may be due to the observed effects of I3C in the up-regulation of p21(WAF1) and p27(Kip1) CDK inhibitors, followed by their association with cyclin D1 and E and down-regulation of CDK6 protein kinase levels and activity. The induction of p21(WAF1) appears to be transcriptionally upregulated and independent of the p53 responsive element. In addition, I3C inhibited the hyperpohosphorylation of the Retinoblastoma (Rb) protein in PC-3 cells. Induction of apoptosis was also observed in this cell line when treated with I3C, as measured by DNA laddering and poly (ADP-ribose) polymersae (PARP) cleavage. We also found an up-regulation of Bax, and down-regulation of Bcl-2 in I3C-treated cells. These effects may also be mediated by the down-regulation of NF-kappaB observed in I3C treated PC-3 cells. From these results, we conclude that I3C inhibits the growth of PC-3 prostate cancer cells by inducing G1 cell cycle arrest leading to apoptosis, and regulates the expression of apoptosis-related genes. These findings suggest that I3C may be an effective chemopreventive or therapeutic agent against prostate cancer

Effects of thymosin in vitro in cancer patients and correlation with clinical course after thymosin immunotherapy.

Chretien PB, Lipson SD, Makuch RW, et al.

Ann N Y Acad Sci. 1979; 332:135-47.

Effects of berberine on arylamine N-acetyltransferase activity in human bladder tumour cells.

Chung JG, Wu LT, Chu CB, et al.

Food Chem Toxicol. 1999 Apr; 37(4):319-26.

Berberine was used to determine inhibition of arylamine N-acetyltransferase (NAT) activity in human bladder tumour cells. The NAT activity was measured by HPLC assaying for the amounts of N-acetyl-2-aminofluorene (AAF) and N-acetyl-p-aminobenzoic acid (N-Ac-PABA) and remaining 2-aminofluorene (AF) and p-aminobenzoic acid (PABA). Two assay systems were performed, one with cellular cytosols, the other with intact bladder tumour cell suspensions. The NAT activity in human bladder tumour cells was inhibited by berberine in a dose-dependent manner, that is, the higher the concentration of berberine, the higher the inhibition of NAT activity. The values of apparent Km and Vmax calculated from cytosol NAT and intact cells were also decreased by berberine. This report is the first demonstration to show berberine did affect human bladder tumour cell NAT activity

Synergistic cytotoxicity, apoptosis and protein-linked DNA breakage by etoposide and camptothecin in human U87 glioma cells: dependence on tyrosine phosphorylation.

Ciesielski MJ, Fenstermaker RA.

J Neurooncol. 1999 Feb; 41(3):223-34.

In this study, simultaneous administration of certain inhibitors of topoisomerase I and topoisomerase II produced synergistic cytotoxicity in a series of human glioma cell lines. Camptothecin (CPT) and etoposide (VP-16) produced combination indices (CI) <1.0 in all glioma cell lines tested, including those that were relatively resistant to the two topoisomerase inhibitors individually. In contrast, CPT and VP-16 produced additive cytotoxicity in HT-29 and SW-620 colon carcinoma cell lines. To explore the molecular basis for synergy in glioma cells, we focused on one glioma cell line (U87) in which even sub-cytotoxic doses of CPT potentiated the action of VP-16. Except for genistein (a topo II agent with tyrosine kinase inhibitory function), all topo II inhibitors tested (doxorubicin, ellipticine, and m-AMSA) were synergistic with CPT. While CPT and VP-16 produced cytotoxicity and protein-linked DNA breaks (PLDB) that were supra-additive in U87 glioma cells, CPT and genistein produced additive results. Pretreatment of U87 cells with the tyrosine kinase inhibitor tyrphostin-A23 or the tyrosine phosphatase activator O-phospho-L-tyrosine (OPLT) reduced combination PLDB from synergistic to additive levels, but had no effect on the formation of PLDB induced by either CPT or VP-16 alone. CPT and VP-16 also produced a synergistic accumulation of sub-G0 (apoptotic) cells which was blocked by tyrphostin-A23. No significant increase in topoisomerase protein levels could be detected in response to combination treatment. Thus, synergistic effects between topoisomerase I and topoisomerase II inhibitors in U87 glioma cells may depend upon phosphorylation of cellular proteins other than the topoisomerases themselves

Effect of curcumin on the aryl hydrocarbon receptor and cytochrome P450 1A1 in MCF-7 human breast carcinoma cells.

Ciolino HP, Daschner PJ, Wang TT, et al.

Biochem Pharmacol. 1998 Jul 15; 56(2):197-206.

We examined the interaction of curcumin, a dietary constituent and chemopreventive compound, with the carcinogen activation pathway mediated by the aryl hydrocarbon receptor (AhR) in MCF-7 mammary epithelial carcinoma cells. Curcumin caused a rapid accumulation of cytochrome P450 1A1 (CYP1A1) mRNA in a time- and concentration-dependent manner, and CYP1A1 monooxygenase activity increased as measured by ethoxyresorufin-O-deethylation. Curcumin activated the DNA-binding capacity of the AhR for the xenobiotic responsive element of CYP1A1 as measured by the electrophoretic-mobility shift assay (EMSA). Curcumin was able to compete with the prototypical AhR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin for binding to the AhR in isolated MCF-7 cytosol, indicating that it interacts directly with the receptor. Although curcumin could activate the AhR on its own, it partially inhibited the activation of AhR, as measured by EMSA, and partially decreased the accumulation of CYP1A1 mRNA caused by the mammary carcinogen dimethylbenzanthracene (DMBA). Curcumin competitively inhibited CYP1A1 activity in DMBA-treated cells and in microsomes isolated from DMBA-treated cells. Curcumin also inhibited the metabolic activation of DMBA, as measured by the formation of DMBA-DNA adducts, and decreased DMBA-induced cytotoxicity. These results suggest that the chemopreventive effect of curcumin may be due, in part, to its ability to compete with aryl hydrocarbons for both the AhR and CYP1A1. Curcumin may thus be a natural ligand and substrate of the AhR pathway

Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group.

Clark LC, Combs GF, Jr., Turnbull BW, et al.

JAMA. 1996 Dec 25; 276(24):1957-63.

OBJECTIVE: To determine whether a nutritional supplement of selenium will decrease the incidence of cancer. DESIGN: A multicenter, double-blind, randomized, placebo-controlled cancer prevention trial. SETTING: Seven dermatology clinics in the eastern United States. PATIENTS: A total of 1312 patients (mean age, 63 years; range, 18-80 years) with a history of basal cell or squamous cell carcinomas of the skin were randomized from 1983 through 1991. Patients were treated for a mean (SD) of 4.5 (2.8) years and had a total follow-up of 6.4 (2.0) years. INTERVENTIONS: Oral administration of 200 microg of selenium per day or placebo. MAIN OUTCOME MEASURES: The primary end points for the trial were the incidences of basal and squamous cell carcinomas of the skin. The secondary end points, established in 1990, were all-cause mortality and total cancer mortality, total cancer incidence, and the incidences of lung, prostate, and colorectal cancers. RESULTS: After a total follow-up of 8271 person-years, selenium treatment did not significantly affect the incidence of basal cell or squamous cell skin cancer. There were 377 new cases of basal cell skin cancer among patients in the selenium group and 350 cases among the control group (relative risk [RR], 1.10; 95% confidence interval [CI], 0.95-1.28), and 218 new squamous cell skin cancers in the selenium group and 190 cases among the controls (RR, 1.14; 95% CI, 0.93-1.39). Analysis of secondary end points revealed that, compared with controls, patients treated with selenium had a nonsignificant reduction in all-cause mortality (108 deaths in the selenium group and 129 deaths in the control group [RR; 0.83; 95% CI, 0.63-1.08]) and significant reductions in total cancer mortality (29 deaths in the selenium treatment group and 57 deaths in controls [RR, 0.50; 95% CI, 0.31-0.80]), total cancer incidence (77 cancers in the selenium group and 119 in controls [RR, 0.63; 95% CI, 0.47-0.85]), and incidences of lung, colorectal, and prostate cancers. Primarily because of the apparent reductions in total cancer mortality and total cancer incidence in the selenium group, the blinded phase of the trial was stopped early. No cases of selenium toxicity occurred. CONCLUSIONS: Selenium treatment did not protect against development of basal or squamous cell carcinomas of the skin. However, results from secondary end-point analyses support the hypothesis that supplemental selenium may reduce the incidence of, and mortality from, carcinomas of several sites. These effects of selenium require confirmation in an independent trial of appropriate design before new public health recommendations regarding selenium supplementation can be made

Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells.

Clement MV, Hirpara JL, Chawdhury SH, et al.

Blood. 1998 Aug 1; 92(3):996-1002.

Resveratrol, a constituent of grapes and other food products, has been shown to prevent carcinogenesis in murine models. We report here that resveratrol induces apoptotic cell death in HL60 human leukemia cell line. Resveratrol-treated tumor cells exhibit a dose-dependent increase in externalization of inner membrane phosphatidylserine and in cellular content of subdiploid DNA, indicating loss of membrane phospholipid asymmetry and DNA fragmentation. Resveratrol-induced cell death is mediated by intracellular caspases as observed by the dose-dependent increase in proteolytic cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and the ability of caspase inhibitors to block resveratrol cytotoxicity. We also show that resveratrol treatment enhances CD95L expression on HL60 cells, as well as T47D breast carcinoma cells, and that resveratrol-mediated cell death is specifically CD95-signaling dependent. On the contrary, resveratrol treatment of normal human peripheral blood lymphocytes (PBLs) does not affect cell survival for up to 72 hours, which correlates with the absence of a significant change in either CD95 or CD95L expression on treated PBLs. These data show specific involvement of the CD95-CD95L system in the anti-cancer activity of resveratrol and highlight the chemotherapeutic potential of this natural product, in addition to its recently reported chemopreventive activity

Assessment of hormonally active agents in the reproductive tract of female nonhuman primates.

Cline JM, Soderqvist G, Register TC, et al.

Toxicol Pathol. 2001 Jan; 29(1):84-90.

Using the ovariectomized macaque model of postmenopausal women's health, we investigated the effects of long-term treatments (5 weeks-3 years) with estradiol, conjugated equine estrogens (CEE), esterified estrogens, progestins such as medroxyprogesterone acetate (MPA) and nomegestrol acetate, CEE + MPA, tamoxifen, soybean phytoestrogens (SPEs), a variety of putative selective estrogen receptor modulators (SERMs), and androgens. Agents tested were selected on the basis of beneficial effects on arteries and/or bone. Doses were scaled on a caloric or serum-concentration basis to approximate human clinical doses. We evaluated endometrial and mammary gland histopathology and morphometry and used immunohistochemistry to evaluate cell proliferation and expression of estrogen receptor alpha and progesterone receptor (PR). Both estradiol and CEE induced endometrial hyperplasia. MPA antagonized epithelial proliferation induced by CEE in endometrium and induced pseudodecidual stromal hyperplasia in some animals. Tamoxifen induced endometrial polyps, cystic hyperplasia, stromal fibrosis, and PR expression but not Ki-67 expression. SPEs were not estrogenic at dietary doses and antagonized estrogen-induced proliferation in the endometrium and breast. Nandrolone induced mucometra and an adenomyosis-like change. The potential SERM 17 alpha dihydroequilenin did not have uterotrophic or mammotrophic effects. In general, experimental findings in macaques have been predictive of outcomes in human clinical trials of the same agents

Garlic extracts stimulate proliferation of rat lymphocytes in vitro by increasing IL-2 and IL-4 production.

Colic M, Savic M.

Immunopharmacol Immunotoxicol. 2000 Feb; 22(1):163-81.

Garlic components are known to modulate certain immune functions. However, mechanisms of their action are not sufficiently elucidated. This study was, therefore, undertaken to examine the effects of aqueous and ethanolic extracts prepared from a garlic powder sample on proliferation of rat spleen lymphocytes in culture. Cells were stimulated with the combination of phorbol myristate acetate (PMA) and a Ca ionophore (A23187) or R73 monoclonal antibody (mAb) directed to the alphabeta chain of T cell receptor. It has been shown that both extracts significantly stimulated proliferation of lymphocytes. The effect correlated with upregulation of the Interleukin 2 receptor alpha (IL-2R alpha) expression and the increase in IL-2 production. Stimulation of IL-2 production by the extracts was higher in cultures with PMA/Ca ionophore than in cultures with R73 mAb. In contrast, both extracts stimulated production of IL-4 by splenocytes triggered by R73 mAb. The complete dependence of lymphocyte proliferation in cultures with R73 mAb and garlic extracts on IL-2 and IL-4 was demonstrated using neutralising mAbs to IL-2R alpha and IL-4. These results suggest that the potentiating effect of garlic extracts on lymphocyte proliferation in vitro differs depending on specific stimulators of cell proliferation and probably on the type of responding cells

Physicians want education about complementary and alternative medicine to enhance communication with their patients.

Corbin WL, Shapiro H.

Arch Intern Med. 2002 May 27; 162(10):1176-81.

BACKGROUND: More than one third of patients in the United States use complementary and alternative medicine (CAM); most also visit conventional physicians. There is little information about how physicians and patients discuss CAM. We hypothesized that physicians frequently fielded questions about CAM treatments but felt uncomfortable discussing them owing to a lack of education. OBJECTIVES: To survey physicians to see how they discussed CAM with their patients and what factors influenced discussions and referrals. METHODS: A total of 751 physicians in the Denver, Colo, area were asked about their experience with CAM and communication about CAM with patients. Analyses were conducted using the SAS system (version 6, 1989; SAS Institute Inc, Cary, NC). RESULTS: Of the 705 deliverable surveys, 302 (43%) were returned: 76% of physicians reported having patients using CAM; 59% had been asked about specific CAM treatments; 48% had recommended CAM to a patient; and 24% had personally used CAM. Physician recommendation of CAM was most strongly associated with physician self-use (odds ratio, 6.98; P<.001). Few physicians felt comfortable discussing CAM with their patients, and the overwhelming majority (84%) thought they needed to learn more about CAM to adequately address patient concerns. CONCLUSIONS: Education about CAM modalities is a significant unmet need among Denver physicians, and education may help alleviate the discomfort physicians have when answering patients' questions about CAM. Physicians who use CAM treatments themselves are much more likely to recommend CAM for their patients than physicians who do not

Butter Enhanced with Natural Fatty Acids Reduces Breast Cancer Risk in Animals.

Cornell News.

Cornell News. 1999

Adriamycin cardiotoxicity: early detection by systolic time interval and possible prevention by coenzyme Q10.

Cortes EP, Gupta M, Chou C, et al.

Cancer Treat Rep. 1978 Jun; 62(6):887-91.

Recent work suggests that adriamycin (ADM) cardiotoxicity results from the depletion of coenzyme 10 (CoQ10) activity in myocardial mitochondria. CoQ10 is indispensable in the bioenergetics of coupled respiration of oxidative phosphorylation. It exists naturally in mitochondria, especially in the myocardium. Bertazzoli et al have reported a decrease in ADM-induced cardiotoxicity by CoQ10 both in vivo and in the in vitro isolated rabbit heart. The systolic time interval (ATI) (pre-ejection period/left ventricular ejection time ratio) has been shown to increase (indicating cardiac dysfunction) with increasing doses of ADM. We have noted a gradual increase in the STI in eight of ten patients receiving 200-500 mg/m2 of ADM. Two of these eight patients had congestive heart failure (CHF) at doses of 200 and 350 mg/m2. The continued daily oral administration of 50 mg of CoQ10 beginning with the first dose of ADM resulted in a decreased incidence of cardiac dysfunction, and a gradual increase in STI occurred in only two of eight patients receiving 200-400 mg/m2 of ADM. CHF was observed inone patient at a dose of 350 mg/m2. It is suggested that CoQ10 was nontoxic and did not affect the antitumor activity or modify the ADM-induced bone marrow toxicity. A prospective randomized study comparing ADM with and without CoQ10 is in progress

Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells.

Cover CM, Hsieh SJ, Cram EJ, et al.

Cancer Res. 1999 Mar 15; 59(6):1244-51.

The current options for treating breast cancer are limited to excision surgery, general chemotherapy, radiation therapy, and, in a minority of breast cancers that rely on estrogen for their growth, antiestrogen therapy. The naturally occurring chemical indole-3-carbinol (I3C), found in vegetables of the Brassica genus, is a promising anticancer agent that we have shown previously to induce a G1 cell cycle arrest of human breast cancer cell lines, independent of estrogen receptor signaling. Combinations of I3C and the antiestrogen tamoxifen cooperate to inhibit the growth of the estrogen-dependent human MCF-7 breast cancer cell line more effectively than either agent alone. This more stringent growth arrest was demonstrated by a decrease in adherent and anchorage-independent growth, reduced DNA synthesis, and a shift into the G1 phase of the cell cycle. A combination of I3C and tamoxifen also caused a more pronounced decrease in cyclin-dependent kinase (CDK) 2-specific enzymatic activity than either compound alone but had no effect on CDK2 protein expression. Importantly, treatment with I3C and tamoxifen ablated expression of the phosphorylated retinoblastoma protein (Rb), an endogenous substrate for the G1 CDKs, whereas either agent alone only partially inhibited endogenous Rb phosphorylation. Several lines of evidence suggest that I3C works through a mechanism distinct from tamoxifen. I3C failed to compete with estrogen for estrogen receptor binding, and it specifically down-regulated the expression of CDK6. These results demonstrate that I3C and tamoxifen work through different signal transduction pathways to suppress the growth of human breast cancer cells and may, therefore, represent a potential combinatorial therapy for estrogen-responsive breast cancer

Selected micronutrient intake and thyroid carcinoma risk.

D'Avanzo B, Ron E, La Vecchia C, et al.

Cancer. 1997 Jun 1; 79(11):2186-92.

BACKGROUND: Protection from thyroid carcinoma due to certain dietary factors was suggested by several studies, but the findings were relatively inconsistent. The role of micronutrients has not yet been systematically analyzed. To investigate the relationship between micronutrient intake and thyroid carcinoma risk, the authors used data from a case-control study conducted in northern Italy between 1986 and 1992. METHODS: The study included 399 incident, histologically confirmed thyroid carcinoma cases and 617 controls admitted to the hospital for acute, nonneoplastic, nonhormone-related diseases. RESULTS: Retinol intake showed a direct association with thyroid carcinoma risk, with odds ratios (ORs) of 1.39 (95% confidence Interval [CI], 0.9-2.0) in the third quartile of consumption and 1.52 (95% CI, 1.0-2.3) in the highest quartile, whereas beta-carotene had an inverse relationship, with ORs of 0.63 (95% CI, 0.4-0.9) in the third quartile of consumption and 0.58 (95% CI, 0.4-0.9) in the highest quartile compared with the lowest quartile. Some protection was observed for measures of vitamin C intake (with an OR of 0.72) and vitamin E (with an OR of 0.67) for the highest quartile of consumption, although the estimates were not statistically significant, and were reduced after adjustment for beta-carotene intake. No clear pattern in risk appeared for vitamin D, lolate, calcium, thiamin, or riboflavin. The inverse relationship between beta-carotene and thyroid carcinoma was observed in both papillary and follicular carcinomas. CONCLUSIONS: In this study, a significant inverse association between beta-carotene and thyroid carcinoma was observed, and some protection against thyroid carcinoma from vitamins C and E was also suggested

Inhibition of tumorigenic potential and prostate-specific antigen expression in LNCaP human prostate cancer cell line by 13-cis-retinoic acid.

Dahiya R, Park HD, Cusick J, et al.

Int J Cancer. 1994 Oct 1; 59(1):126-32.

Prostate-specific antigen (PSA) is a member of the kallikrein family and has been an important biological marker for prostate cancer. The mechanisms regulating PSA expression in prostatic cancer cells are unclear. The present study was designed to elucidate the role of 13-cis-retinoic acid (RA) in regulation of PSA and the tumorigenic potential of the human prostate cancer cell line LNCaP. The growth regulation of LNCaP cells was examined by DNA synthesis and doubling time. The tumorigenic potential of prostate cancer cells was analyzed by soft agar colony-forming assay, in vitro invasion assay, type IV collagenase assay and binding to extracellular matrix assay. The nuclear receptors for retinoic acid (RAR alpha, -beta, -gamma and RXR alpha, -beta, -gamma) as well as PSA mRNA were determined by Northern blot using specific oligonucleotide probes. Our results suggest that 13-cis-RA significantly inhibits PSA secretion and expression both at the mRNA and protein levels compared with untreated cells. Electron microscopic studies suggest that after 13-cis-RA treatment, cells become more differentiated as they contain lumina, lined by plasma membrane and microvilli. Prostate cancer cell growth and tumorigenic potential after 13-cis-RA treatment was significantly decreased compared with controls. Nude mice tumorigenicity studies showed that 13-cis-RA-treated cells produced significantly smaller tumors compared with untreated cell tumors. There was also a significant increase in the expression of RXRa mRNA after 13-cis-RA treatment compared with untreated cells

Population-based case-control study of soyfood intake and breast cancer risk in Shanghai.

Dai Q, Shu XO, Jin F, et al.

Br J Cancer. 2001 Aug 3; 85(3):372-8.

We evaluated the association of soyfood intake and breast cancer risk in a population-based case-control study among Chinese women in Shanghai. Included in the study were 1459 cases and 1556 age-matched controls, with respective response rates of 91.1% and 90.3%. Usual soyfood intake was assessed using a food frequency questionnaire (FFQ). Separate analyses were performed for all subjects and for the subset who reported no recent change in soyfood intake. The intake levels of soyfoods among women in Shanghai are high, with 96.6% women reporting soyfood consumption at least once a week. A statistically non-significant reduced risk (odds ratio (OR) = 0.78 95% CI = 0.52-1.16) of breast cancer was observed among those who reported eating soyfood at least once a week. Compared to those in the lowest decile intake group, women in the highest decile intake group had a 30% reduced risk of breast cancer (OR = 0.66, 95% CI = 0.46-0.95), but no monotonic dose-response relation was observed (P for trend, 0.28). Stratified analyses showed that the inverse association was restricted primarily among women who had a high body mass index (BMI), with an adjusted OR of 0.30 (95% CI = 0.10-0.94) observed for the highest intake group. The reduction in risk was stronger for breast cancer positive for both oestrogen receptor (ER) and progesterone receptor (PR) (OR = 0.44, 95% CI = 0.25-0.78) than those with other ER/PR status. More pronounced inverse associations were observed in analyses among those who reported no recent change in soyfood intake than those conducted in all subjects. A dose-response relation between soyfood intake and breast cancer risk was observed in this subset of women (P for trend, 0.02), with an OR of 0.46 (95%CI = 0.28-0.75) for those in the highest decile intake group. No clear monotonic dose-response relation was found between soyfood intake and breast cancer risk among regular soy eaters, but nevertheless the results suggest that regular soyfood consumption may reduce the risk of breast cancer, particularly for those positive for ER and PR; the effect may be modified by body mass index

Genistein, a component of soy, inhibits the expression of the EGF and ErbB2/Neu receptors in the rat dorsolateral prostate.

Dalu A, Haskell JF, Coward L, et al.

Prostate. 1998 Sep 15; 37(1):36-43.

BACKGROUND: Epidemiological reports suggest that Asians consuming a diet high in soy have a low incidence of prostate cancer. In animal models, soy and genistein have been demonstrated to suppress the development of prostate cancer. In this study, we investigate the mechanism of action, bioavailability, and potential for toxicity of dietary genistein in a rodent model. METHODS: Lobund-Wistar rats were fed a 0.025-1.0-mg genistein/g AIN-76A diet. The dorsolateral prostate was subjected to Western blot analysis for expression of tyrosine-phosphorylated proteins, and of the EGF and ErbB2/Neu receptors. Genistein concentrations were measured from serum and prostate using HPLC-mass spectrometry. Body and prostate weights, and circulating testosterone levels, were measured. RESULTS: Increasing concentrations of genistein in the diet inhibited tyrosine-phosphorylated proteins with molecular weights of 170,000 and 85,000 in the dorsolateral prostate. Western blot analysis revealed that the 1-mg genistein/g AIN-76A diet inhibited by 50% the expression of the EGF receptor and its phosphorylation. In rats fed this diet, serum-free and total genistein concentrations were 137 and 2,712 pmol/ml, respectively. The free and total genistein IC50 values for the EGF receptor were 150 and 600 pmol/g prostate tissue, respectively. Genistein in the diet also inhibited the ErbB2/Neu receptor. Body and dorsolateral prostate weights, and circulating testosterone concentrations, were not adversely effected from exposure to genistein in the diet for 3 weeks. CONCLUSIONS: We conclude that genistein in the diet can downregulate the EGF and ErbB2/Neu receptors in the rat prostate with no apparent adverse toxicity to the host. The concentration needed to achieve a 50% reduction in EGF receptor expression can be achieved by eating a diet high in soy products or with genistein supplementation. Genistein inhibition of the EGF signaling pathway suggests that this phytoestrogen may be useful in both protecting against and treating prostate cancer

Distinct Chk2 activation pathways are triggered by genistein and DNA-damaging agents in human melanoma cells.

Darbon JM, Penary M, Escalas N, et al.

J Biol Chem. 2000 May 19; 275(20):15363-9.

Genistein, a natural isoflavone found in soybeans, exerts a number of biological actions suggesting that it may have a role in cancer prevention. We have previously shown that it potently inhibits OCM-1 melanoma cell proliferation by inducing a G(2) cell cycle arrest. Here we show that genistein exerts this effect by impairing the Cdc25C-dependent Tyr-15 dephosphorylation of Cdk1, as the overexpression of this phosphatase allows the cells to escape G(2) arrest and enter an abnormal chromatin condensation stage. Caffeine totally overrides the genistein-induced G(2) arrest, whereas the block caused by etoposide is not bypassed and that caused by adriamycin is only partially abolished. We also report that genistein activates the checkpoint kinase Chk2 as efficiently as the two genotoxic agents and that caffeine may counteract the activation of Chk2 by genistein but not by etoposide. In contrast, caffeine abolishes the accumulation of p53 caused by all the compounds. Wortmannin does not suppress the Chk2 activation in any situation, suggesting that the ataxia telangiectasia-mutated kinase is not involved in this regulation. Finally, unlike etoposide and adriamycin, genistein induces only a weak response in terms of DNA damage in OCM-1 cells. Taken together, these results suggest that the G(2) checkpoints activated by genistein and the two genotoxic agents involve different pathways

[From cancers of the uterus and breast to cancers of the spirit (XVIII-XIX centuries)].

Darmon P.

Contracept Fertil Sex. 1993 Feb; 21(2):185-6.

Cancer, particularly uterus and breast cancer, is since Antiquity attributed to melancholy and psychological reasons. Testimonies become especially numerous at XVIII and XIX centuries

Effects of soy or rye supplementation of high-fat diets on colon tumour development in azoxymethane-treated rats.

Davies MJ, Bowey EA, Adlercreutz H, et al.

Carcinogenesis. 1999 Jun; 20(6):927-31.

Evidence is accumulating that a diet high in plant-derived foods may be protective against cancer. One class of plant component under increasing investigation is the phytoestrogens of which there are two main groups: the isoflavones, found mainly in soy products, and the lignans, which are more ubiquitous and are found in fruit, vegetables and cereals with high levels being found in flaxseed. In this study, we have used carefully balanced high-fat (40% energy) diets: a control diet (containing low isoflavone soy protein as the sole protein source), a rye diet (the control diet supplemented with rye bran) and a soy diet (containing as protein source a high isoflavone soy protein). The effect of these diets on the development of colonic cancer was studied in F-344 rats treated with the carcinogen, azoxymethane (two doses of 15 mg/kg given 1 week apart). Colons from treated animals were examined for aberrant crypt foci (ACF) and tumours after 12 and 31 weeks. Results after 12 weeks showed no differences in the total number of ACF in the control, soy or rye bran groups. However, the soy group had increased numbers of small ACF (less than four crypts/focus) while the rye group had decreased numbers of large ACF (greater than six crypts/focus). Examination of colons after 31 weeks gave similar low numbers of ACF in each group with no differences in multiplicity. There were no differences in the number of tumours between the control (1.36 tumours/rat) and soy (1.38 tumours/rat) groups. However, there was a significant decrease in the number of tumours in the rye group (0.17 tumours/rat). These results suggest that soy isoflavones have no effect on the frequency of colonic tumours in this model while rye bran supplementation decreases the frequency of colon cancer. This effect is due not to a decrease in early lesions but in their progression to larger multi-crypt ACF. The study also supports the hypothesis that larger ACF are more predictive of subsequent tumorigenicity

Selenium-enriched broccoli decreases intestinal tumorigenesis in multiple intestinal neoplasia mice.

Davis CD, Zeng H, Finley JW.

J Nutr. 2002 Feb; 132(2):307-9.

Multiple intestinal neoplasia (Min) mice are a good model for the investigation of the effects of dietary alterations in a genetic model for intestinal cancer. Previous studies have shown that selenium-enriched broccoli is protective against chemically induced colon cancer susceptibility. This study investigated whether selenium-enriched broccoli would be protective against intestinal cancer susceptibility in Min mice. Five-week-old heterozygotic male Min mice were fed an AIN-93-based diet containing either low-selenium broccoli or an equivalent amount of high-selenium broccoli for 10 wk. Mice fed the selenium-enriched broccoli had fewer (P < 0.02) small intestinal (46.4 +/- 3.7 vs. 65.6 +/- 6.1) and large intestinal (0.43 +/- 0.17 vs. 1.93 +/- 0.27) tumors than those fed an equivalent amount of unenriched broccoli. Min mice fed the selenium-enriched broccoli had small but significant (P < 0.0001) increases in plasma and liver selenium concentrations and red blood cell glutathione peroxidase activity. These results extend previous observations that selenium-enriched broccoli is protective against chemically induced mammary and colon cancer in rats

Soy isoflavone supplementation in healthy men prevents NF-kappa B activation by TNF-alpha in blood lymphocytes.

Davis JN, Kucuk O, Djuric Z, et al.

Free Radic Biol Med. 2001 Jun 1; 30(11):1293-302.

Dietary intake of soy has been associated with a decreased risk of cancer. Soy isoflavones have been postulated to be the protective compounds in soybeans; however, the precise mechanism by which soy isoflavones prevent human cancer is not known. The major soy isoflavones, genistein and daidzein, are antioxidant compounds, therefore one possible mechanism of action is through their antioxidant effect. We have previously demonstrated that the soy isoflavone, genistein, inhibits the activation of the redox-sensitive transcription factor, NF-kappa B, in prostate cancer cells in vitro. In this study, we have demonstrated that genistein, but not daidzein, inhibits TNF-alpha-induced NF-kappa B activation in cultured human lymphocytes. Additionally, we investigated the in vivo effect of soy isoflavone supplementation on NF-kappa B activation induced by TNF-alpha in vitro in peripheral blood lymphocytes of six healthy men. We show that healthy male subjects receiving 50 mg isoflavone mixture (Novasoy) twice daily for 3 weeks are protected from TNF-alpha induced NF-kappa B activation. Additionally, we observed a reduction of 5-hydroxymethyl-2'-deoxyuridine (5-OHmdU), a marker for oxidative DNA damage, following isoflavone supplementation. The inhibitory effect of soy isoflavones was no longer present 3 months after the supplementation. This preliminary study demonstrates that soy isoflavone supplementation may protect cells from oxidative stress-inducing agents by inhibiting NF-kappa B activation and decreasing DNA adduct levels

Metabolic, desmutagenic and anticarcinogenic effects of N-acetylcysteine.

De Flora S, Rossi GA, De Flora A.

Respiration. 1986; 50 Suppl 1:43-9.

N-acetylcysteine (NAC) is often administered to respiratory patients with histories of exposure to noxious agents (e.g. cigarette smoke and atmospheric pollutants), which are known to act as glutathione (GSH) depletors and as cancer initiators and/or promoters. Since NAC is a precursor of intracellular GSH, we investigated its effects on GSH metabolism and on the biotransformation of carcinogenic and/or mutagenic compounds. In vitro, NAC induced a significant increase in oxidized glutathione (GSSG) reductase activity in rat liver preparations and counteracted the mutagenicity of direct-acting compounds (such as epichlorohydrin, hydrogen peroxide, 4-nitroquinoline-N-oxide and dichromate), as a result of its reducing and scavenging properties. At high concentrations, the drug completely inhibited the mutagenicity of procarcinogens (cigarette smoke condensate, tryptophan pyrolysate, cyclophosphamide, 2-aminofluorene, benzo(a)pyrene and aflatoxin B1) by binding their electrophilic metabolites. In contrast, their metabolic activation was stimulated by decreasing NAC concentrations, especially when liver preparations from enzyme-induced rats were used. Lung and liver subcellular preparations of rats treated in vivo with NAC, in various combinations with enzyme inducers and/or GSH depletors, also affected the mutagenicity of a number of compounds. NAC generally increased intracellular GSH and restored its levels following depletion. It did not affect the levels nor the spectral properties of cytochromes P-450 in pulmonary and hepatic microsomes, whereas it stimulated, especially in Aroclor-pretreated animals, cytosolic enzyme activities involved in NADP or GSSG reduction (G6PD, 6PGD and GSSG reductase) and in the reductive detoxification of xenobiotics (DT diaphorase). When administered with the diet, at a nontoxic posology (120 mg/kg b.w.), NAC markedly inhibited the induction of lung tumors in mice by a potent carcinogen (urethane)

N-Acetylcysteine as antimutagen and anticarcinogen.

De Flora S.

Toxicol Lett. 1992; 53

W4/L2

Synergism between N-acetylcysteine and doxorubicin in the prevention of tumorigenicity and metastasis in murine models.

De Flora S, D'Agostini F, Masiello L, et al.

Int J Cancer. 1996 Sep 17; 67(6):842-8.

The thiol N-acetylcysteine (NAC) is a promising cancer chemopreventive agent which acts through a variety of mechanisms, including its nucleophilic and antioxidant properties. We have recently shown that NAC inhibits type-IV collagenase activity as well as invasion, tumor take and metastasis of malignant cells in mice. NAC is also known to attenuate the cardiotoxicity of the cytostatic drug doxorubicin (DOX, Adriamycin). The present study was designed to evaluate whether the combination of NAC and DOX treatments in mice injected with cancer cells could affect their tumorigenic and metastatic properties. Six separate experiments were carried out, using a total of 291 adult female mice. In experimental metastasis assays, in which B16-F10 melanoma cells were injected i.v. into (CD-1)BR nude mice, DOX significantly reduced the number of lung metastases when administered i.v. at a dose of 10 mg/kg body weight, 3 days after the i.v. injection of cancer cells. NAC inhibited lung metastases when added to the medium of cancer cells before their i.v. injection. The combined treatment with DOX and NAC, under various experimental conditions, was highly effective, showing a synergistic reduction in the number of mestastases. In tumorigenicity and spontaneous metastasis assays, in which B16-BL6 melanoma cells were injected s.c. into the footpad of C57BL/6 mice, DOX decreased the number of lung metastases when given i.p. at 2 mg/kg body weight. Oral NAC exerted significant protective effects, and considerably prolonged survival of mice. The combined treatment with DOX and NAC again showed synergistic effects on the frequency and weight of primary tumors and local recurrences, and completely prevented the formation of lung metastases in the experiment in which these end-points were evaluated at fixed times. While injection of DOX 7 days after implantation of cancer cells failed to improve the cancer-protective effects of NAC, its injection after I day resulted in a striking inhibition of lung metastases. These findings demonstrate an evident synergism between DOX (given parenterally) and NAC (given with drinking water) in preventing tumorigenicity and metastases. The indications of these animal studies warrant further evaluation in clinical trials

Dietary carotenoids and risk of gastric cancer: a case-control study in Uruguay.

De Stefani E, Boffetta P, Brennan P, et al.

Eur J Cancer Prev. 2000 Oct; 9(5):329-34.

In the period 1997-1999, 120 incident and histologically verified cases of stomach cancer were frequency matched on age, sex, residence and urban/rural status with 360 controls in order to study the role of diet in gastric cancer in Uruguay. Our attention was focused on the role of carotenoids in gastric carcinogenesis, after controlling for major confounders. According to the results, vitamin A, alpha-carotene and lycopene were associated with strong inverse relationships with stomach cancer (OR of stomach cancer for high alpha-carotene intake 0.34, 95% CI 0.17-0.65). Joint exposure to high intakes of alpha-carotene and vitamin C intakes were associated with a strong reduction in risk (OR 0.11, 95% CI 0.03-0.36). It was also suggested that high lycopene intake explained most of the reduction in risk of gastric cancer associated with vegetable intake, whereas no such effect was observed for fruit intake

Striking regression of radiation-induced fibrosis by a combination of pentoxifylline and tocopherol.

Delanian S.

Br J Radiol. 1998 Aug; 71(848):892-4.

Radiation-induced fibrosis (RIF) is a terminal sequela to irradiation that does not regress spontaneously. A preliminary study of a combination of pentoxifylline (PTX) and tocopherol (vit-E) has shown clinical activity with 50% superficial RIF regression at 6 months in half of the patients studied. The present report is of a 67-year-old woman presenting with bulky cervicothoracic RIF who, 10 years previously, had received radiochemotherapy for a small cell thyroid carcinoma to a dose of 50 Gy, with severe acute side-effects. She had palpable cervicosternal fibrosis measuring 10 x 8 cm, with local inflammatory signs and functional consequences (cough, restricted cervical movement, dyspnoea and bronchitis) with a SOMA scale for grading the long-term side effects of radiation therapy of 19/14. CT showed deep RIF extending from the vocal cords to the carina, with laryngotracheal compression but without cancer recurrence. PTX (800 mg d-1) and vit-E (1000 U d-1), orally administered daily for 18 months, were well tolerated. The patient exhibited clinical regression and functional improvement. The linear dimensions and SOMA scale were, respectively, 8 x 6 cm and 11 at 6 months; 4 x 4 cm and 7 at 12 months; and complete response with no measurable RIF and 1 at 18 months. This is the first time that the combination of PTX and vit-E has had a significant antifibrotic effect by completely reversing deep RIF as shown by CT scan normalization

Estradiol activation of human colon carcinoma-derived Caco-2 cell growth.

Di Domenico M, Castoria G, Bilancio A, et al.

Cancer Res. 1996 Oct 1; 56(19):4516-21.

This is the first report on estrogen-dependent growth of human-derived colon carcinoma cells. Under selected conditions, growth of subconfluent Caco-2 cells is triggered by estradiol. Cell growth is estradiol concentration dependent, with maximal effect occurring at about 0.4 nM. Growth is prevented by two different antiestrogens: the partial agonist, OH-Tamoxifen, and the pore antagonist, ICI 182,780. The growth effect is specific for estradiol since other hormonal steroids tested do not affect cell growth. The amount of estradiol receptor in subconfluent Caco-2 cells, detected by blot with monoclonal antibodies directed against the receptor as well as estradiol binding assays, is similar to that of the classical estradiol-responsive, human mammary cancer-derived MCF-7 cells. Estradiol treatment of subconfluent Caco-2 cells rapidly and reversibly stimulates four important intermediates in a signal transduction pathway that is known to trigger cell proliferation: two members of the large family of c-src-related tyrosine kinases, c-src and c-yes, and two serine/threonine kinases, the mitogen-activated protein (MAP) kinases, erk-1 and erk-2. Tyrosine kinases activated by estradiol are up-stream MAP kinases and Caco-2 cell proliferation. In fact, genistein, a specific tyrosine kinase inhibitor, abolishes the estradiol stimulatory effect on both erk-2 activity and cell proliferation. Our findings show that in subconfluent Caco-2 cells, the estradiol-receptor complex activates the c-src, c-yes/MAP kinase pathway and activates growth. This could have important implications for the understanding of human intestinal carcinogenesis

Effect of lactoferrin on Helicobacter felis induced gastritis.

Dial EJ, Lichtenberger LM.

Biochem Cell Biol. 2002; 80(1):113-7.

Lactoferrin possesses antibiotic, antiinflammatory, and immune-modulating properties that may be active against the gastritis-, ulcer- and cancer-inducing bacterium Helicobacter pylori. In vitro testing of bovine and human lactoferrin by several laboratories has shown significant bacteriostatic and bactericidal activity. Subsequent in vivo testing of bovine lactoferrin in animal models of H. pylori infection has shown beneficial effects of this agent. Our laboratory has utilized a mouse model that is infected with the feline strain of this bacterium, H. felis. The resulting gastritis that develops in this model and the effects of bovine lactoferrin and recombinant human lactoferrin (from Aspergillus niger var. awamori, Agennix Inc., Houston, Tex.) treatment were assessed by various measures. Infected animals treated with orally administered lactoferrin showed reversals in all parameters. In addition, when recombinant human lactoferrin was used in combination with low doses of amoxicillin or tetracycline, there was an enhancement in gastritis-reducing activity. Possible mechanisms for these effects of lactoferrin are discussed. Lactoferrin has significant, orally active in vivo actions and should be further investigated for clinical situations involving Helicobacter infections where it may have utility when administered alone and also when given in combination with established antibiotic agents

Reduction in new metastases in breast cancer with adjuvant clodronate treatment.

Diel IJ, Solomayer EF, Costa SD, et al.

N Engl J Med. 1998 Aug 6; 339(6):357-63.

BACKGROUND: Bisphosphonates are effective against the increased bone resorption caused by certain diseases because they inhibit the activity of osteoclasts. In patients who have breast cancer and metastatic bone disease, the bisphosphonate clodronate (clodronic acid) reduces the frequency of skeletal complications. Experiments in animals and preliminary clinical observations indicate that early clodronate therapy reduces the incidence of new bony metastases in breast cancer. We investigated the effects of clodronate on the incidence and extent of new metastases in patients with breast cancer. METHODS: Between 1990 and 1995, 302 patients with primary breast cancer and tumor cells in the bone marrow (the presence of which is a risk factor for the development of distant metastases) were randomly assigned to receive clodronate at a dose of 1600 mg per day orally for two years (157 patients) or standard follow-up (145 patients). The median length of observation was 36 months. All patients in both groups received standard surgical treatment and customary hormonal therapy or chemotherapy. RESULTS: Distant metastases were detected in 21 patients in the clodronate group and in 42 patients in the control group (P<0.001). The incidence of both osseous and visceral metastases was significantly lower in the clodronate group than in the control group (P="0.003" for both osseous and visceral metastases). Six patients in the clodronate group died, as did 22 in the control group (P="0.001)." The mean number of bony metastases per patient in the clodronate group was roughly half that in the control group (3.1 vs. 6.3). CONCLUSIONS: Clodronate can reduce the incidence and number of new bony and visceral metastases in women with breast cancer who are at high risk for distant metastases

Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications.

Dimitroulakos J, Ye LY, Benzaquen M, et al.

Clin Cancer Res. 2001 Jan; 7(1):158-67.

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the rate-limiting enzyme of the mevalonate pathway, the diverse array of end products of which are vital for a variety of cellular functions, including cholesterol synthesis and cell cycle progression. We showed previously that this enzyme holds a critical role in regulating tumor cell fate, including cell death, as its expression is down-regulated in response to retinoic acid, a potent anticancer therapeutic. Indeed, direct inhibition of HMG-CoA reductase with lovastatin, a competitive inhibitor of this enzyme, induced a pronounced apoptotic response in neuroblastoma and acute myeloid leukemic cells. We have now extended this work and evaluated a wide variety and large number of tumor-derived cell lines for their sensitivity to lovastatin-induced apoptosis. These cell lines were exposed to a wide range (0-100 microM) of lovastatin for 2 days and assayed for cell viability using the 3,4,5-dimethyl thiazlyl-2,2,5-diphenyltetrazolium bromide assay and the induction of apoptosis by flow cytometric and ultrastructural analyses. Lovastatin induced a pronounced apoptotic response in cells derived from juvenile monomyelocytic leukemia, pediatric solid malignancies (rhabdomyosarcoma and medulloblastoma), and squamous cell carcinoma of the cervix and of the head and neck. Interestingly, the subset of malignancies that are particularly sensitive to lovastatin-induced apoptosis correspond to those tumor subtypes that are sensitive to the biological and antiproliferative effects of retinoids in vitro. The nature of the biologically active form of lovastatin has been challenged recently as the growth-inhibitory effects of this drug were attributed to its prodrug lactone form that does not inhibit HMG-CoA reductase function. In this report, we demonstrate that the apoptotic properties of lovastatin are triggered by the open ring acid form that is a potent inhibitor of HMG-CoA reductase activity. Thus, we have identified a subset of tumors that are sensitive to lovastatin-induced apoptosis and show HMG-CoA reductase as a potential therapeutic target of these cancers

Lipoxygenase inhibitors abolish proliferation of human pancreatic cancer cells.

Ding XZ, Iversen P, Cluck MW, et al.

Biochem Biophys Res Commun. 1999 Jul 22; 261(1):218-23.

Epidemiologic and animal studies have linked pancreatic cancer growth with fat intake, especially unsaturated fats. Arachidonic acid release from membrane phospholipids is essential for tumor cell proliferation. Lipoxygenases (LOX) constitute one pathway for arachidonate metabolism, but their role in pancreatic cancer growth is unknown. The expression of 5-LOX and 12-LOX as well as their effects on cell proliferation was investigated in four human pancreatic cancer cell lines (PANC-1, MiaPaca2, Capan2, and ASPC-1). Expression of 5-LOX and 12-LOX mRNA was measured by nested RT-PCR. Effects of LOX inhibitors and specific LOX antisense oligonucleotides on pancreatic cancer cell proliferation were measured by (3)H-thymidine incorporation. Our results showed that (1) 5-LOX and 12-LOX were expressed in all pancreatic cancer cell lines tested, while they were not detectable in normal human pancreatic ductal cells; (2) both LOX inhibitors and LOX antisense markedly inhibited cell proliferation in a concentration-dependent and time-dependent manner; (3) the 5-LOX and 12-LOX metabolites 5-HETE and 12-HETE as well as arachidonic and linoleic acids directly stimulated pancreatic cancer cell proliferation; (4) LOX inhibitor-induced growth inhibition was reversed by 5-HETE and 12-HETE. The current studies indicate that both 5-LOX and 12-LOX expression is upregulated in human pancreatic cancer cells and LOX plays a critical role in pancreatic cancer cell proliferation. LOX inhibitors may be valuable for the treatment of pancreatic cancer

Bisphosphonates in multiple myeloma.

Djulbegovic B, Wheatley K, Ross J, et al.

Cochrane Database Syst Rev. 2001;(4):CD003188.

BACKGROUND: Multiple myeloma is a disease characterized by the neoplastic proliferation of a clone of plasma cells that can lead to bone destruction. Bisphosphonates are specific inhibitors of osteoclastic activity. Therefore, there is a pharmacological basis for their use in multiple myeloma. However, the exact clinical role of bisphosphonates in multiple myeloma remains unclear. OBJECTIVES: Primary: to determine whether adding bisphosphonates to standard therapy in multiple myeloma decreases skeletal-related morbidity (pathological fractures), skeletal-related mortality and overall mortality. Secondary: to determine the effects of bisphosphonates on pain, quality of life and incidence of hypercalcemia. SEARCH STRATEGY: We searched MEDLINE (1

L-arginine inhibits apoptosis via a NO-dependent mechanism in Nb2 lymphoma cells.

Dodd F, Limoges M, Boudreau RT, et al.

J Cell Biochem. 2000 Apr; 77(4):624-34.

Prolactin (PRL) inhibits apoptosis and stimulates proliferation of the PRL-dependent rat Nb2 lymphoma cell line by divergent signaling pathways. Nitric oxide (NO) was recently identified as a downstream regulator of PRL action, and as an inhibitor of apoptosis in immune cells. In the present study, the role of NO in PRL-regulated Nb2 cell function was investigated. Nb2 cells expressed the endothelial nitric oxide synthase (eNOS) isoform, whereas neuronal NOS (nNOS) and inducible NOS (iNOS) mRNAs were undetectable. The eNOS mRNA was abundantly expressed in PRL-deprived, growth-arrested cells but decreased by at least 3-fold at 3-24 h following PRL treatment. Downregulation of eNOS was not accompanied by a corresponding decrease in the eNOS protein, the level of which remained constant for at least 24 h after PRL treatment. PRL had no effect on the phosphorylation state or subcellular redistribution of the eNOS enzyme, or on production of NO by Nb2 cells. However, increasing concentrations of L-arginine (NOS substrate) alone increased NO production in these cells and significantly enhanced PRL-stimulated cell proliferation. NO releasers (SNAP, DEA/NO, SIN-1) also significantly enhanced Nb2 cell proliferation in the presence of a submaximal dose of PRL (0.125 ng/ml). In the absence of PRL, the NO releasers alone promoted cell survival and maintained a viable cell density significantly higher than that of untreated PRL-deprived cells. L-arginine or the NO releaser DEA/NO alone significantly inhibited apoptosis in Nb2 cells deprived of PRL for 5 days. Expression of the anti-apoptotic gene bcl-2, which was stimulated within 1 h by PRL, was upregulated by L-arginine or DEA/NO alone at 2 h and 8 h, respectively. These findings suggest that NO produced by eNOS inhibits apoptosis and promotes the survival of growth-arrested Nb2 lymphoma cells via a prolactin-independent, Bcl-2-mediated pathway

Goitrogenic and estrogenic activity of soy isoflavones.

Doerge DR, Sheehan DM.

Environ Health Perspect. 2002 Jun; 110 Suppl 3:349-53.

Soy is known to produce estrogenic isoflavones. Here, we briefly review the evidence for binding of isoflavones to the estrogen receptor, in vivo estrogenicity and developmental toxicity, and estrogen developmental carcinogenesis in rats. Genistein, the major soy isoflavone, also has a frank estrogenic effect in women. We then focus on evidence from animal and human studies suggesting a link between soy consumption and goiter, an activity independent of estrogenicity. Iodine deficiency greatly increases soy antithyroid effects, whereas iodine supplementation is protective. Thus, soy effects on the thyroid involve the critical relationship between iodine status and thyroid function. In rats consuming genistein-fortified diets, genistein was measured in the thyroid at levels that produced dose-dependent and significant inactivation of rat and human thyroid peroxidase (TPO) in vitro. Furthermore, rat TPO activity was dose-dependently reduced by up to 80%. Although these effects are clear and reproducible, other measures of thyroid function in vivo (serum levels of triiodothyronine, thyroxine, and thyroid-stimulating hormone; thyroid weight; and thyroid histopathology) were all normal. Additional factors appear necessary for soy to cause overt thyroid toxicity. These clearly include iodine deficiency but may also include additional soy components, other defects of hormone synthesis, or additional goitrogenic dietary factors. Although safety testing of natural products, including soy products, is not required, the possibility that widely consumed soy products may cause harm in the human population via either or both estrogenic and goitrogenic activities is of concern. Rigorous, high-quality experimental and human research into soy toxicity is the best way to address these concerns. Similar studies in wildlife populations are also appropriate

Therapeutic potential of curcumin in human prostate cancer. III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo.

Dorai T, Cao YC, Dorai B, et al.

Prostate. 2001 Jun 1; 47(4):293-303.

BACKGROUND: Earlier work from our laboratory highlighted the therapeutic potential of curcumin (turmeric), used as a dietary ingredient and as a natural anti-inflammatory agent in India and other Southeast Asian countries. This agent was shown to decrease the proliferative potential and induce the apoptosis potential of both androgen-dependent and androgen-independent prostate cancer cells in vitro, largely by modulating the apoptosis suppressor proteins and by interfering with the growth factor receptor signaling pathways as exemplified by the EGF-receptor. To extend these observations made in vitro and to study the efficacy of this potential anti-cancer agent in vivo, the growth of LNCaP cells as heterotopically implanted tumors in nude mice was followed. METHODS: The androgen-dependent LNCaP prostate cancer cells were grown, mixed with Matrigel and injected subcutaneously into nude mice. Experimental group received a synthetic diet containing 2% curcumin for up to 6 weeks. At the end point, sections taken from the excised tumors were evaluated for pathology, cell proliferation, apoptosis, and vascularity. RESULTS: Curcumin causes a marked decrease in the extent of cell proliferation as measured by the BrdU incorporation assay and a significant increase in the extent of apoptosis as measured by an in situ cell death assay. Moreover, a significant decrease in the microvessel density as measured by the CD31 antigen staining was also seen. CONCLUSIONS: Curcumin could be a potentially therapeutic anti-cancer agent, as it significantly inhibits prostate cancer growth, as exemplified by LNCaP in vivo, and has the potential to prevent the progression of this cancer to its hormone refractory state

Combined effect of lipoic acid and doxorubicin in murine leukemia.

Dovinova I, Novotny L, Rauko P, et al.

Neoplasma. 1999; 46(4):237-41.

Our experiments indicate that administration of a toxic drug with high rate of free-radical formation (doxorubicin, DOX) combined with an antioxidant (alpha-lipoic acid, LA) may lead to a decrease in drug-toxicity. However, the effects of antioxidant may be concentration-dependent and it is therefore crucial to choose its appropriate dosage. LA at a low concentration (1 micromol/l) acts as a growth factor and at a higher concentration (100 micromol/l) acts as an antiproliferation agent. Both concentrations of LA in combination with DOX were examined in cytotoxic and antitumor effects in L1210 mouse leukemia cells employing a MTT chemosensitivity assay. In most concentration combinations, DOX and LA effect were antagonistic and synergistic action was only found at the higher concentration of both agents (DOX 2.5 micromol/l and LA 100 micromol/l). Use of LA in doxorubicin therapy lead to an increase (though marginally significant) in survival of animals. Combined single-dose administration of DOX (5 mg/kg) and LA (16 mg/kg) lead to super-additive effect of the combination on survival of leukemic mice

A 2-week pretreatment with 13-cis-retinoic acid + interferon-alpha-2a prior to definitive radiation improves tumor tissue oxygenation in cervical cancers.

Dunst J, Hansgen G, Krause U, et al.

Strahlenther Onkol. 1998 Nov; 174(11):571-4.

BACKGROUND: We have evaluated the tumor tissue pO2 in cervical cancers in patients treated with 13-cis-retinoic acid and interferon-alpha-2a prior to and during radiotherapy. PATIENTS AND METHODS: From June 1995 through April 1997, 22 patients with squamous cell carcinoma FIGO IIB/III of the cervix who were scheduled for definitive radiotherapy with curative intent received additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) plus interferon-alpha-2a (IFN-alpha-2a) as part of a phase-II protocol. cRA/IFN-alpha-2a started 14 days prior to radiotherapy (1 mg per kilogramme body weight cRA orally daily plus 6 x 10(6) IU IFN-alpha-2a subcutaneously daily). After this induction period, standard radiotherapy was administered (external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus HDR-brachytherapy). During radiotherapy, cRA/IFN-alpha-2a treatment was continued with 50% of the daily doses. Tumor tissue pO2-measurements were performed prior to and after the cRA/IFN-induction period as well as at 20 Gy and at the end of radiotherapy with an Eppendorf-pO2-histograph. RESULTS: In 11 out of the 22 patients, pO2-measurements were performed prior to the cRA/IFN-induction therapy. The median pO2 of these untreated tumors was 17.7 +/- 16.3 mm Hg. The relative frequency of hypoxic readings with pO2-values below 5 mm Hg ranged from 0% to 60.6% (mean 24.3 +/- 21.0%). After the 2-week induction period with cRA/IFN, the median pO2 had increased from 17.7 +/- 16.3 mm Hg to 27.6 +/- 19.1 mm Hg (not significant). In all 5 patients with hypoxic tumors prior to cRA/IFN (median pO2 of 10 mm Hg or less), the median pO2 was above 20 mm Hg after the 2-week cRA/IFN-induction. In this subgroup of hypoxic tumors, the median pO2 increased from 6.3 +/- 2.7 mm Hg to 27.0 +/- 5.6 mm Hg (p = 0.004, t-test for paired samples). The frequency of hypoxic readings (pO2-values < 5 mm Hg) decreased from 44.7 +/- 17.1% to 2.0 +/- 2.5% (p = "0.012," t-test for paired samples). There was, however, no obvious volume reduction after 14 weeks of cRA/IFN on clinical examination. A complete clinical remission of the local tumor was observed in 19/22 patients after radiotherapy and additional cRA/IFN-alpha-2a-treatment. In primarily hypoxic tumors (with a median pO2 below 10 mm Hg prior to treatment), 4/5 achieved complete remission. CONCLUSIONS: Pretreatment with cRA/IFN improves oxygenation of primarily hypoxic cervical cancers. The mechanisms of action remain unclear and further investigation of the combination regimen is recommended

Oxygenation of cervical cancers during radiotherapy and radiotherapy + cis-retinoic acid/interferon.

Dunst J, Hansgen G, Lautenschlager C, et al.

Int J Radiat Oncol Biol Phys. 1999 Jan 15; 43(2):367-73.

PURPOSE: We have evaluated the tumor tissue pO2 in cervical cancers during radiotherapy with special emphasis on the course of the pO2 in primarily hypoxic tumors and in patients treated with radiotherapy plus 13-cis-retinoic acid/interferon-alpha-2a. METHODS AND MATERIALS: From June 1995 through April 1997, 49 patients with squamous cell carcinoma FIGO IIB-IVA of the cervix who were treated with definitive radiotherapy with curative intent underwent polarographic measurement of tumor tissue pO2 with an Eppendorf pO2-histograph prior to and during radiation treatment. Radiotherapy consisted of external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus high dose rate (HDR) brachytherapy. Twenty-two patients had additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) and interferon-alpha-2a (IFN-alpha-2a). Therapy with cRA/IFN in these patients started 2 weeks before radiotherapy; during this induction period, cRA was administered in a dosage of 1 mg per kilogram body weight orally daily and IFN-alpha-2a in a dosage of 6x10(6) I.U. subcutaneously daily. After start of external radiotherapy (XRT), cRA/IFN was continued concomitantly with radiotherapy in reduced doses (0.5 mg cRA per kg body weight orally daily plus 3x10(6) I.U. IFN-alpha-2a subcutaneously three times weekly until the end of the radiation treatment). PO2 measurements were performed prior to radiotherapy, at 20 Gy, and at the end of radiotherapy. RESULTS: A poor oxygenation defined as a median pO2 of 10 mm Hg or less was present in 15/38 tumors (39%) in which measurements prior to any treatment were done. Low pO2 readings below 5 mm Hg were present in 70% of all tumors prior to treatment. In 13 of 15 hypoxic tumors, pO2 measurements at 19.8 Gy were performed. In these tumors, a significant increase of the median pO2 from 6.0+/-3.1 mm Hg to 20.7+/-21.2 mm Hg was found, p10 mm Hg), 20/23 (87%) achieved a clinically complete response. In patients with primarily hypoxic tumors, 6/6 patients whose primarily hypoxic tumors showed an increase of the median pO2 above 10 mm Hg at 19.8 Gy achieved a complete remission (CR). In contrast, only 4/7 patients with a low pretreatment and persisting low median pO2 achieved a CR. CONCLUSIONS: There are evident changes in the oxygenation of cervical cancers during a course of fractionated radiotherapy. In primarily hypoxic tumors, a significant increase of the median pO2 was found. An additional treatment with cis-retinoic acid/interferon further improved the oxygenation. An impact of the different patterns of oxygenation on local control is to be evaluated

Oxygenation of cervical cancers during radiotherapy and radiotherapy + cis-retinoic acid/interferon.

Dunst J, Hansgen G, Lautenschlager C, et al.

Int J Radiat Oncol Biol Phys. 1999 Jan 15; 43(2):367-73.

PURPOSE: We have evaluated the tumor tissue pO2 in cervical cancers during radiotherapy with special emphasis on the course of the pO2 in primarily hypoxic tumors and in patients treated with radiotherapy plus 13-cis-retinoic acid/interferon-alpha-2a. METHODS AND MATERIALS: From June 1995 through April 1997, 49 patients with squamous cell carcinoma FIGO IIB-IVA of the cervix who were treated with definitive radiotherapy with curative intent underwent polarographic measurement of tumor tissue pO2 with an Eppendorf pO2-histograph prior to and during radiation treatment. Radiotherapy consisted of external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus high dose rate (HDR) brachytherapy. Twenty-two patients had additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) and interferon-alpha-2a (IFN-alpha-2a). Therapy with cRA/IFN in these patients started 2 weeks before radiotherapy; during this induction period, cRA was administered in a dosage of 1 mg per kilogram body weight orally daily and IFN-alpha-2a in a dosage of 6x10(6) I.U. subcutaneously daily. After start of external radiotherapy (XRT), cRA/IFN was continued concomitantly with radiotherapy in reduced doses (0.5 mg cRA per kg body weight orally daily plus 3x10(6) I.U. IFN-alpha-2a subcutaneously three times weekly until the end of the radiation treatment). PO2 measurements were performed prior to radiotherapy, at 20 Gy, and at the end of radiotherapy. RESULTS: A poor oxygenation defined as a median pO2 of 10 mm Hg or less was present in 15/38 tumors (39%) in which measurements prior to any treatment were done. Low pO2 readings below 5 mm Hg were present in 70% of all tumors prior to treatment. In 13 of 15 hypoxic tumors, pO2 measurements at 19.8 Gy were performed. In these tumors, a significant increase of the median pO2 from 6.0+/-3.1 mm Hg to 20.7+/-21.2 mm Hg was found, p10 mm Hg), 20/23 (87%) achieved a clinically complete response. In patients with primarily hypoxic tumors, 6/6 patients whose primarily hypoxic tumors showed an increase of the median pO2 above 10 mm Hg at 19.8 Gy achieved a complete remission (CR). In contrast, only 4/7 patients with a low pretreatment and persisting low median pO2 achieved a CR. CONCLUSIONS: There are evident changes in the oxygenation of cervical cancers during a course of fractionated radiotherapy. In primarily hypoxic tumors, a significant increase of the median pO2 was found. An additional treatment with cis-retinoic acid/interferon further improved the oxygenation. An impact of the different patterns of oxygenation on local control is to be evaluated

The inhibitory effect of curcumin, genistein, quercetin and cisplatin on the growth of oral cancer cells in vitro.

Elattar TM, Virji AS.

Anticancer Res. 2000 May; 20(3A):1733-8.

Epidemiological evidence indicates that plant derived flavonoids and other phenolic antioxidants protect against heart disease and cancer. In the current investigation utilizing human oral squamous carcinoma cell line (SCC-25), we have evaluated the potency of three different plant phenolics, viz., curcumin, genistein and quercetin in comparison with that of cisplatin on growth and proliferation of SCC-25. Test agents were dissolved in DMSO and incubated in triplicates in 25 cm2 flasks in DMEM- HAM's F-12 (50:50)supplemented with 10% calf serum and antibiotics in an atmosphere 5% CO2 in air for 72 hours cell growth was determined by counting the number of cells in a hemocytometer. Cell proliferation was determined by measuring DNA synthesis by the incorporation of [3H]-thymidine in nuclear DNA. Cisplatin (0.1, 1.0, 10.0 microM) and curcumin (0.1, 1.0, 10.0 microM) induced significant dose-dependent inhibition in both cell growth as well as cell proliferation. Genistein and quercetin (1.0, 10.0, 100.0 microM) had biphasic effect, depending on their concentrations, on cell growth as well as cell proliferation. Based on these findings, it is concluded that curcumin is considerably more potent than genistein and quercetin, but cisplatin is five fold more potent than curcumin in inhibition of growth and DNA synthesis in SCC-25

Activation of c-Neu tyrosine kinase by o,p'-DDT and beta-HCH in cell-free and intact cell preparations from MCF-7 human breast cancer cells.

Enan E, Matsumura F.

J Biochem Mol Toxicol. 1998; 12(2):83-92.

It has been suggested that there is a positive correlation between increased incidence of breast cancer and the presence of organochlorine residues such as DDT and HCH in breast tissues in the United States. To study possible biochemical links between these two parameters, we have examined the effect of o,p'-DDT, the most estrogenic congener of the DDT family of chemicals and beta-HCH on protein phosphorylation activities in MCF-7, a line derived from human breast cancer cells. Both of these organochlorine chemicals were found to be potent activators of protein kinases. Among kinases activated, protein tyrosine kinases (PTK) appear to be most affected as judged by the antagonistic action of genistein, a class-specific PTK inhibitor. Moreover, these organochlorines were found to activate PTK even under cell-free conditions, indicating that they are likely to interact directly with the target protein tyrosine kinase. As a result of immunoprecipitation with specific antibodies, and testing on the action of these organochlorines, we could show that the major kinase activated by o,p'-DDT is c-Neu (= c-erbB2 product protein). The concentrations of these organochlorines required to activate c-Neu were extremely low (0.1-1 nM range), whereas an inactive analog p,p'-DDT showed no stimulatory property even at 100 nM. Such an action of these organochlorine compounds were not antagonized by the presence of 1 microM tamoxifen, indicating that it is not mediated through the estrogen receptor. In addition, their c-Neu activating actions were specifically antagonized by a c-Neu antibody known to interact with the extracellular domain of c-Neu only without affecting the EGF receptor. Moreover, these chemicals did not cause downregulation of the EGF receptor during the 72 hour test period. Together these data indicate that the action of these chemicals on c-Neu kinase is very specific

Ubiquinol: an endogenous antioxidant in aerobic organisms.

Ernster L, Forsmark-Andree P.

Clin Investig. 1993; 71(8 Suppl):S60-S65.

Ubiquinone (coenzyme Q), in addition to its function as an electron and proton carrier in mitochondrial and bacterial electron transport linked to ATP synthesis, acts in its reduced form (ubiquinol) as an antioxidant, preventing the initiation and/or propagation of lipid peroxidation in biological membranes and in serum low-density lipoprotein. The antioxidant activity of ubiquinol is independent of the effect of vitamin E, which acts as a chain-breaking antioxidant inhibiting the propagation of lipid peroxidation. In addition, ubiquinol can efficiently sustain the effect of vitamin E by regenerating the vitamin from the tocopheroxyl radical, which otherwise must rely on water-soluble agents such as ascorbate (vitamin C). Ubiquinol is the only known lipid-soluble antioxidant that animal cells can synthesize de novo, and for which there exist enzymic mechanisms that can regenerate the antioxidant from its oxidized form resulting from its inhibitory effect of lipid peroxidation. These features, together with its high degree of hydrophobicity and its widespread occurrence in biological membranes and in low-density lipoprotein, suggest an important role of ubiquinol in cellular defense against oxidative damage. Degenerative diseases and aging may be manifestations of a decreased capacity to maintain adequate ubiquinol levels

Treatment of 32 cervico-uterine cancer patients with 13-cis-retinoic acid and interferon alpha.

Espinoza P.

Rev Invest Clin. 1994; 46(2):105-11.

Therapeutic potential of glutathione.

Exner R, Wessner B, Manhart N, et al.

Wien Klin Wochenschr. 2000 Jul 28; 112(14):610-6.

Reactive oxygen species, formed in various biochemical reactions, are normally scavenged by antioxidants. Glutathione in its reduced form (GSH) is the most powerful intracellular antioxidant, and the ratio of reduced to oxidised glutathione (GSH:GSSG) serves as a representative marker of the antioxidative capacity of the cell. Several clinical conditions are associated with reduced GSH levels which as a consequence can result in a lowered cellular redox potential. GSH and the redox potential of the cell are components of the cell signaling system influencing the translocation of the transcription factor NF kappa B which regulates the synthesis of cytokines and adhesion molecules. Therefore, one possibility to protect cells from damage caused by reactive oxygen species is to restore the intracellular glutathione levels. Cellular GSH concentration can be influenced by exogenous administration of GSH (as intravenous infusion or as aerosol), of glutathione esters or of GSH precursors such as glutamine or cysteine (in form of N-acetyl-L-cysteine, alpha-lipoic acid). The modulation of GSH metabolism might present a useful adjuvant therapy in many pathologies such as intoxication, diabetes, uremia, sepsis, inflammatory lung processes, coronary disease, cancer and immunodeficiency states

Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens.

Fahey JW, Zhang Y, Talalay P.

Proc Natl Acad Sci U S A. 1997 Sep 16; 94(19):10367-72.

Induction of phase 2 detoxication enzymes [e.g., glutathione transferases, epoxide hydrolase, NAD(P)H: quinone reductase, and glucuronosyltransferases] is a powerful strategy for achieving protection against carcinogenesis, mutagenesis, and other forms of toxicity of electrophiles and reactive forms of oxygen. Since consumption of large quantities of fruit and vegetables is associated with a striking reduction in the risk of developing a variety of malignancies, it is of interest that a number of edible plants contain substantial quantities of compounds that regulate mammalian enzymes of xenobiotic metabolism. Thus, edible plants belonging to the family Cruciferae and genus Brassica (e.g., broccoli and cauliflower) contain substantial quantities of isothiocyanates (mostly in the form of their glucosinolate precursors) some of which (e.g., sulforaphane or 4-methylsulfinylbutyl isothiocyanate) are very potent inducers of phase 2 enzymes. Unexpectedly, 3-day-old sprouts of cultivars of certain crucifers including broccoli and cauliflower contain 10-100 times higher levels of glucoraphanin (the glucosinolate of sulforaphane) than do the corresponding mature plants. Glucosinolates and isothiocyanates can be efficiently extracted from plants, without hydrolysis of glucosinolates by myrosinase, by homogenization in a mixture of equal volumes of dimethyl sulfoxide, dimethylformamide, and acetonitrile at -50 degrees C. Extracts of 3-day-old broccoli sprouts (containing either glucoraphanin or sulforaphane as the principal enzyme inducer) were highly effective in reducing the incidence, multiplicity, and rate of development of mammary tumors in dimethylbenz(a)anthracene-treated rats. Notably, sprouts of many broccoli cultivars contain negligible quantities of indole glucosinolates, which predominate in the mature vegetable and may give rise to degradation products (e.g., indole-3-carbinol) that can enhance tumorigenesis. Hence, small quantities of crucifer sprouts may protect against the risk of cancer as effectively as much larger quantities of mature vegetables of the same variety

Effect of eicosapentaenoic acid and other fatty acids on the growth in vitro of human pancreatic cancer cell lines.

Falconer JS, Ross JA, Fearon KC, et al.

Br J Cancer. 1994 May; 69(5):826-32.

A number of polyunsaturated fatty acids have been shown to inhibit the growth of malignant cells in vitro. To investigate whether fatty acids modify the growth of human pancreatic cancer, lauric, stearic, palmitic, oleic, linoleic, alpha-linolenic, gamma-linolenic, arachidonic, docosahexaenoic and eicosapentaenoic (EPA) acids were each incubated with the cells lines MIA PaCa-2, PANC-1 and CFPAC at concentrations ranging from 1.25 microM to 50 microM and the effect of each fatty acid on cell growth was examined. All the polyunsaturated fatty acids tested had an inhibitory effect, with EPA being the most potent (ID50 2.5-5 microM). Monounsaturated or saturated fatty acids were not inhibitory. The action of EPA could be reversed with the anti-oxidant vitamin E acetate or with oleic acid. The cyclo-oxygenase inhibitors indomethacin and piroxicam had no effect on the action of EPA. The action of EPA appeared to be associated with the generation of lipid peroxides, although the level of lipid peroxidation did not always appear to correlate directly with the extent of cell death. The ability of certain fatty acids to inhibit significantly the growth of three human pancreatic cancer cell lines in vitro at concentrations which could be achieved in vivo suggests that administration of such fatty acids may be of therapeutic benefit in patients with pancreatic cancer

Isoflavonoids inhibit catabolism of vitamin D in prostate cancer cells.

Farhan H, Wahala K, Adlercreutz H, et al.

J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Sep 25; 777(1-2):261-8.

The high ingestion of soybean products in Asian countries has been suggested to be responsible for a reduced incidence of prostate cancer. The mechanism of action, however, is unknown. Our data demonstrate that genistein and some isoflavone metabolites reduce the activity of 25-D3-24-hydroxylase (CYP24) in the human prostate cancer-derived cell line DU-145. CYP24 is also responsible for degradation of the active vitamin D metabolite 1,25-dihydroxyvitamin D3 which is known to be antimitotic and prodifferentiating in prostate cancer cells. High levels of CYP24 frequently found in prostate cancer cells may thus degrade the active metabolite. This could be prevented by ingestion of genistein-containing food such as soybeans

Effect of Gutamine on the Initiation and Promotion Phases of DMBA-Induced Mammary Tumor Development 1997.

Feng Z.

2004

Modulatory effects of selenium and zinc on the immune system.

Ferencik M, Ebringer L.

Folia Microbiol (Praha). 2003; 48(3):417-26.

Almost all nutrients in the diet play a crucial role in maintaining an "optimal" immune response, and both insufficient and excessive intakes can have negative consequences on the immune status and susceptibility to a variety of pathogens. We summarize the evidence for the importance of two micronutrients, selenium and zinc, and describe the mechanisms through which they affect the immune status and other physiological functions. As a constituent of selenoproteins, selenium is needed for the proper functioning of neutrophils, macrophages, NK cells, T lymphocytes and some other immune mechanisms. Elevated selenium intake may be associated with reduced cancer risk and may alleviate other pathological conditions including oxidative stress and inflammation. Selenium appears to be a key nutrient in counteracting the development of virulence and inhibiting HIV progression to AIDS. It is required for sperm motility and may reduce the risk of miscarriage. Selenium deficiency has been linked to adverse mood states and some findings suggest that selenium deficiency may be a risk factor in cardiovascular diseases. Zinc is required as a catalytic, structural and regulatory ion for enzymes, proteins and transcription factors, and is thus a key trace element in many homeostatic mechanisms of the body, including immune responses. Low zinc ion bioavailability results in limited immunoresistance to infection in aging. Physiological supplementation of zinc for 1-2 months restores immune responses, reduces the incidence of infections and prolongs survival. However, in every single individual zinc supplementation of food should be adjusted to the particular zinc status in views of the great variability in habitat conditions, health status and dietary requirements

Host circadian clock as a control point in tumor progression.

Filipski E, King VM, Li X, et al.

J Natl Cancer Inst. 2002 May 1; 94(9):690-7.

BACKGROUND: The circadian timing system controlled by the suprachiasmatic nuclei (SCN) of the hypothalamus regulates daily rhythms of motor activity and adrenocortical secretion. An alteration in these rhythms is associated with poor survival of patients with metastatic colorectal or breast cancer. We developed a mouse model to investigate the consequences of severe circadian dysfunction upon tumor growth. METHODS: The SCN of mice were destroyed by bilateral electrolytic lesions, and body activity and body temperature were recorded with a radio transmitter implanted into the peritoneal cavity. Plasma corticosterone levels and circulating lymphocyte counts were measured (n = 75 with SCN lesions, n = 64 sham-operated). Complete SCN destruction was ascertained postmortem. Mice were inoculated with implants of Glasgow osteosarcoma (n = 16 with SCN lesions, n = 12 sham-operated) or pancreatic adenocarcinoma (n = 13 with SCN lesions, n = 13 sham-operated) tumors to determine the effects of altered circadian rhythms on tumor progression. Time series for body temperature and rest-activity patterns were analyzed by spectral analysis and cosinor analysis. Parametric data were compared by the use of analysis of variance (ANOVA) and survival curves with the log-rank test. All statistical tests were two-sided. RESULTS: The 24-hour rest-activity cycle was ablated and the daily rhythms of serum corticosterone level and lymphocyte count were markedly altered in 75 mice with complete SCN destruction as compared with 64 sham-operated mice (two-way ANOVA for corticosterone: sampling time effect P<.001, lesion effect P =".001," and time x lesion interaction P<.001; for lymphocytes P =".001,.002," and.002 respectively). Body temperature rhythm was suppressed in 60 of the 75 mice with SCN lesions (P<.001). Both types of tumors grew two to three times faster in mice with SCN lesions than in sham-operated mice (two-way ANOVA: P<.001 for lesion and for tumor effects; P =".21" for lesion x tumor effect interaction). Survival of mice with SCN lesions was statistically significantly shorter compared with that of sham-operated mice (log-rank P =".0062)." CONCLUSIONS: Disruption of circadian rhythms in mice was associated with accelerated growth of malignant tumors of two types, suggesting that the host circadian clock may play an important role in endogenous control of tumor progression

Growth inhibition, cell-cycle arrest and apoptosis in human T-cell leukemia by the isothiocyanate sulforaphane.

Fimognari C, Nusse M, Cesari R, et al.

Carcinogenesis. 2002 Apr; 23(4):581-6.

Glucosinolates (GL) can inhibit, retard or reverse experimental multistage carcinogenesis. When brassica plant tissue is broken, GLs are hydrolyzed by the endogenous enzyme myrosinase (Myr), releasing many products including isothiocyanates (ITC). Synthetic ITCs like sulforaphane exert chemopreventive effects against chemically induced tumors in animals, modulating enzymes required for carcinogens' activation/detoxification and/or the induction of cell-cycle arrest and apoptosis in tumor cell lines. To investigate the chemopreventive potential of ITCs while reproducing the circumstances of dietary contact with sulforaphane, we studied proliferation, apoptosis induction and p53, bcl-2 and bax protein expression in Jurkat T-leukemia cells by sulforaphane, the ITC generated in situ in a quantitative manner by Myr starting from glucoraphanin (GRA). Jurkat cells were treated with different doses of GRA-Myr mixture. Effects on cell growth or survival were evaluated by counting trypan blue-excluding cells. Cell-cycle progression, apoptosis and expression of p53, bax and bcl-2 proteins were analyzed by flow cytometry. Results were analyzed by two-sided Fisher's exact test. Sulforaphane, but not GRA, caused G(2)/M-phase arrest (P = 0.028) and increase of apoptotic cell fraction (P < 0.0001) in a time- and dose-dependent manner. Necrosis was observed after prolonged exposure to elevated sulforaphane doses. Moreover, it markedly increased p53 and bax protein expression, and slightly affected bcl-2 expression. These findings indicate that sulforaphane but not the native GL GRA can exert both protective and toxic effects inhibiting leukemic cell growth. Sulforaphane therefore deserves study as a potential chemopreventive/chemotherapeutic antileukemic agent

Effect of histamine and the H2 antagonist cimetidine on the growth and migration of human neoplastic glia.

Finn PE, Purnell P, Pilkington GJ.

Neuropathol Appl Neurobiol. 1996 Aug; 22(4):317-24.

Histamine is known to act, at least in part, as a growth factor, as production of this neurotransmitter has been found to accelerate the rate of tissue proliferation in wound repair, embryogenesis and malignant growth. Histamine favours in vivo tumour cell proliferation via H2 receptors. Cimetidine is an H2 blocker and has been shown to inhibit tumour cell growth. In the present study, the growth modulating effects of histamine and cimetidine were assessed on five cell lines derived from human brain tumours of different histological types and grades of malignancy. Each cell line was treated with either cimetidine or histamine for 24 h before kinetic analyses, with PCNA, or motility assays, using Transwell migration chambers incorporating a microporous membrane, were carried out. Cimetidine significantly inhibited cell proliferation in three out of the five cell lines, which may indicate the dependence of proliferation of these cell lines on stimulation of the H2 receptor. With regard to migration, it was observed that in the majority of cell lines, cimetidine induced migration whilst histamine inhibited it. It was concluded that the link between effects of histamine on proliferation and its effects on migration must be clarified using a larger sample of cell lines

Milk thistle (Silybum marianum) for the therapy of liver disease.

Flora K, Hahn M, Rosen H, et al.

Am J Gastroenterol. 1998 Feb; 93(2):139-43.

Silymarin, derived from the milk thistle plant, Silybum marianum, has been used for centuries as a natural remedy for diseases of the liver and biliary tract. As interest in alternative therapy has emerged in the United States, gastroenterologists have encountered increasing numbers of patients taking silymarin with little understanding of its purported properties. Silymarin and its active constituent, silybin, have been reported to work as antioxidants scavenging free radicals and inhibiting lipid peroxidation. Studies also suggest that they protect against genomic injury, increase hepatocyte protein synthesis, decrease the activity of tumor promoters, stabilize mast cells, chelate iron, and slow calcium metabolism. In this article we review silymarin's history, pharmacology, and properties, and the clinical trials pertaining to patients with acute and chronic liver disease

Lovastatin decreases coenzyme Q levels in quantitative review of primary prevention trials.

Folkers K.

Br J Med. 1990; 301:309-14.

Coenzyme Q10 increases T4/T8 ratios of lymphocytes in ordinary subjects and relevance to patients having the AIDS related complex.

Folkers K, Hanioka T, Xia LJ, et al.

Biochem Biophys Res Commun. 1991 Apr 30; 176(2):786-91.

Coenzyme Q10 (CoQ10) is indispensable to biochemical mechanisms of bioenergetics, and it has a non-specific role as an antioxidant. CoQ10 has shown a hematological activity for the human and has shown an influence on the host defense system. The T4/T8 ratios of lymphocytes are known to be low in patients with AIDS, ARC and malignancies. Our two patients with ARC have survived four-five years without any symptoms of adenopathy or infection on continuous treatment with CoQ10. We have newly found that 14 ordinary subjects responded to CoQ10 by increases in the T4/T8 ratios and an increase in blood levels of CoQ10; both by p less than 0.001. This knowledge and survival of two ARC patients for four-five years on CoQ10 without symptoms, and new data on increasing ratios of T4/T8 lymphocytes in the human by treatment with CoQ10 constitute a rationale for new double blind clinical trials on treating patients with AIDS, ARC and diverse malignancies with CoQ10

Survival of cancer patients on therapy with coenzyme Q10.

Folkers K, Brown R, Judy WV, et al.

Biochem Biophys Res Commun. 1993 Apr 15; 192(1):241-5.

Over ca. 25 years, assays in animal models established the hematopoietic activities of coenzyme Q's in rhesus monkeys, rabbits, poultry, and children having kwashiorkor. Surprisingly, a virus was found to cause a deficiency of CoQ9. Patients with AIDS showed a-"striking"-clinical response to therapy with CoQ10. The macrophage potentiating activity of CoQ10 was recorded by the carbon clearance method. CoQ10 significantly increased the levels of IgG in patients. Eight new case histories of cancer patients plus two reported cases support the statement that therapy of cancer patients with CoQ10, which has no significant side effect, has allowed survival on an exploratory basis for periods of 5-15 years. These results now justify systematic protocols

Activities of vitamin Q10 in animal models and a serious deficiency in patients with cancer.

Folkers K, Osterborg A, Nylander M, et al.

Biochem Biophys Res Commun. 1997 May 19; 234(2):296-9.

New data on blood levels of vitamin Q10 in 116 cancer patients reveal an incidence of 23.1% of patients (N=17) with breast cancer whose blood levels were below 0.5 microg/ml. The incidence of breast cancer cases with levels below 0.6 microg/ml was 38.5%. The incidence is higher (p<0.05) than that for a group of ordinary people. Patients (N="15)" with myeloma showed a mean blood level of 0.67 +/- 0.17 microg/ml. The incidence of a vitamin Q10 blood level below 0.7 microg/ml for these 15 cases of myeloma was 53.3%, which is higher (p<0.05) than the 24.5% found for a group of ordinary people

Dietary genistein down-regulates androgen and estrogen receptor expression in the rat prostate.

Fritz WA, Wang J, Eltoum IE, et al.

Mol Cell Endocrinol. 2002 Jan 15; 186(1):89-99.

The incidence of clinically manifested prostate cancer is higher in the United States and Europe than in Asian countries. One of the major differences in lifestyle between these populations is the diet, with Asians consuming a greater amount of soy. Soy and genistein, the predominant isoflavone found in soy, inhibit prostate tumor development in animal models. The purpose of this study was to investigate the effect of dietary genistein on sex steroid receptor expression in the dorsolateral prostate, on circulating androgens, and the potential for toxicity in the male rat reproductive tract. Male Sprague-Dawley rats were fed 25 and 250 mg genistein/kg diet from conception until day 70 postpartum, or 250 and 1000 mg genistein/kg diet from day 56 to 70 postpartum. Exposure to genistein in the diet, starting at conception, resulted in down-regulated androgen receptor (AR), and estrogen receptors (ER)-alpha and -beta mRNA expression in the dorsolateral prostate in a dose-dependent manner. Also, genistein fed to adult rats for 2 weeks reduced mRNA expression of AR, ER-alpha and ER-beta in the dorsolateral prostate. ER-alpha protein levels were significantly reduced in animals fed 1000 mg genistein/kg diet compared to control animals. There were no significant alterations to male reproductive tract histomorphology or weights. We conclude that dietary genistein down-regulated expression of the AR and ER-alpha and -beta in the rat prostate at concentrations comparable to those found in humans on a soy diet. Down-regulated sex steroid receptor expression may be responsible for the lower incidence of prostate cancer in populations on a diet containing high levels of phytoestrogens

Bisphosphonates induce breast cancer cell death in vitro.

Fromigue O, Lagneaux L, Body JJ.

J Bone Miner Res. 2000 Nov; 15(11):2211-21.

Breast cancer frequently spreads to bone and is almost always associated with osteolysis. This tumor-induced osteolysis is caused by increased osteoclastic bone resorption. Bisphosphonates are used successfully to inhibit bone resorption in tumor bone disease and may prevent development of new osteolytic lesions. The classical view is that bisphosphonates only act on bone cells. We investigated their effects on breast cancer cells using three human cell lines, namely, MCF-7, T47D, and MDA.MB.231, and we tested four structurally different bisphosphonates: clodronate, pamidronate, ibandronate, and zoledronate. We performed time course studies for each bisphosphonate at various concentrations and found that all four compounds induced a nonreversible growth inhibition in both MCF-7 and T47D cell lines in a time- and dose-dependent manner. The MDA.MB.231 cell line was less responsive. Bisphosphonates induced apoptosis in MCF-7 and cell necrosis in T47D cells. The inhibition of MCF-7 cell proliferation could be reverted almost completely by the benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone (z-VAD-fmk) inhibitor of caspases, suggesting that the apoptotic process observed in the MCF-7 cell line is mediated, at least partly, by the caspase system. Caspase activity was little changed by bisphosphonates in T47D cells and the inhibitor of caspase did not modify bisphosphonates effects. In summary, we found that bisphosphonates inhibit breast cancer cell growth by inducing cell death in vitro. Such effects could contribute to the beneficial role of bisphosphonates in the treatment and the prevention of tumor-induced osteolysis

Lung cancer prevention with (-)-epigallocatechin gallate using monitoring by heterogeneous nuclear ribonucleoprotein B1.

Fujimoto N, Sueoka N, Sueoka E, et al.

Int J Oncol. 2002 Jun; 20(6):1233-9.

Considering the problems involved in prevention of human lung cancer, growth inhibition of human lung cancer cell line A549 was studied with emphasis on two parameters: green tea polyphenols, such as (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG); and heterogeneous nuclear ribonucleoprotein B1 (hnRNP B1), a new biomarker of human lung cancer which is highly expressed in the very early stages of human lung cancer. The inhibitory potencies of green tea polyphenols were compared with those of genistein as a control. EGCG or ECG and genistein as a control dose-dependently inhibited the growth of A549 cells, which strongly elevated hnRNP B1 protein, and increased G2/M phase cells associated with induction of apoptotic cells. The results were confirmed by previous evidence with human lung cancer cell line PC-9. Some larger differences in mechanisms of action between green tea polyphenols and genistein were presented. Treatment of A549 cells with EGCG, ECG or genistein significantly inhibited the expression levels of hnRNP B1 mRNA and the elevated levels of hnRNP B1 protein, both of which are constitutively elevated in cancer cells. Furthermore, both EGCG and genistein inhibited the promoter activity of hnRNP A2/B1 gene expression, with IC50 values 29 microM for EGCG and 66 microM for genistein, suggesting the interaction of EGCG or genistein with the transcriptional complex. Looking at our results here, and those of previously reported epidemiological studies with green tea, we discuss the steadily accumulating evidence that clinical trials with green tea extract would be an efficient means of lung cancer prevention

Inhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells.

Fukuda K, Hibiya Y, Mutoh M, et al.

J Ethnopharmacol. 1999 Aug; 66(2):227-33.

The enzyme cyclooxygenase-2 (COX-2) is abundantly expressed in colon cancer cells and plays a key role in colon tumorigenesis. Compounds inhibiting COX-2 transcriptional activity have therefore potentially a chemopreventive property against colon tumor formation. An assay method for estimating COX-2 transcriptional activity in human colon cancer cells was established using a beta-galactosidase reporter gene system, and examination was made of various medicinal herbs and their ingredients for an inhibitory effect on COX-2 transcriptional activity. We found that berberine, an isoquinoline alkaloid present in plants of the genera Berberis and Coptis, effectively inhibits COX-2 transcriptional activity in colon cancer cells in a dose- and time-dependent manner at concentrations higher than 0.3 microM. The present findings may further explain the mechanism of anti-inflammatory and anti-tumor promoting effects of berberine

Detoxification.

Galland L.

Presented at Comprehensive Cancer Care 2000, Arlington, VA, June 7-11, 2000. 2000;June 7-11, 2000

Immunomodulatory activity of resveratrol: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production.

Gao X, Xu YX, Janakiraman N, et al.

Biochem Pharmacol. 2001 Nov 1; 62(9):1299-308.

trans-Resveratrol, a phytoalexin found in grapes, wine, and other plant products, has been shown to have anti-inflammatory, antioxidant, and antitumor activities. Many of these beneficial effects of resveratrol require participation of the cells of the immune system; however, the effect of resveratrol on the development of immunological responses remains unknown. We have investigated the effect of resveratrol on mitogen/antigen-induced proliferation of splenic lymphocytes, induction of cytotoxic T lymphocytes (CTLs) and lymphokine activated killer (LAK) cells, and the production of the cytokines interferon (IFN)-gamma, interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, and IL-12. We found that mitogen-, IL-2-, or alloantigen-induced proliferation of splenic lymphocytes and the development of antigen-specific CTLs were suppressed significantly at 25-50 microM resveratrol. The generation of LAK cells at similar concentrations was less sensitive to the suppressive effect of resveratrol. The suppression of cell proliferation and CTL generation by resveratrol was not only reversible, but in some cases the response (mitogen/IL-2-induced proliferation and CTL generation) was actually enhanced following pretreatment of cells with resveratrol. Resveratrol also inhibited the production of IFN-gamma and IL-2 by splenic lymphocytes, and the production of TNF-alpha and IL-12 by peritoneal macrophages. The inhibition of cytokine production by resveratrol was irreversible. Further, resveratrol blocked the activation of the transcription factor NF-kappaB without affecting basal NF-kappaB activity. The latter result suggests that resveratrol inhibits cell proliferation, cell-mediated cytotoxicity, and cytokine production, at least in part through the inhibition of NF-kappaB activation

Genistein inhibits the growth of human-patient BPH and prostate cancer in histoculture.

Geller J, Sionit L, Partido C, et al.

Prostate. 1998 Feb 1; 34(2):75-9.

BACKGROUND: There is strong epidemiological evidence that prostate disease is significantly less prevalent in the Orient, where the intake of soy products is very high, than in the United States. We therefore undertook a study of the effects of genistein, a major component of soy, on growth of human-patient benign prostatic hypertrophy (BPH) and prostate cancer tissue in three-dimensional collagen gel-supported histoculture. METHODS: Surgical specimens of human BPH and cancer were histocultured for 5 days to study the effects of genistein on growth, as measured by inhibition of 3H-thymidine incorporation per microgram protein on day 5. RESULTS: Genistein in doses of 1.25-10 micrograms/ml decreased the growth of BPH tissue in histoculture in a dose-dependent manner, with little additional effect at higher doses. Prostate cancer tissue in histoculture was similarly inhibited by these doses of genistein. CONCLUSIONS: Genistein decreases the growth of both BPH and prostate cancer tissue in histoculture. The data suggest that genistein has potential as a therapeutic agent for BPH and prostate cancer

Enhancement of human natural killer cell activity by modified arabinoxylan from rice brain (MGN-3).

Ghoneum M.

Int J Immunother. 1998; 14(2):89-99.

Synergistic Effect of Modified Arabinoxylan (MGN-3) and Low Dose of Recombinant IL-2 on Human NK cell Activity and TNF-A Production 1998 Aug. East Rutherford, NJ: American Academy of Anti-Aging Medicine; (Abstract) see also - Production of tumor necrosis factor-alpha and interferon-gamma from human peripheral blood lymphocytes by MGN-3, a modified arabinoxylan from rice bran, and its synergy with interleukin-2 in vitro.

Ghoneum M, Jewett A.

Cancer Detect Prev. 1998; 24(4):314-24.

Effect of MGN-3 on human natural killer cell activity and interferon-? synthesis in vitro.

Ghoneum M.

FASEB. 1996; 10(6):26-32.

Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells.

Ghosh J, Myers CE.

Proc Natl Acad Sci U S A. 1998 Oct 27; 95(22):13182-7.

Diets high in fat are associated with an increased risk of prostate cancer, although the molecular mechanism is still unknown. We have previously reported that arachidonic acid, an omega-6 fatty acid common in the Western diet, stimulates proliferation of prostate cancer cells through production of the 5-lipoxygenase metabolite, 5-HETE (5-hydroxyeicosatetraenoic acid). We now show that 5-HETE is also a potent survival factor for human prostate cancer cells. These cells constitutively produce 5-HETE in serum-free medium with no added stimulus. Exogenous arachidonate markedly increases the production of 5-HETE. Inhibition of 5-lipoxygenase by MK886 completely blocks 5-HETE production and induces massive apoptosis in both hormone-responsive (LNCaP) and -nonresponsive (PC3) human prostate cancer cells. This cell death is very rapid: cells treated with MK886 showed mitochondrial permeability transition between 30 and 60 min, externalization of phosphatidylserine within 2 hr, and degradation of DNA to nucleosomal subunits beginning within 2-4 hr posttreatment. Cell death was effectively blocked by the thiol antioxidant, N-acetyl-L-cysteine, but not by androgen, a powerful survival factor for prostate cancer cells. Apoptosis was specific for 5-lipoxygenase-programmed cell death was not observed with inhibitors of 12-lipoxygenase, cyclooxygenase, or cytochrome P450 pathways of arachidonic acid metabolism. Exogenous 5-HETE protects these cells from apoptosis induced by 5-lipoxygenase inhibitors, confirming a critical role of 5-lipoxygenase activity in the survival of these cells. These findings provide a possible molecular mechanism by which dietary fat may influence the progression of prostate cancer

Vitamin C mediated protection on cisplatin induced mutagenicity in mice.

Giri A, Khynriam D, Prasad SB.

Mutat Res. 1998 Nov 3; 421(2):139-48.

In present studies the development of chromosomal aberrations, micronuclei in bone marrow cells and sperm head abnormalities were used as mutagenic bioassay in Swiss albino mice treated with cisplatin alone or ascorbic plus cisplatin. It was noted that in the combined treated hosts the frequency of all the mutagenic parameters were always significantly less than that treated with cisplatin alone. These findings suggest a protective role of ascorbic acid against cisplatin induced mutagenic potentials. Interestingly, in combined treated hosts glutathione (GSH) level in bone marrow cells increased significantly which may suggest a possible mechanism of ascorbic acid mediated protection against cisplatin induced mutagenic potentials in the hosts

Effects of Thomsen-Friedenreich antigen-specific peptide P-30 on beta-galactoside-mediated homotypic aggregation and adhesion to the endothelium of MDA-MB-435 human breast carcinoma cells.

Glinsky VV, Huflejt ME, Glinsky GV, et al.

Cancer Res. 2000 May 15; 60(10):2584-8.

Both the ability of malignant cells to form multicellular aggregates via homotypic or heterotypic aggregation and their adhesion to the endothelium are important if not critical during early stages of cancer metastasis. The tumor-associated carbohydrate Thomsen-Friedenreich antigen (T antigen) and beta-galactoside binding lectins (galectins) have been implicated in tumor cell adhesion and tissue invasion. In this study, we demonstrate the involvement of T antigen in both homotypic aggregation of MDA-MB-435 human breast carcinoma cells and their adhesion to the endothelium. The T antigen-specific peptide P-30 (HGRFILPWWYAFSPS) selected from a bacteriophage display library was able to inhibit spontaneous homotypic aggregation of MDA-MB-435 cells up to 74% in a dose-dependent manner. Because T antigen has beta-galactose as a terminal sugar, the expression profile of beta-galactoside-binding lectins (galectins) in MDA-MB-435 cells was studied. Our data indicated the abundant expression of [35S]methionine/cysteine-labeled galectin-1 and galectin-3 in this cell line, which suggested possible interactions between galectins and T antigen. As revealed by laser confocal microscopy, both galectin-1 and galectin-3 also participate in the adhesion of the MDA-MB-435 cells to the endothelium. We observed the clustering of galectin-3 on endothelial cells at the sites of the contact with tumor cells, consistent with its possible interaction with T antigen on cancer cells The galectin-1 signal, however, strongly accumulated at the sites of cell-cell contacts predominantly on tumor cells. The T antigen-specific P-30 significantly (50%) inhibited this adhesion, which indicated that T antigen participates in the adhesion of MDA-MB-435 breast cancer cells to the endothelium. The ability of synthetic P-30 to inhibit both the spontaneous homotypic aggregation of MDA-MB-435 cells and their adhesion to the endothelium (>70 and 50%, respectively) suggests its potential functional significance for antiadhesive therapy of cancer metastasis

Stress and hopelessness in the promotion of cervical intraepithelial neoplasia to invasive squamous cell carcinoma of the cervix.

Goodkin K, Antoni MH, Blaney PH.

J Psychosom Res. 1986; 30(1):67-76.

Stress and hopelessness have been associated with the development of invasive cervical cancer by previous research. Subjects in this study were recruited from a colposcopy clinic awaiting work-up of an abnormal pap smear and from those admitted to an in-patient gynecology ward for cone biopsy of the cervix or hysterectomy to treat a symptomatic pelvic mass thought to be uterine leiomyomas. After data collection, pathology reports and colposcopic findings were used to determine group assignment independent of subjects' knowledge of their diagnosis. A modest stress-promotion correlation was derived, which was greatly enhanced by significant interactions with low levels of cooperative coping style and for high levels of premorbid pessimism, future despair, somatic anxiety, and life threat reactivity. These stress-moderator interactions are discussed in terms of immune system deficit with concomitant enhancement of promotion of CIN to invasive squamous cell cervical cancer

Germanium-The Health and Life Enhancer.

Goodman S.

2004

[The treatment of cutaneous radiation-induced fibrosis with pentoxifylline and vitamin E. An empirical report].

Gottlober P, Krahn G, Korting HC, et al.

Strahlenther Onkol. 1996 Jan; 172(1):34-8.

BACKGROUND: Radiation fibrosis represents a severe complication of radiation therapy; standardized treatment protocols are lacking so far. Surgical excision rarely results in complete healing. PATIENT AND METHODS: We report on a 58-year-old female patient who developed a squamous cell carcinoma within the fibrotic area of the irradiation field on the right chest, resulting from a radiotherapy following mastectomy for breast cancer 17 years ago. After surgical excision of the carcinoma a combined treatment with pentoxifylline tablets (3 x 400 mg/d p.o.) and vitamin-E capsules (1 x 400 mg/d p.o.) was initiated. Skin thickness was quantified by 20 MHz-ultrasound before and during treatment. RESULTS: The patient noted an increasing improvement of the condition of the affected skin starting from 4 months. A continuing decrease of skin thickness as documented by 20 MHz-ultrasound could be demonstrated from the 6th month on. The treatment was tolerated well, no side effects were observed. CONCLUSION: The data indicate a beneficial therapeutic effect of pentoxifylline and vitamin E on radiation-induced fibrosis. Little is known about the mechanism of action of this combined treatment protocol including pentoxifylline and vitamin E. Controlled clinical trials should be performed to confirm this observation

Effects of exogenous inositol hexakisphosphate (InsP(6)) on the levels of InsP(6) and of inositol trisphosphate (InsP(3)) in malignant cells, tissues and biological fluids.

Grases F, Simonet BM, Vucenik I, et al.

Life Sci. 2002 Aug 16; 71(13):1535-46.

InsP(6) is abundant in cereals and legumes. InsP(6) and lower inositol phosphates, in particular InsP(3), participate in important intracellular processes. In addition, InsP(6) possess significant health benefits, such as anti-cancer effect, kidney stones prevention, lowering serum cholesterol. Because of the insensitivity of existing methods for determination of non-radiolabeled inositol phosphates, little is known about the natural occurrence, much less on the concentrations of InsP(6) and InsP(3) in biological samples. Using gas chromatography-mass detection analysis of HPLC chromatographic fractions, we report a measurement of unlabeled total InsP(3) and InsP(6) (a) as they occur within cells culture, tissues, and plasma, and (b) their changes depending on the presence of exogenous InsP(6). When rats were fed on a purified diet in which InsP(6) was undetectable (AIN-76A) the levels of InsP(6) in brain were 3.35 +/- 0.57 (SE) micromol.kg(-1) and in plasma 0.023 +/- 0.008 (SE) micromol.l(-1). The presence of InsP(6) in diet dramatically influenced its levels in brain and in plasma. When rats were given an InsP(6)-sufficient diet (AIN-76A + 1% InsP(6)), the levels of InsP(6) were about 100-fold higher in brain tissues (36.8 +/- 1.8 (SE)) than in plasma (0.29 +/- 0.02 (SE)); InsP(6) concentrations were 8.5-fold higher than total InsP(3) concentrations in either plasma (0.033 +/- 0.012 (SE)) and brain (4.21 +/- 0.55 (SE)). When animals were given an InsP(6)-poor diet (AIN-76A only), there was a 90% decrease in InsP(6) content in both brain tissue and plasma (p < 0.001); however, there was no change in the level of total InsP(3). In non-stimulated malignant cells (MDA-MB 231 and K562) the InsP(6) contents were 16.2 +/- 9.1 (SE) micromol.kg(-1) for MDA-MB 231 cells and 15.6 +/- 2.7 (SE) for K 562 cells. These values were around 3-fold higher than those of InsP(3) (4.8 +/- 0.5 micromol.kg(-1) and 6.9 +/- 0.1 (SE) for MDA-MB 231 and K562 cells respectively). Treatment of malignant cells with InsP(6) resulted in a 2-fold increase in the intracellular concentrations of total InsP(3) (9.5 +/- 1.3 (SE) and 10.8 +/- 1.0 (SE) micromol.kg(-1) for MDA-MB 231 and K562 cells respectively, p < 0.05), without changes in InsP(6) levels. These results indicate that exogenous InsP(6) directly affects its physiological levels in plasma and brain of normal rats without changes on the total InsP(3) levels. Although a similar fluctuation of InsP(6) concentration was not seen in human malignant cell lines following InsP(6) treatment, an increased intracellular levels of total InsP(3) was clearly observed

Modified citrus pectin (MCP) increases the prostate-specific antigen doubling time in men with prostate cancer: a phase II pilot study.

Guess BW, Scholz MC, Strum SB, et al.

Prostate Cancer Prostatic Dis. 2003; 6(4):301-4.

This trial investigated the tolerability and effect of modified citrus pectin (Pecta-Sol((R))) in 13 men with prostate cancer and biochemical prostate-specific antigen (PSA) failure after localized treatment, that is, radical prostatectomy, radiation, or cryosurgery. A total of 13 men were evaluated for tolerability and 10 for efficacy. Changes in the prostate-specific antigen doubling time (PSADT) of the 10 men were the primary end point in the study. We found that the PSADT increased (P-value<0.05) in seven (70%) of 10 men after taking MCP for 12 months compared to before taking MCP. This study suggests that MCP may lengthen the PSADT in men with recurrent prostate cancer.Prostate Cancer and Prostatic Diseases (2003) 6, 301-304. doi:10.1038/sj.pcan.4500679

Insulin: a novel factor in carcinogenesis.

Gupta K, Krishnaswamy G, Karnad A, et al.

Am J Med Sci. 2002 Mar; 323(3):140-5.

Cancer is a leading cause of mortality in the United States. Despite much research on specific carcinogens, the cause of many cancers remains unclear. The identification of novel causative agents offers the potential for cancer prevention. Diseases such as obesity and diabetes mellitus, characterized by hyperinsulinemia, are associated with increased risk of endometrial, colorectal, and breast carcinomas. There is increasing evidence that insulin is a growth factor for tumor formation. The mechanisms underlying insulin-mediated neoplasia may include enhanced DNA synthesis with resultant tumor cell growth, inhibition of apoptosis, and altered sex hormone milieu. The reduced insulin levels seen with physical activity, weight loss, and a high fiber diet may account for decreased cancer risk. The role of newer drugs that restore sensitivity to insulin, thereby reducing hyperinsulinemia, is an exciting potential area of cancer prevention. In this review, we discuss the potential role of insulin as a tumor growth factor

Inhibition of proliferation of estrogen receptor-negative MDA-MB-435 and -positive MCF-7 human breast cancer cells by palm oil tocotrienols and tamoxifen, alone and in combination.

Guthrie N, Gapor A, Chambers AF, et al.

J Nutr. 1997 Mar; 127(3):544S-8S.

Tocotrienols are a form of vitamin E, having an unsaturated isoprenoid side-chain rather than the saturated side-chain of tocopherols. The tocotrienol-rich fraction (TRF) from palm oil contains alpha-tocopherol and a mixture of alpha-, gamma- and delta-tocotrienols. Earlier studies have shown that tocotrienols display anticancer activity. We previously reported that TRF, alpha-, gamma- and delta-tocotrienols inhibited proliferation of estrogen receptor-negative MDA-MB-435 human breast cancer cells with 50% inhibitory concentrations (IC50) of 180, 90, 30 and 90 microg/mL, respectively, whereas alpha-tocopherol had no effect at concentrations up to 500 microg/mL. Further experiments with estrogen receptor-positive MCF-7 cells showed that tocotrienols also inhibited their proliferation, as measured by [3H] thymidine incorporation. The IC50s for TRF, alpha-tocopherol, alpha-, gamma- and delta-tocotrienols were 4, 125, 6, 2 and 2 microg/mL, respectively. Tamoxifen, a widely used synthetic antiestrogen inhibits the growth of MCF-7 cells with an IC50 of 0.04 microg/mL. We tested 1:1 combinations of TRF, alpha-tocopherol and the individual tocotrienols with tamoxifen in both cell lines. In the MDA-MB-435 cells, all of the combinations were found to be synergistic. In the MCF-7 cells, only 1:1 combinations of gamma- or delta-tocotrienol with tamoxifen showed a synergistic inhibitory effect on the proliferative rate and growth of the cells. The inhibition by tocotrienols was not overcome by addition of excess estradiol to the medium. These results suggest that tocotrienols are effective inhibitors of both estrogen receptor-negative and -positive cells and that combinations with tamoxifen should be considered as a possible improvement in breast cancer therapy

Vitamin D and vitamin D analogs as cancer chemopreventive agents.

Guyton KZ, Kensler TW, Posner GH.

Nutr Rev. 2003 Jul; 61(7):227-38.

Epidemiologic studies have associated vitamin D, attained through nutrition and sun exposure, with reduced cancer risk. Although dose-limiting hypercalcemia has limited the use of natural vitamin D in cancer prevention, several promising new synthetic vitamin D analogs (deltanoids) are under development. Examples are KH-1060, EB-1089, 1alpha-hydroxyvitamin D5, vitamin D2, and QW-1624F2-2. Clinical targets for deltanoids include colon, prostate, and breast. Studies to elucidate the molecular mechanisms underlying the observed efficacy of deltanoids are ongoing. The vitamin D receptor, a steroid/thyroid receptor superfamily member, appears to control most deltanoid effects on proliferation, apoptosis, differentiation, and angiogenesis

Three percent dietary fish oil concentrate increased efficacy of doxorubicin against MDA-MB 231 breast cancer xenografts.

Hardman WE, Avula CP, Fernandes G, et al.

Clin Cancer Res. 2001 Jul; 7(7):2041-9.

Omega 3 polyunsaturated fatty acids (the type of fat found in fish oil) have been used to kill or slow the growth of cancer cells in culture and in animal models and to increase the effectiveness of cancer chemotherapeutic drugs. An AIN-76 diet containing 5% corn oil (CO) was modified to contain 3% w/w fish oil concentrate (FOC) and 2% CO to test whether a clinically applicable amount of FOC is beneficial during doxorubicin (DOX) treatment of cancer xenografts in mice. Compared with the diet containing 5% CO, consumption of FOC increased omega 3 polyunsaturated fatty acids and lipid peroxidation in tumor and liver, significantly decreased the ratio of glutathione peroxidase activity to superoxide dismutase activity (a putative indicator of increased oxidative stress) in tumor but not in the liver, and significantly decreased the tumor-growth rate. The decreased glutathione peroxidase:superoxide dismutase ratio, indicating an altered redox state, in the tumor of FOC-fed mice was significantly correlated with decreased tumor-growth rate. Assay of the body weight change, blood cell counts, and number of micronuclei in peripheral erythrocytes indicated that the toxicity of DOX to the host mouse was not increased in mice fed FOC. Thus, a small amount of FOC increased the effectiveness of DOX but did not increase the toxicity of DOX to the host mouse. These positive results justify clinical testing of FOC in conjunction with cancer chemotherapy

Lowering cholesterol with Lovastatin. The wrong approach. A survey of usually overlooked literature.

Hattersley JG.

J Orthomolecular Med. 2004; 9(1):54-7.

Coenzyme Q10 and cancer.

Hattersley JG.

J Orthomolecular Med. 1996; 11(1)

Identification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebrates.

Hattori A, Migitaka H, Iigo M, et al.

Biochem Mol Biol Int. 1995 Mar; 35(3):627-34.

Twenty-four edible plants were investigated for the presence of melatonin, heretofore considered to be a molecule found only in the animal kingdom. The amount of melatonin in different plants varied greatly with highest melatonin being present in plants of the rice family. Melatonin was identified by radioimmunoassay and verified by high performance liquid chromatography with fluorescence detection. Feeding a diet containing plant products rich in melatonin to chicks increased radioimmunoassayable levels of melatonin in their blood. Likewise, melatonin extracted from plants inhibited binding of [125I]iodomelatonin to rabbit brain. Thus, melatonin ingested in foodstuffs enters the blood and is capable of binding to melatonin binding sites in the brain of mammals

Inhibition of hepatocarcinogenic responses to 1,2-dimethylhydrazine by diallyl sulfide, a component of garlic oil.

Hayes MA, Rushmore TH, Goldberg MT.

Carcinogenesis. 1987 Aug; 8(8):1155-7.

The mechanisms by which diallyl sulfide (DAS), a component of garlic oil, inhibits hepatocarcinogenicity of 1,2-dimethylhydrazine (DMH) were examined in male Fischer 344 rats. Rats were subjected to partial hepatectomy to stimulate hepatocellular proliferation required for initiation by DMH (50-200 mg/kg i.p.) given 12 h later. Initiation was assessed by the numbers of foci and nodules of hepatocytes that were positive for gamma-glutamyl transpeptidase (gamma-GT) or glutathione-S-transferase-P (GST-P) after 6 weeks promotion by orotic acid (1% in semi-purified diet). DAS at doses above 50 mg/kg (by gavage) administered 1 h before DMH (50 mg/kg) partially reduced the numbers of gamma-GT and GST-P-positive foci. By comparison, all doses of DAS (25-100 mg/kg) completely prevented liver necrosis by DMH (200 mg/kg). DAS substantially reduced macromolecular binding of [14C]DMH in cultured liver cells, but had no effect on their levels of glutathione-S-transferase, glutathione reductase or glutathione peroxidase at 18 h. These findings suggest that low dosages of DAS which reduce DMH binding appear more likely to inhibit hepatocarcinogenicity by reducing the promoting influences of post-necrotic regeneration than by preventing initiation

[Role of sodium selenite as an adjuvant in radiotherapy of rectal carcinoma].

Hehr T, Hoffmann W, Bamberg M.

Med Klin (Munich). 1997 Sep 15; 92 Suppl 3:48-9.

BACKGROUND: In various epidemiologic studies an association of low selenium blood levels and reduced glutathione peroxidase with an increased risk of cancer incidence was described. The antitumoral therapy and a suboptimal nutrition could intensify this deficiency. Every reduction of disease related and therapeutic caused symptoms may improve life quality. APPLICATION: We report our preliminary experiences in the adjuvant radiochemotherapy of advanced rectal cancer (UICC II/III) corresponding to the NCl recommendation. An oral selenium supplementation was carried out with 2000 micrograms Na2SeO3 after every course of fluorouracil chemotherapy and daily 400 micrograms Na2SeO3 after irradiation of tumor region and lymph nodes. A weekly life quality assessment was explored with special interest in diarrhea, dysurie, pain, appetite, nausea and emesis. CONCLUSION: Damages to normal tissue specially to DNA enzymes and membranes caused by free radicals is one mechanism in tumorgenesis, tumor progression and therapeutic consequence. A radioprotective effect of selenium is verified by in vitro and in vivo data. Our data show that oral selenium intake in rectal cancer patients is easily tolerated with no side effects. Improving life quality and secondary cancer prevention with supplementation of selenium has to be proven in prospective randomized studies

Association between alpha-tocopherol, gamma tocopherol, selenium, and subsequent prostate cancer.

Helzlsourer KJ.

J Natl Cancer Inst. 2000; 92(24):2018-23.

Dietary supplementation with L-arginine: modulation of tumour-infiltrating lymphocytes in patients with colorectal cancer.

Heys SD, Segar A, Payne S, et al.

Br J Surg. 1997 Feb; 84(2):238-41.

BACKGROUND: Dietary supplementation with L-arginine enhances natural cytotoxicity in peripheral blood lymphocytes but its effect on infiltrating lymphoreticular cells within a tumour microenvironment is unknown. The effects of dietary supplementation with L-arginine on tumour-infiltrating lymphocytes (TILs) in patients with colorectal cancer were evaluated. METHODS: Eighteen patients received either a standard hospital diet (controls) or a standard diet supplemented with 30 g per day of L-arginine for 3 days before surgery. Tumour biopsies were taken at surgery and lymphocyte subsets (CD antigens) and macrophages examined immunohistochemically. RESULTS: Tumours from patients receiving L-arginine contained increased numbers of specific cell subsets within the tumour which expressed CD16 (P = 0.004) and CD56 (P = 0.001) surface markers, when compared with tumours from control patients. There were no differences in the total number of T and B cells, T helper and T suppressor cells. CONCLUSION: Dietary supplementation with L-arginine significantly alter the spectrum of TILs in human colorectal cancers in vivo. These findings have important implications for new strategies in anticancer treatment

1,1-Diphenyl-2-picrylhydrazyl radical-scavenging compounds from soybean miso and antiproliferative activity of isoflavones from soybean miso toward the cancer cell lines.

Hirota A, Taki S, Kawaii S, et al.

Biosci Biotechnol Biochem. 2000 May; 64(5):1038-40.

Guided by their DPPH radical-scavenging activity, nine compounds were isolated from soybean miso. Of these, 8-hydroxydaidzein, 8-hydroxygenistein and syringic acid had as high DPPH radical-scavenging activity as that of alpha-tocopherol. The antiproliferative activity of four of the isolated isoflavones toward three cancer cell lines was examined. 8-Hydroxygenistein showed the highest activity (IC50=5.2 microM) toward human promyelocytic leukemia cells (HL-60)

Lycopene lowers PSA in prostate cancer patients.

Holzman D.

Life Extension Magazine 2002 Jan. 2004 8(1):25.

Comparative study of concentration of isoflavones and lignans in plasma and prostatic tissues of normal control and benign prostatic hyperplasia.

Hong SJ, Kim SI, Kwon SM, et al.

Yonsei Med J. 2002 Apr; 43(2):236-41.

OBJECTIVE: Isoflavones and lignans are phytoestrogens that have recently gained interest as dietary factors related to prostatic diseases. However, no data on the concentrations in prostate tissue in humans is available. Therefore, the concentrations of isoflavones and lignans in plasma and prostatic tissues according to the prostate volume were compared to determine their possible effect on the benign prostatic growth. METHODS: Fasting plasma and prostatic tissue specimens were acquired from 25 men over 50 years of age with similar normal dietary habits and no previous history of drug intake that could affect the isoflavones and lignans levels. The tissue was acquired either during a transurethral resection of the prostate in 15 patients with benign prostatic hyperplasia (BPH) with prostate volume over 40 ml or during a radical cystoprostatectomy in 10 patients with bladder cancer with a prostate volume < 25 ml, who were used as the controls. Quantitative analysis of the isoflavones, specifically equol, daidzein and genistein and lignans, particularly enterodiol and enterolactone, was performed by gas chromatography-mass spectrometry. RESULTS: The mean prostatic concentrations of enterodiol, enterolactone, equol and daidzein in the BPH and the control groups were similar. However, the mean prostatic concentration of genistein was significantly lower in the BPH group than in the control group (65.43 +/- 17.05 vs 86.96 +/- 37.75 ng/ ml, respectively, p="0.032)." The plasma concentration of isoflavones and lignans in the two groups were comparable. CONCLUSION: Isoflavones, but not lignans, have some influence the benign prostatic growth, and the prostatic concentration of genistein possibly has the closest association among them. More studies to further clarify the roles and mechanisms of isoflavone action on BPH including pharmacokinetic studies are recommended

Effects of allyl sulfur compounds and garlic extract on the expression of Bcl-2, Bax, and p53 in non small cell lung cancer cell lines.

Hong YS, Ham YA, Choi JH, et al.

Exp Mol Med. 2000 Sep 30; 32(3):127-34.

Allyl sulfur compounds play a major role in the chemoprevention against carcinogenesis. The present study compared the antiproliferative effects of diallyl sulfide (DAS), diallyl disulfide (DADS) and garlic extract on p53-wild type H460 and p53-null type H1299 non small cell lung cancer cells (NSCLC). The DAS and DADS treatment of both H460 and H1299 cells resulted in the highest numbers of cells in apoptotic state as measured by acridine orange staining, however, garlic extract treatment did not induce any significant apoptotic cells by MTT assay. DADS was found to be more effective in inducing apoptosis on NSCLC. The level of p53 protein in H460 cell was increased following DADS treatment. DAS and garlic extract treatment of H460 cells induced a rise in the level of Bax and a fall of Bcl-2 level. These results demonstrate that DAS, DADS and garlic extract are effective in reduction of anti-proliferative gene in NSCLC and suggest that modulation of apoptosis-associated cellular proteins by DAS, DADS and garlic extract may be the mechanism for apoptosis which merit further investigation as potential chemoprevention agents

Phytoestrogens and thyroid cancer risk: the San Francisco Bay Area thyroid cancer study.

Horn-Ross PL, Hoggatt KJ, Lee MM.

Cancer Epidemiol Biomarkers Prev. 2002 Jan; 11(1):43-9.

Epidemiological and pathological data suggest that thyroid cancer may well be an estrogen-dependent disease. The relationship between thyroid cancer risk and dietary phytoestrogens, which can have both estrogenic and antiestrogenic properties, has not been previously studied. We present data from a multiethnic population-based case-control study of thyroid cancer conducted in the San Francisco Bay Area. Of 817 cases diagnosed between 1995 and 1998 (1992 and 1998 for Asian women), 608 (74%) were interviewed. Of 793 controls identified through random-digit dialing, 558 (70%) were interviewed. Phytoestrogen consumption was assessed via a food-frequency questionnaire and a newly developed nutrient database. The consumption of traditional and nontraditional soy-based foods and alfalfa sprouts were associated with reduced risk of thyroid cancer. Consumption of "western" foods with added soy flour or soy protein did not affect risk. Of the seven specific phytoestrogenic compounds examined, the isoflavones, daidzein and genistein [odds ratio (OR), 0.70; 95% confidence interval (CI), 0.44-1.1; and OR, 0.65, 95% CI, 0.41-1.0, for the highest versus lowest quintile of daidzein and genistein, respectively] and the lignan, secoisolariciresinol (OR, 0.56; 95% CI, 0.35-0.89, for the highest versus lowest quintile) were most strongly associated with risk reduction. Findings were similar for white and Asian women and for pre- and postmenopausal women. Our findings suggest that thyroid cancer prevention via dietary modification of soy and/or phytoestrogen intake in other forms may be possible but warrants further research at this time

Effect of cimetidine on development of gastric cancer in rats after gastrojejunostomy.

Hortemo GS, Maartmann-Moe H, Rokke O, et al.

Eur J Surg. 1999 Mar; 165(3):259-61.

OBJECTIVE: To find out if cimetidine has an immunomodulating effect on gastric carcinogenesis in rats. DESIGN: Experimental prospective study. SETTING: Teaching hospital, Norway. ANIMALS: 132 male PGV/Mol rats given gastrojejunostomies. INTERVENTION: Half the rats were given cimetidine in their drinking water postoperatively for a minimum of 38 weeks. They were killed after 52 weeks observation and the stomach was investigated macroscopically and microscopically. MAIN OUTCOME MEASURE: In the cimetidine fed group 19/48 animals developed cancer (49%), versus 12/43 (28%) in the control group (p = 0.24). CONCLUSION: Cimetidine had no immunomodulatory effect on the development of gastric cancer in rats

Prostate cancer risk and serum levels of insulin and leptin: a population-based study.

Hsing AW, Chua S Jr, Gao YT, et al.

J Natl Cancer Inst. 2001 May 16; 93(10):783-9.

BACKGROUND: In a previous study of Chinese men, we found that men with a higher waist-to-hip ratio (WHR) have a higher prostate cancer risk. Because leptin and insulin are related to body fat distribution, we examined whether leptin and insulin were associated with prostate cancer risk. METHODS: Blood samples were collected from 128 case patients with incident prostate cancer and from 306 healthy control subjects randomly selected from residents of Shanghai, CHINA: Epidemiologic information and anthropometric measurements were collected in personal interviews. Serum leptin, insulin, and sex hormone levels were measured by radioimmunoassay, and insulin-like growth factor-I (IGF-I) was measured by enzyme-linked immunosorbent assay. Multiple logistic regression analyses were used to estimate odds ratios for prostate cancer in relation to serum insulin and leptin levels. All statistical tests were two-sided. RESULTS: After adjustment for body mass index, WHR, IGF-I, and sex hormone levels, higher serum insulin levels were associated with a statistically significantly elevated risk of prostate cancer (P0.900) and insulin (>8.83 microU/mL) had 8.55 times (95% CI = 2.80 to 26.10) the prostate cancer risk of men in the lowest tertiles of both, and those in the lowest tertile of WHR (<0.873) and highest tertile of insulin had 4.30 times (95% CI = "1.17" to 15.70) the risk. By contrast, the association between leptin levels and prostate cancer risk was not statistically significant. CONCLUSION: Our results suggest that serum insulin levels may influence the risk of prostate cancer in Chinese men. Further research, especially prospective studies, is needed to confirm these findings in high-risk populations and to clarify the underlying mechanisms involved

Inhibitory effects of topical application of low doses of curcumin on 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion and oxidized DNA bases in mouse epidermis.

Huang MT, Ma W, Yen P, et al.

Carcinogenesis. 1997 Jan; 18(1):83-8.

The effects of topical applications of very low doses of curcumin (the major yellow pigment in turmeric and the Indian food curry) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidation of DNA bases in the epidermis and on tumor promotion in mouse skin were investigated. CD-1 mice were treated topically with 200 nmol of 7,12-dimethylbenz[a]anthracene followed one week later by 5 nmol of TPA alone or together with 1, 10, 100 or 3000 nmol of curcumin twice a week for 20 weeks. Curcumin-mediated effects on TPA-induced formation of the oxidized DNA base 5-hydroxymethyl-2'-deoxyuridine (HMdU) and tumor formation were determined. All dose levels of curcumin inhibited the mean values of TPA-induced HMdU formation in epidermal DNA (62-77% inhibition), but only the two highest doses of curcumin strongly inhibited TPA-induced tumor promotion (62-79% inhibition of tumors per mouse and tumor volume per mouse). In a second experiment, topical application of 20 or 100 nmol (but not 10 nmol) of curcumin together with 5 nmol TPA twice a week for 18 weeks markedly inhibited TPA-induced tumor promotion. Curcumin had a strong inhibitory effect on DNA and RNA synthesis (IC50 = 0.5-1 microM) in cultured HeLa cells, but there was little or no effect on protein synthesis

1,25-dihydroxyvitamin D3 regulates estrogen metabolism in cultured keratinocytes.

Hughes SV, Robinson E, Bland R, et al.

Endocrinology. 1997 Sep; 138(9):3711-8.

Local estrogen metabolism may play an important role in modulating cell development in peripheral tissues such as breast, adipose, and bone. C19 androgens are converted to C18 estrogens by the enzyme aromatase, overexpression of which is associated with breast cancer. Interconversion of active estradiol (E2) to inactive estrone is controlled by various isoforms of the enzyme 17beta-hydroxysteroid dehydrogenase (17betaHSD). We have studied the expression of these two enzymes in human keratinocytes and report rapid changes in 17betaHSD activity in response to treatment with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. Keratinocytes cultured in serum-free medium showed aromatase activity of 2.5 fmol/h x mg cell protein, which was unaffected by any culture treatment. A much higher level of 17betaHSD activity was observed in the keratinocytes, predominantly conversion of E2 to estrone (approximately 120 pmol/h x mg cell protein). This inactivation of E2 increased in a dose-dependent fashion after treatment of the cells with antiproliferative doses of 1,25-(OH)2D3 (0.1-200 nM). The effect of 1,25-(OH)2D3 on 17betaHSD activity was enhanced by simultaneous treatment with dexamethasone, which also increased the antiproliferative action of 1,25-(OH)2D3. Reverse transcription-PCR and Northern analysis showed that keratinocytes expressed messenger RNA for three 17betaHSD isoenzymes (types I, II, and IV). Treatment with 1,25-(OH)2D3 (10 nM for 20 h) resulted in the up-regulation of messenger RNA levels for type 2 17betaHSD. Further RNA studies combined with E2 binding experiments demonstrated the presence of estrogen receptors in the cultured keratinocytes. These data indicate that keratinocytes are potential targets for systemically or locally produced estrogens, which may, in turn, play a key role in the development of normal skin. In particular, we propose that 17betaHSD isoenzymes are key target genes for 1,25-(OH)2D3 in keratinocytes and may be an important feature of the antipsoriatic effects of vitamin D and its analogs

Carotenoids, alpha-tocopherols, and retinol in plasma and breast cancer risk in northern Sweden.

Hulten K, Van Kappel AL, Winkvist A, et al.

Cancer Causes Control. 2001 Aug; 12(6):529-37.

OBJECTIVE: Using a nested case-referent design we evaluated the relationship between plasma levels of six carotenoids, alpha-tocopherol, and retinol, sampled before diagnosis, and later breast cancer risk. METHODS: In total, 201 cases and 290 referents were selected from three population-based cohorts in northern Sweden, where all subjects donated blood samples at enrolment. All blood samples were stored at -80 degrees C. Cases and referents were matched for age, age of blood sample, and sampling centre. Breast cancer cases were identified through the regional and national cancer registries. RESULTS: Plasma concentrations of carotenoids were positively intercorrelated. In analysis of three cohorts as a group none of the carotenoids was found to be significantly related to the risk of developing breast cancer. Similarly, no significant associations between breast cancer risk and plasma levels of alpha-tocopherol or retinol were found. However, in postmenopausal women from a mammography cohort with a high number of prevalent cases, lycopene was significantly associated with a decreased risk of breast cancer. A significant trend of an inverse association between lutein and breast cancer risk was seen in premenopausal women from two combined population-based cohorts with only incident cases. A non-significant reduced risk with higher plasma alpha-carotene was apparent throughout all the sub-analyses. CONCLUSION: In conclusion, no significant associations were found between plasma levels of carotenoids, alpha-tocopherol or retinol and breast cancer risk in analysis of three combined cohorts. However, results from stratified analysis by cohort membership and menopausal status suggest that lycopene and other plasma-carotenoids may reduce the risk of developing breast cancer and that menopausal status has an impact on the mechanisms involved

Dietary beta-carotene intake and the risk of epithelial ovarian cancer: a meta-analysis of 3,782 subjects from five observational studies.

Huncharek M, Klassen H, Kupelnick B.

In Vivo. 2001 Jul; 15(4):339-43.

OBJECTIVE: The etiology of epithelial ovarian cancer is unknown. Prior work suggests that high dietary beta-carotene intake is associated with a decreased risk of this tumor although this association remains speculative. A meta-analysis was performed to evaluate this suspected relationship. METHODS: Using previously described methods, a protocol was developed for a meta-analysis examining the association between high dietary beta-carotene intake versus low intake and the risk of epithelial ovarian cancer. Literature search techniques, study inclusion criteria and statistical procedures were prospectively defined. Data from observational studies were pooled using a general variance based meta-analytic method employing confidence intervals previously described by Greenland. The outcome of interest was a summary relative risk (RRs) reflecting the risk of ovarian cancer associated with high beta-carotene intake versus low dietary intake. Sensitivity analyses were performed when necessary to evaluate any observed statistical heterogeneity. RESULTS: Five observational studies enrolling 3,782 subjects were initially pooled in a meta-analysis subsequent to an analysis showing a lack of statistical heterogeneity. The meta-analysis showed a summary relative risk of 0.84 with a 95% confidence interval of 0.75-0.94, a statistically significant result. These data suggest that high (versus low) dietary intake of beta-carotene is associated with a sixteen percent decrease in ovarian cancer risk. Sensitivity analyses showed no impact of study design or differences in quantitative measure of beta-carotene intake across studies on the summary relative risk. CONCLUSIONS: High dietary intake of beta-carotene appears to represent a protective factor for the development of ovarian cancer although its magnitude is modest. Further work is needed to clarify factors that may modify the effects of beta-carotene in vivo

Inhibition of the expression of inducible cyclooxygenase and proinflammatory cytokines by sesquiterpene lactones in macrophages correlates with the inhibition of MAP kinases.

Hwang D, Fischer NH, Jang BC, et al.

Biochem Biophys Res Commun. 1996 Sep 24; 226(3):810-8.

In our previous studies (Refs. 1 and 2), it was shown that protein tyrosine kinase (PTK) inhibitors, radicicol and herbimycin A, inhibit the expression of the mitogen-inducible cyclooxygenase (COX-2) and proinflammatory cytokines. Radicicol and herbimycin A possess polarized double bonds which can conjugate sulphydryl groups of proteins. Parthenolide, the predominant sesquiterpene lactone in European feverfew (Tanacetum parthenium), contains alpha-methylene-gamma-lactone (MGL) and an epoxide in its structure. These moieties can interact with biological nucleophiles such as a sulfhydryl group. Parthenolide inhibited the expression of COX-2 and proinflammatory cytokines (TNF alpha and IL-1) in lipopolysaccharide (LPS)-stimulated macrophages. The structure-function relationship indicates that the MGL moiety confers the inhibitory effect. Parthenolide suppressed LPS-stimulated protein tyrosine phosphorylation in the murine macrophage cell line (RAW 264.7). This suppression was correlated with its inhibitory effect on the expression of COX-2 and the cytokines. Among tyrosine phosphorylated proteins, mitogen-activated protein kinases (MAPKs) exhibited the most dramatic inhibition

Chemoprevention by curcumin during the promotion stage of tumorigenesis of mammary gland in rats irradiated with gamma-rays.

Inano H, Onoda M, Inafuku N, et al.

Carcinogenesis. 1999 Jun; 20(6):1011-8.

We have evaluated the chemopreventive effects of curcumin on diethylstilbestrol (DES)-induced tumor promotion of rat mammary glands initiated with radiation. Sixty-four pregnant rats received whole body irradiation with 2.6 Gy gamma-rays from a 60Co source at day 20 of pregnancy and were divided into two groups after weaning. In the control group of 39 rats fed a basal diet and then implanted with a DES pellet for 1 year, 33 (84.6%) developed mammary tumors. Twenty-five rats were fed diet containing 1% curcumin immediately after weaning and received a DES pellet, as for the control. The administration of dietary curcumin significantly reduced the incidence (28.0%) of mammary tumors. Multiplicity and Iball's index of mammary tumors were also decreased by curcumin. Rats fed the curcumin diet showed a reduced incidence of the development of both mammary adenocarcinoma and ER(+)PgR(+) tumors in comparison with the control group. On long-term treatment with curcumin, body weight and ovarian weight were reduced, but liver weight was increased. Compared with the control rats, the curcumin-fed rats showed a significant reduction in serum prolactin, whereas estradiol-17beta and progesterone concentrations were not significantly different between the two groups. Curcumin did not have any effect on the concentration of free cholesterol, cholesterol ester and triglyceride. Feeding of the curcumin diet caused a significant increase in the concentrations of tetrahydrocurcumin, arachidonic acid and eicosapentaenoic acid and a significant decrease in thiobarbituric acid-reactive substance concentration in serum. Whole mounts of the mammary glands showed that curcumin yielded morphologically indistinguishable proliferation and differentiation from the glands of the control rats. These findings suggest that curcumin has a potent preventive activity during the DES-dependent promotion stage of radiation-induced mammary tumorigenesis

Tea and coffee consumption and the risk of digestive tract cancers: data from a comparative case-referent study in Japan.

Inoue M, Tajima K, Hirose K, et al.

Cancer Causes Control. 1998 Mar; 9(2):209-16.

OBJECTIVES: The purpose of this study was to examine the hypothesis that tea and coffee consumption have a protective effect against development of digestive tract cancers. METHODS: A comparative case-referent study was conducted using Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC) data from 1990 to 1995 in Nagoya, Japan. This study comprised 1,706 histologically diagnosed cases of digestive tract cancers (185 esophagus, 893 stomach, 362 colon, 266 rectum) and a total of 21,128 non-cancer outpatients aged 40 years and over. Logistic regression was used to analyze the data, adjusting for gender; age; year and season at hospital-visit; habitual smoking and alcohol drinking; regular physical exercise; fruit, rice, and beef intake; and beverage intake. RESULTS: The odds ratio (OR) of stomach cancer decreased to 0.69 (95 percent confidence interval [CI] = 0.48-1.00) with high intake of green tea (seven cups or more per day). A decreased risk was also observed for rectal cancer with three cups or more daily intake of coffee (OR = 0.46, CI = 0.26-0.81). CONCLUSIONS: The results suggest the potential for protective effect against site-specific digestive tract cancer by consumption of green tea and coffee, although most associations are limited only to the upper category of intake and have no clear explanation for site-specificity

Induction of apoptosis by conjugated linoleic acid in cultured mammary tumor cells and premalignant lesions of the rat mammary gland.

Ip C, Ip MM, Loftus T, et al.

Cancer Epidemiol Biomarkers Prev. 2000 Jul; 9(7):689-96.

Conjugated linoleic acid (CLA) is an effective agent in preventing mammary cancer in rats treated with a carcinogen. The appearance of a tumor mass is the net result of cell proliferation minus cell death. Thus, apoptosis could be an important mechanism in controlling clonal expansion of the early premalignant lesions. The overall objective of this report was to determine whether CLA stimulated apoptosis. In the first part of the study, CLA was found to increase chromatin condensation (visualized through fluorescent 4',6-diamidino-2-phenylindole staining to DNA) and to induce DNA laddering, both evidence of apoptosis, in a rat mammary tumor cell line. The second part was to investigate the effect of CLA feeding on the development of histologically identifiable premalignant lesions in the rat mammary gland, as well as on the quantification of apoptosis (by terminal uridyltransferase nick end labeling assay) and the expression by immunohistochemistry of apoptosis regulatory proteins (bcl-2, bak, and bax) in normal versus premalignant mammary structures. CLA inhibited the formation of premalignant lesions by approximately 50%. It also significantly increased apoptosis and reduced the expression of bcl-2 in these lesions, but it did not modulate the levels of bak or bax. In contrast, neither apoptosis nor any of the apoptosis regulatory proteins was affected by CLA in normal mammary gland alveoli or terminal end buds. The data suggest that early pathological lesions may be particularly sensitive to CLA. In addition to providing a molecular basis for elucidating the mechanism of action of CLA in cancer prevention, the research on CLA-responsive biomarkers also has a practical side because these assays can be applied to biopsied human tissue samples in future CLA intervention trials

Conjugated linoleic acid inhibits proliferation and induces apoptosis of normal rat mammary epithelial cells in primary culture.

Ip MM, Masso-Welch PA, Shoemaker SF, et al.

Exp Cell Res. 1999 Jul 10; 250(1):22-34.

The trace fatty acid conjugated linoleic acid (CLA) inhibits rat mammary carcinogenesis when fed prior to carcinogen during pubertal mammary gland development or during the promotion phase of carcinogenesis. The following studies were done to investigate possible mechanisms of these effects. Using a physiological model for growth and differentiation of normal rat mammary epithelial cell organoids (MEO) in primary culture, we found that CLA, but not linoleic acid (LA), inhibited growth of MEO and that this growth inhibition was mediated both by a reduction in DNA synthesis and a stimulation of apoptosis. The effects of CLA did not appear to be mediated by changes in epithelial protein kinase C (PKC) since neither total activity nor expression nor localization of PKC isoenzymes alpha, beta II, delta, epsilon, eta, or zeta were altered in the epithelium of CLA-fed rats. In contrast, PKCs delta, epsilon, and eta were specifically upregulated and associated with a lipid-like, but acetone-insoluble, fibrillar material found exclusively in adipocytes from CLA-fed rats. Taken together, these observations demonstrate that CLA can act directly to inhibit growth and induce apoptosis of normal MEO and may thus prevent breast cancer by its ability to reduce mammary epithelial density and to inhibit the outgrowth of initiated MEO. Moreover, the changes in mammary adipocyte PKC expression and lipid composition suggest that the adipose stroma may play an important in vivo role in mediating the ability of CLA to inhibit mammary carcinogenesis

Quantitative analysis of estrogen receptor-alpha and -beta messenger RNA expression in breast carcinoma by real-time polymerase chain reaction.

Iwao K, Miyoshi Y, Egawa C, et al.

Cancer. 2000 Oct 15; 89(8):1732-8.

BACKGROUND: Estrogen action is mediated not only through a classic estrogen receptor (ER) (ER-alpha) but also through a second ER (ER-beta) that has a structure and function similar to ER-alpha. A correlation between ER-beta mRNA expression with ER and progesterone receptor (PR) protein levels as well as prognostic factors remains to be established in breast carcinoma. METHODS: The authors conducted a quantitative analysis of ER-alpha and ER-beta mRNA expression in 116 breast tumors using real-time polymerase chain reaction (PCR), and investigated a possible correlation between ER-alpha and ER-beta mRNA expression and ER and PR status as determined by enzyme immunoassay as well as with various prognostic factors. RESULTS: ER-alpha mRNA levels were significantly (P < 0.01) higher in ER positive compared with ER negative tumors. Conversely, ER-beta mRNA levels were significantly (P < 0.01) lower in ER positive compared with ER negative tumors. Accordingly, the ratio of ER-beta to ER-alpha was significantly (P < 0.01) higher in ER negative compared with ER positive tumors. A subset analysis based on ER and PR status showed that ER-beta mRNA levels as well as the ratios of ER-beta to ER-alpha mRNA level were highest in ER negative and PR negative tumors (P < 0.05). ER-alpha mRNA levels were significantly (P < 0.05) higher in postmenopausal compared with premenopausal tumors. Histologic Grade 3 tumors showed a significant decrease in ER-alpha mRNA levels compared with Grade 1 and 2 tumors (P < 0.01 and P < 0.05, respectively). No significant correlation between ER-alpha and ER-beta mRNA levels and histologic type, tumor size, or lymph node status was observed. CONCLUSIONS: An absolute and relative increase in ER-beta mRNA levels in ER negative and PR negative breast tumors, which rarely respond to endocrine therapy, suggests the possible involvement of up-regulation of ER-beta mRNA in the development of estrogen-independent tumors

DNA fragmentation, DNA-protein crosslinks, postlabeled nucleotidic modifications, and 8-hydroxy-2'-deoxyguanosine in the lung but not in the liver of rats receiving intratracheal instillations of chromium(VI). Chemoprevention by oral N-acetylcysteine.

Izzotti A, Bagnasco M, Camoirano A, et al.

Mutat Res. 1998 May 25; 400(1-2):233-44.

An in vivo study was carried out with the objectives of evaluating (a) the localization of DNA lesions resulting from exposure to chromium(VI) by the respiratory route, (b) the molecular nature of DNA alterations, and (c) modulation of DNA damage by a known chemopreventive agent. To this purpose, Sprague-Dawley rats received intratracheal instillations of sodium dichromate (0.25 mg/kg body weight) for three consecutive days, and the day after the last treatment lung and liver were removed for DNA purification. The results showed a selective localization of DNA lesions in the lung but not in the liver, which can be ascribed to toxicokinetics and metabolic characteristics of chromium(VI). DNA alterations included DNA-protein crosslinks, DNA fragmentation, nucleotidic modifications, and 8-hydroxy-2'-deoxyguanosine. The last two endpoints were evaluated, for the first time in chromium toxicology, by means of postlabeling procedures. This methodology was adapted to the detection of the DNA damage produced by those reactive oxygen species which result from the intracellular reduction of chromium(VI). The oral administration of the thiol N-acetylcysteine completely prevented any induction of DNA lesions in lung cells

Milk thistle for the treatment of liver disease: a systematic review and meta-analysis.

Jacobs BP, Dennehy C, Ramirez G, et al.

Am J Med. 2002 Oct 15; 113(6):506-15.

PURPOSE: Milk thistle, an herbal compound, is the dietary supplement taken most frequently by patients with chronic liver disease. We performed a systematic review of the literature to determine the efficacy and safety of this herb for the treatment of liver disease. METHODS: We searched English and non-English reports through July 1999 using thirteen databases and reference lists, and contacting manufacturers and technical experts. Reviewers independently screened all reports to identify randomized placebo-controlled trials that evaluated milk thistle for the treatment of liver disease. Outcomes of primary interest included mortality, histological findings on liver biopsy specimens, serum aminotransferase and albumin levels, and prothrombin times. RESULTS: Fourteen trials met inclusion criteria. Four trials reported outcomes for mortality among 433 participants. The overall summary odds ratio for mortality in the milk thistle group compared with placebo was 0.8 (95% confidence interval [CI]: 0.5 to 1.5; P = 0.6). Three trials assessed histology on liver biopsy; study quality was inversely associated with the likelihood of histological benefit for milk thistle compared with placebo. There were no differences in serum alanine aminotransferase, aspartate aminotransferase, or albumin levels, or prothrombin times, among participants assigned to milk thistle compared with those assigned to placebo. The only statistically significant difference was a greater reduction in alanine aminotransferase levels among patients with chronic liver disease assigned to milk thistle (-9 IU/L, 95% CI: -18 to -1 IU/L; P = 0.05), but this reduction was of negligible clinical importance and no longer statistically significant after limiting analyses to studies of longer duration or of higher quality. The frequency of adverse effects was low and, in clinical trials, indistinguishable from placebo. CONCLUSION: Treatment with milk thistle appears to be safe and well tolerated. We found no reduction in mortality, in improvements in histology at liver biopsy, or in biochemical markers of liver function among patients with chronic liver disease. Data are too limited to exclude a substantial benefit or harm of milk thistle on mortality, and also to support recommending this herbal compound for the treatment of liver disease

Does high soy milk intake reduce prostate cancer incidence? The Adventist Health Study (United States).

Jacobsen BK, Knutsen SF, Fraser GE.

Cancer Causes Control. 1998 Dec; 9(6):553-7.

OBJECTIVES: Recent experimental studies have suggested that isoflavones (such as genistein and daidzein) found in some soy products may reduce the risk of cancer. The purpose of this study was to evaluate the relationship between soy milk, a beverage containing isoflavones, and prostate cancer incidence. METHODS: A prospective study with 225 incident cases of prostate cancer in 12,395 California Seventh-Day Adventist men who in 1976 stated how often they drank soy milk. RESULTS: Frequent consumption (more than once a day) of soy milk was associated with 70 per cent reduction of the risk of prostate cancer (relative risk = 0.3, 95 percent confidence interval 0.1-1.0, p-value for linear trend = 0.03). The association was upheld when extensive adjustments were performed. CONCLUSIONS: Our study suggests that men with high consumption of soy milk are at reduced risk of prostate cancer. Possible associations between soy bean products, isoflavones and prostate cancer risk should be further investigated

The Effect of MGN-3 on Cisplatin and Adriamycin Induced Toxicity in the Rat 2000.

Jacoby H.

2004

Risk reduction for DDT toxicity and carcinogenesis through dietary modification.

Jaga K, Duvvi H.

J R Soc Health. 2001 Jun; 121(2):107-13.

Organochlorine pesticides, including dichlorodiphenyltrichloroethane (DDT), are an environmental hazard due to their persistent nature and potential health effects. DDT and 1,1,dichloro-2,2,bis(p-chlorophenyl)ethylene (DDE) are lipid-soluble pesticides which accumulate in fatty tissues and are, therefore, more present in fat-containing foods such as meat, fish, milk, cheese and oil than in fruit, vegetables and grain. Scientists have for some time been concerned about the human exposure to DDT and the potential risk of breast cancer due to its oestrogenic activity. The introduction of foods containing chemopreventive agents in the diet could inhibit the oestrogenic effects of DDT and the risk of developing cancer. Phytooestrogens are weak oestrogens found in certain plants such as soybean. They compete with DDT for oestrogen receptors and inhibit the oestrogenic effect of DDT on cultured human breast (MCF) cells. Curcumin, a spice widely used in Indian dishes, has anti-carcinogenic and anti-inflammatory properties. It also inhibits the oestrogenic effects of DDT and is synergistic with phytooestrogens. Indole-3-carbinol, a compound naturally found in cruciferous vegetables, stimulates oestrogen metabolism towards 2-hydroxyoestrone which reduces the oestrogenic response in MCF cells and the risk of breast cancer. Since DDT is lipid soluble and accumulates in adipose tissue it could have a role in lipid metabolism. Would a low fat diet reduce DDT bioaccumulation? A reduction in calories can decrease oestrogen levels and possibly reduce the risk of breast cancer. A dietary modification with the introduction of soy products, curcumin, cruciferous vegetables and low fat could be beneficial in reducing the risk of developing cancer and possibly the effects of DDT

Dietary polyunsaturated fatty acids and inflammatory mediator production.

James MJ, Gibson RA, Cleland LG.

Am J Clin Nutr. 2000 Jan; 71(1 Suppl):343S-8S.

Many antiinflammatory pharmaceutical products inhibit the production of certain eicosanoids and cytokines and it is here that possibilities exist for therapies that incorporate n-3 and n-9 dietary fatty acids. The proinflammatory eicosanoids prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) are derived from the n-6 fatty acid arachidonic acid (AA), which is maintained at high cellular concentrations by the high n-6 and low n-3 polyunsaturated fatty acid content of the modern Western diet. Flaxseed oil contains the 18-carbon n-3 fatty acid alpha-linolenic acid, which can be converted after ingestion to the 20-carbon n-3 fatty acid eicosapentaenoic acid (EPA). Fish oils contain both 20- and 22-carbon n-3 fatty acids, EPA and docosahexaenoic acid. EPA can act as a competitive inhibitor of AA conversion to PGE(2) and LTB(4), and decreased synthesis of one or both of these eicosanoids has been observed after inclusion of flaxseed oil or fish oil in the diet. Analogous to the effect of n-3 fatty acids, inclusion of the 20-carbon n-9 fatty acid eicosatrienoic acid in the diet also results in decreased synthesis of LTB(4). Regarding the proinflammatory ctyokines, tumor necrosis factor alpha and interleukin 1beta, studies of healthy volunteers and rheumatoid arthritis patients have shown < or = "90%" inhibition of cytokine production after dietary supplementation with fish oil. Use of flaxseed oil in domestic food preparation also reduced production of these cytokines. Novel antiinflammatory therapies can be developed that take advantage of positive interactions between the dietary fats and existing or newly developed pharmaceutical products

Cancer chemopreventive activity of resveratrol.

Jang M, Pezzuto JM.

Drugs Exp Clin Res. 1999; 25(2-3):65-77.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a naturally occurring compound shown to inhibit carcinogen-induced preneoplastic lesion formation in mouse mammary organ culture and tumorigenesis in the two-stage mouse skin model. Cancer chemopreventive potential was also suggested in various assays reflective of the three major stages of carcinogenesis. Anti-initiation activity was indicated by its antioxidant and antimutagenic effects, inhibition of the hydroperoxidase function of cyclooxygenase (COX), and induction of phase II drug-metabolizing enzymes. Antipromotion activity was indicated by antiinflammatory effects, inhibition of production of arachidonic acid metabolites catalyzed by either COX-1 or COX-2, and chemical carcinogen-induced neoplastic transformation of mouse embryo fibroblasts. Antiprogression activity was demonstrated by its ability to induce human promyelocytic leukemia (HL-60) cell differentiation. Moreover, pretreatment of mouse skin with resveratrol significantly counteracted 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced oxidative stress, as evidenced by numerous biochemical responses. Resveratrol reduced the generation of hydrogen peroxide, and normalized levels of myeloperoxidase and oxidized-glutathione reductase activities. It also restored glutathione levels and superoxide dismutase activity. As judged by the reverse transcriptase-polymerase chain reaction, resveratrol selectively inhibited TPA-induced expression of c-fos and transforming growth factor-beta 1 (TGF-beta 1), but did not affect other TPA-induced gene products including COX-1, COX-2, c-myc, c-jun, and tumor necrosis factor-alpha. These data indicate that resveratrol may interfere with reactive oxidant pathways and/or modulate the expression of c-fos and TGF-beta 1 to inhibit tumorigenesis in mouse skin. As reported herein, in addition to the activities described above, resveratrol inhibited the de novo formation of inducible nitric oxide synthase (iNOS) in mouse macrophages stimulated with lipopolysaccharide. This finding suggests an additional mechanism by which resveratrol may function as a cancer chemopreventive agent

An eicosapentainoic acid (EPA)-enriched supplement versus megestrol acetate (MA) versus both for patients with cancer-associated wasting.

Jatoi A RKLC.

Proc Am Soc Clin Oncol. 2003;(22):743.

2987

Curcumin induces a p53-dependent apoptosis in human basal cell carcinoma cells.

Jee SH, Shen SC, Tseng CR, et al.

J Invest Dermatol. 1998 Oct; 111(4):656-61.

Curcumin, a potent antioxidant and chemopreventive agent, has recently been found to be capable of inducing apoptosis in human hepatoma and leukemia cells by way of an elusive mechanism. Here, we demonstrate that curcumin also induces apoptosis in human basal cell carcinoma cells in a dose- and time-dependent manner, as evidenced by internucleosomal DNA fragmentation and morphologic change. In our study, consistent with the occurrence of DNA fragmentation, nuclear p53 protein initially increased at 12 h and peaked at 48 h after curcumin treatment. Prior treatment of cells with cycloheximide or actinomycin D abolished the p53 increase and apoptosis induced by curcumin, suggesting that either de novo p53 protein synthesis or some proteins synthesis for stabilization of p53 is required for apoptosis. In electrophoretic mobility gel-shift assays, nuclear extracts of cells treated with curcumin displayed distinct patterns of binding between p53 and its consensus binding site. Supportive of these findings, p53 downstream targets, including p21(CIP1/WAF1) and Gadd45, could be induced to localize on the nucleus by curcumin with similar p53 kinetics. Moreover, we immunoprecipitated extracts from basal cell carcinoma cells with different anti-p53 antibodies, which are known to be specific for wild-type or mutant p53 protein. The results reveal that basal cell carcinoma cells contain exclusively wild-type p53; however, curcumin treatment did not interfere with cell cycling. Similarly, the apoptosis suppressor Bcl-2 and promoter Bax were not changed with the curcumin treatment. Finally, treatment of cells with p53 antisense oligonucleotide could effectively prevent curcumin-induced intracellular p53 protein increase and apoptosis, but sense p53 oligonucleotide could not. Thus, our data suggest that the p53-associated signaling pathway is critically involved in curcumin-mediated apoptotic cell death. This evidence also suggests that curcumin may be a potent agent for skin cancer prevention or therapy

Effect of soy protein foods on low-density lipoprotein oxidation and ex vivo sex hormone receptor activity--a controlled crossover trial.

Jenkins DJ, Kendall CW, Garsetti M, et al.

Metabolism. 2000 Apr; 49(4):537-43.

Plant-derived estrogen analogs (phytoestrogens) may confer significant health advantages including cholesterol reduction, antioxidant activity, and possibly a reduced cancer risk. However, the concern has also been raised that phytoestrogens may be endocrine disrupters and major health hazards. We therefore assessed the effects of soy foods as a rich source of isoflavonoid phytoestrogens on LDL oxidation and sex hormone receptor activity. Thirty-one hyperlipidemic subjects underwent two 1-month low-fat metabolic diets in a randomized crossover study. The major differences between the test and control diets were an increase in soy protein foods (33 g/d soy protein) providing 86 mg isoflavones/2,000 kcal/d and a doubling of the soluble fiber intake. Fasting blood samples were obtained at the start and at weeks 2 and 4, with 24-hour urine collections at the end of each phase. Soy foods increased urinary isoflavone excretion on the test diet versus the control (3.8+/-0.7 v 0.0+/-0.0 mg/d, P < .001). The test diet decreased both oxidized LDL measured as conjugated dienes in the LDL fraction (56+/-3 v 63+/-3 micromol/L, P < .001) and the ratio of conjugated dienes to LDL cholesterol (15.0+/-1.0 v 15.7+/-0.9, P = ".032)," even in subjects already using vitamin E supplements (400 to 800 mg/d). No significant difference was detected in ex vivo sex hormone activity between urine samples from the test and control periods. In conclusion, consumption of high-isoflavone foods was associated with reduced levels of circulating oxidized LDL even in subjects taking vitamin E, with no evidence of increased urinary estrogenic activity. Soy consumption may reduce cardiovascular disease risk without increasing the risk for hormone-dependent cancers

Anti-angiogenic potential of a cancer chemopreventive flavonoid antioxidant, silymarin: inhibition of key attributes of vascular endothelial cells and angiogenic cytokine secretion by cancer epithelial cells.

Jiang C, Agarwal R, Lu J.

Biochem Biophys Res Commun. 2000 Sep 16; 276(1):371-8.

In recent studies, we have shown that silymarin, a naturally occurring flavonoid antioxidant, exhibits anti-cancer effects against several epithelial cancers. Here, we assessed its potential as an anti-angiogenic agent employing human umbilical vein endothelial cells (HUVEC) and human prostate and breast cancer epithelial cells. When sub-confluent HUVEC were treated for 48 h, adherent cell number decreased by 50 and 90% at 50 and 100 microg/ml doses, respectively. Apoptotic cell death principally accounted for cell loss at >50 microg/ml doses. In biochemical analysis, silymarin treatment of HUVEC for 6 h resulted in a concentration-dependent decrease in the secretion and cellular content of matrix metalloproteinase (MMP)-2/gelatinase A. Silymarin also inhibited HUVEC tube formation (in vitro capillary differentiation) on a reconstituted extracellular matrix, Matrigel. In other studies, 5 to 6 h exposure of DU145 prostate, and MCF-7 and MDA-MB-468 breast cancer cells to silymarin resulted in a dose-dependent decrease in the secreted vascular endothelial growth factor (VEGF) level in conditioned media without any visible change in cell morphology. The inhibitory effect of silymarin on VEGF secretion occurred as early as 1 h. These observations indicate a rapid inhibitory action of silymarin on the secretion of this primary angiogenic cytokine by cancer epithelial cells. Taken together, the results of this study support the hypothesis that silymarin possesses an anti-angiogenic potential that may critically contribute to its cancer chemopreventive efficacy

gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention.

Jiang Q, Christen S, Shigenaga MK, et al.

Am J Clin Nutr. 2001 Dec; 74(6):714-22.

gamma-tocopherol is the major form of vitamin E in many plant seeds and in the US diet, but has drawn little attention compared with alpha-tocopherol, the predominant form of vitamin E in tissues and the primary form in supplements. However, recent studies indicate that gamma-tocopherol may be important to human health and that it possesses unique features that distinguish it from alpha-tocopherol. gamma-Tocopherol appears to be a more effective trap for lipophilic electrophiles than is alpha-tocopherol. gamma-Tocopherol is well absorbed and accumulates to a significant degree in some human tissues; it is metabolized, however, largely to 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), which is mainly excreted in the urine. gamma-CEHC, but not the corresponding metabolite derived from alpha-tocopherol, has natriuretic activity that may be of physiologic importance. Both gamma-tocopherol and gamma-CEHC, but not alpha-tocopherol, inhibit cyclooxygenase activity and, thus, possess antiinflammatory properties. Some human and animal studies indicate that plasma concentrations of gamma-tocopherol are inversely associated with the incidence of cardiovascular disease and prostate cancer. These distinguishing features of gamma-tocopherol and its metabolite suggest that gamma-tocopherol may contribute significantly to human health in ways not recognized previously. This possibility should be further evaluated, especially considering that high doses of alpha-tocopherol deplete plasma and tissue gamma-tocopherol, in contrast with supplementation with gamma-tocopherol, which increases both. We review current information on the bioavailability, metabolism, chemistry, and nonantioxidant activities of gamma-tocopherol and epidemiologic data concerning the relation between gamma-tocopherol and cardiovascular disease and cancer

Regulation of cell adhesion, a central mechanism in the anticancer action of essential fatty acids (review).

Jiang WG.

Int J Mol Med. 1998 Mar; 1(3):621-5.

Certain members of essential fatty acids (EFAs) are known to have anticancer functions. It has been established in recent years that some of these anticancer actions are via the effects of these fatty acids on the adhesive properties of cancer cells, including cell-cell and cell-matrix adhesions. These discoveries have implicated EFAs as a group of novel agents, able to regulate adhesive function of cancer cells and thus bearing clinical importance

Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice.

Jin L, Qi M, Chen DZ, et al.

Cancer Res. 1999 Aug 15; 59(16):3991-7.

Mice that express transgenes for human papillomavirus type 16 under a keratin 14 promoter (K14-HPV16 mice) develop cervical cancer when they are given 17beta-estradiol chronically. We asked whether the antiestrogenic phytochemical indole-3-carbinol (I3C), found in cruciferous vegetables, administered at physiological doses, would prevent the cervical-vaginal cancer that is promoted in these mice by high doses of estrogen. We compared mice that were fed a control diet with those that were fed a diet supplemented with 2000 ppm I3C. In the group fed the control diet, at a dose of estradiol of 0.125 mg per 60-day release, 19 of 25 transgenic mice developed cervical-vaginal cancer within 6 months, and the remainder had dysplasia. Only 2 mice of 24 in the group fed the I3C supplemented diet developed cancer, and the remainder had dysplasia or hyperplasia. I3C reduced dysplasia in the nontransgenic mice. Similar results were obtained at a higher dose of estradiol (0.250 mg per 60-day release), and I3C helped to prevent morbidity associated with retention of fluid in the bladder that frequently occurred with the higher estradiol dose. Additionally, I3C appeared to reduce skin cancer in transgenic mice. These data indicate that I3C is a useful preventive for cervical-vaginal cancer and, possibly, other cancers with a papillomavirus component

Soy isoflavones increase latency of spontaneous mammary tumors in mice.

Jin Z, MacDonald RS.

J Nutr. 2002 Oct; 132(10):3186-90.

Soy protein, with and without isoflavones, is being added to foods by manufacturers in response to the Food and Drug Administration (FDA)-approved health claim for cardiovascular protection. Furthermore, soy isoflavones are increasingly consumed by women in the United States as an alternative to hormone replacement therapy. The role of these phytoestrogens in breast cancer is controversial. Although exposure of rodents to soy isoflavones during the perinatal period appears to reduce mammary cancer formation, exposure in utero or during adulthood may increase tumor growth. The mouse mammary tumor virus (MMTV)-neu mouse spontaneously develops mammary tumors due to overexpression of the ErbB-2/neu/HER2 oncogene. This model is comparable with human breast cancer because overexpression of the neu oncogene occurs in 20-40% of human breast cancers. We fed MMTV-neu mice AIN-93G diets containing no isoflavones, 250 mg/kg genistein, 250 mg/kg daidzein or an isoflavone mixture (NovaSoy, equivalent to 250 mg genistein/kg) from 7 wk of age. Mammary tumor latency was significantly delayed in mice fed isoflavones compared with the control. Once tumors formed, however, the isoflavones did not reduce the number or size of tumors such that at 34 wk of age there were no differences in tumor burden among the treatment groups. Hence, in the MMTV-neu mouse, soy isoflavones delayed mammary tumorigenesis. Further studies are warranted to define the cellular mechanisms through which these compounds affect mammary tumorigenesis in this model

Plasma coenzyme Q10 concentrations in breast cancer: prognosis and therapeutic consequences.

Jolliet P, Simon N, Barre J, et al.

Int J Clin Pharmacol Ther. 1998 Sep; 36(9):506-9.

BACKGROUND: Coenzyme Q10 or ubiquinone is a redox component of the respiratory chain, which may be involved in the pathogenesis of cancer. METHODS: In order to better understand the role of this vitamin in the pathogenesis of breast cancer, a clinical trial including 200 women hospitalized for the biopsy and/or the ablation of a breast tumor was conducted. Ubiquinone plasma concentrations were determined simultaneously with vitamin E plasma concentrations (as antioxidant reference) by HPLC. RESULTS: A coenzyme Q10 deficiency was noted both in carcinomas (80 patients) and non-malignant lesions (120 patients), while vitamin E concentrations were within the normal range. A correlation was shown between the intensity of the deficiency and the bad prognosis of the breast disease based on high TNM and SBR values or the lack of estrogen receptors. However, neither cathepsin D level nor adenopathy invasion was related to ubiquinone levels. CONCLUSIONS: Since prooxidants may promote tumorigenesis, ubiquinone supplementation in breast cancer could be relevant

Physiological concentrations of dietary genistein dose-dependently stimulate growth of estrogen-dependent human breast cancer (MCF-7) tumors implanted in athymic nude mice.

Ju YH, Allred CD, Allred KF, et al.

J Nutr. 2001 Nov; 131(11):2957-62.

Previously our laboratory has shown that the soy isoflavone, genistein, stimulates growth of human breast cancer (MCF-7) cells in vivo and in vitro. In this study, the dose-response analysis of genistein at the physiologically achievable concentration range between 125 and 1,000 microg/g in the diet was conducted in ovariectomized athymic nude mice implanted with MCF-7 cells. We hypothesized that genistein at this concentration range can stimulate dose-dependently the breast tumor growth, cell proliferation and an estrogen-responsive pS2 gene induction. Tumor size and body weight were monitored weekly. At completion of the study, we analyzed cellular proliferation of tumors using incorporation of BrdU, pS2 expression of tumors using a Northern blot analysis and total genistein level in plasma using liquid chromatography-isotope dilution mass spectrometry (LC-ES/MS). Dietary genistein (> or = 250 microg/g) increased tumor size in a dose-dependent manner [8.4x the negative control (NC) group in the 250 microg/g group, 12.0x in the 500 microg/g group, 20.2x in the 1,000 microg/g group and 23.2x in the positive control (PC) group]. The percentage of proliferating cells was significantly increased by genistein at and above 250 microg/g (5.3x the NC group in the 250 microg/g, 5.6x in the 500 microg/g, 5.0x in the 1,000 microg/g and 4.8x in the PC group). Expression of pS2 mRNA was also significantly increased with increasing dietary genistein levels (11.25x the NC group in the 500 microg/g group and 15.84x in the 1,000 microg/g group). Total plasma genistein concentrations were between 0.39 and 3.36 micromol/L in mice fed between 125 and 1,000 microg/g genistein. In conclusion, dietary treatment with genistein at physiological concentrations produces blood levels of genistein sufficient to stimulate estrogenic effects, such as breast tumor growth, cellular proliferation and pS2 expression in athymic mice in a dose-responsive manner similar to that seen in vitro

Effects of dietary broccoli on human drug metabolising activity.

Kall MA, Vang O, Clausen J.

Cancer Lett. 1997 Mar 19; 114(1-2):169-70.

Eighteen volunteers received 500 g fresh broccoli every day for 12 days after a 6-day period of standard diet. The activity of CYP1A2, CYP2E1 and the estrone 2 and 16alpha-hydroxylation were determined prior to and after the broccoli diet. The average activity of CYP1A2 and the average 2/16alpha-hydroxyestrone ratio were increased 19% (P < 0.0005) and 29.5% (P < 0.05), respectively; however, no effects were observed on the CYP2E1 activity

Wine antioxidant polyphenols inhibit the proliferation of human prostate cancer cell lines.

Kampa M, Hatzoglou A, Notas G, et al.

Nutr Cancer. 2000; 37(2):223-33.

The effect of different wine antioxidant polyphenols (catechin, epicatechin, quercetin, and resveratrol) on the growth of three prostate cancer cell lines (LNCaP, PC3, and DU145) was investigated. A dose- and time-dependent inhibition of cell growth by polyphenols was found at nanomolar concentrations. The proliferation of LNCaP and PC3 cells was preferentially inhibited by flavonoids (catechin, epicatechin, and quercetin), whereas resveratrol was the most potent inhibitor of DU145 cell growth. Possible mechanisms of action were investigated: 1) The competition of polyphenols for androgen binding in LNCaP cells revealed significant interaction only in the case of high concentrations of quercetin, at least at five orders of magnitude higher than the concentrations needed for cell growth inhibition. All other phenols showed low interactions. 2) Oxygen species production after mitogen stimulation and H2O2 sensitivity of these cell lines did not correlate with the observed antiproliferative effects, ruling out such a mode of action. 3) NO production revealed two different patterns: LNCaP and DU145 cells produced high concentrations of NO, whereas PC3 cells produced low concentrations. Phorbol ester stimulation of cells did not reveal any additional effect in LNCaP and DU145 cells, whereas it enhanced the secretion of NO in PC3 cells. Polyphenols decreased NO secretion. This effect correlates with their antiproliferative action and the inhibition of inducible NO synthase. It is therefore proposed that the antiproliferative effect of polyphenols is mediated through the modulation of NO production. In conclusion, our data show a direct inhibitory effect of low concentrations of antioxidant wine phenols on the proliferation of human prostate cancer cell lines mediated by the production of NO, further suggesting potential beneficial effects of wine and other phenol-containing foods or drinks for the control of prostate cancer cell growth

Resveratrol derivatives potently induce apoptosis in human promyelocytic leukemia cells.

Kang JH, Park YH, Choi SW, et al.

Exp Mol Med. 2003 Dec 31; 35(6):467-74.

Resveratrol has been shown to possess antioxidant and anticancer activities, but little is known on the effect of resveratrol derivatives. Recently we have isolated resveratrol and its dimers and trimers from peony (Paeonia lactiflora) seeds, and reported their strong antioxidant and cytotoxic activity. In the present study, we have evaluated cellular effects of resveratrol derivatives; viniferin, gnetin H, and suffruticosol B on the proliferation and apoptosis in HL-60 cells in vitro. All resveratrol and its derivatives reduced viability of HL-60 cells in a dose-dependent manner with their IC(50) values of 20-90 microM. Ascending orders of IC(50) values were suffruticosol B, gnetin H, viniferin and resveratrol respectively. HL-60 cells treated with the four stilbenes exhibited the distinct morphological changes characteristics of cell apoptosis such as chromatin condensation, apoptotic bodies, and DNA fragmentations. A time-dependent histogram of the cellular DNA analyzed by flow cytometry revealed a rapid increase in subdiploid cells and a concomitant decrease in diploid cells exposed to 100 microM resveratrol for 0-24 h. Cells treated with 25 microM of resveratrol, viniferin, gnetin H, and suffruticosol B for 24 h resulted in increment of sub-G1 population by 51, 5, 11 and 59%, respectively. Treatment of cells with 0-20 microM resveratrol for 5 h produced a concentration-dependent decrease in cytochrome P450 (CYP) 1B1 mRNA levels. Suffruticosol B also suppressed CYP1B1 gene expression. These results demonstrated that resveratrol oligomers also strongly suppressed HL-60 cell proliferation, and induced DNA damage. In addition, CYP1B1 gene supression may suggest an involvement in the resveratrol-induced apoptosis in HL-60 cells

Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study.

Kao YC, Zhou C, Sherman M, et al.

Environ Health Perspect. 1998 Feb; 106(2):85-92.

Flavone and isoflavone phytoestrogens are plant chemicals and are known to be competitive inhibitors of cytochrome P450 aromatase with respect to the androgen substrate. Aromatase is the enzyme that converts androgen to estrogen; therefore, these plant chemicals are thought to be capable of modifying the estrogen level in women. In this study, the inhibition profiles of four flavones [chrysin (5, 7-dihydroxyflavone), 7,8-dihydroxyflavone, baicalein (5,6,7-trihydroxyflavone), and galangin (3,5,7-trihydroxyflavone)], two isoflavones [genistein (4,5,7-trihydroxyisoflavone) and biochanin A (5,7-dihydroxy-4-methoxyisoflavone)], one flavanone [naringenin (4, 5,7-trihydroxyflavanone)], and one naphthoflavone (alpha-naphthoflavone) on the wild-type and six human aromatase mutants (I133Y, P308F, D309A, T310S, I395F, and I474Y) were determined. In combination with computer modeling, the binding characteristics and the structure requirement for flavone and isoflavone phytoestrogens to inhibit human aromatase were obtained. These compounds were found to bind to the active site of aromatase in an orientation in which rings A and C mimic rings D and C of the androgen substrate, respectively. This study also provides a molecular basis as to why isoflavones are significantly poorer inhibitors of aromatase than flavones

[S35 lipoic acid distribution and its effect on pyruvate dehydrogenase activity in rats with Walker carcinoma].

Karpov LM, Dvuzhil'naia ED, Savvov VI, et al.

Vopr Onkol. 1977; 23(10):87-90.

S35-lipoic acid injected intraperitoneally in rats with Walker carcinosarcoma in a dose of 250 mg/Kg is accumulated in their organs and tissues to much higher concentrations compared with normal animals during all terms of the observation (15 min, 1 hour, 24 hours). Differences were especially great after 24 hours. Pyruvate dehydrogenase activity in tumor rats organs was considerably reduced when calculated per 1 Kg of tissue, but it is practically unchanged when calculated per 1 mg of protein, which amount in 1 g of tissue in them is distinctly lower than in normal animals. Single injections of lipoic acid in tumor-bearing rats do restore the enzyme activity to normal (in 1 hour), while repeated ones (10 days)--prolong animals lifeterms by 25%

Pharmacologic activities of aged garlic extract in comparison with other garlic preparations.

Kasuga S, Uda N, Kyo E, et al.

J Nutr. 2001 Mar; 131(3s):1080S-4S.

We investigated the pharmacologic activities of four garlic preparations, raw garlic juice (RGJ), heated garlic juice (HGJ), dehydrated garlic powder (DGP) and aged garlic extract (AGE). The study used three animal models, i.e., testicular hypogonadism (hypospermatogensis and impotence) induced by warm water treatment, intoxication of acetaldehyde and growth of inoculated tumor cells. RGJ was found to be effective only in recovery of testicular function. The efficacy of HGJ was observed in three models; however, it did not improve impotence. DGP was effective in recovery of spermatogenesis and stimulated acetaldehyde detoxification. Significant beneficial effects of AGE were found in all three models. Although all four garlic preparations significantly enhanced natural killer (NK) and killer cell activities of the spleen cells of tumor-bearing mice, only AGE and HGJ inhibited the growth of inoculated tumor cells. These results suggest that different types of garlic preparations have different pharmacologic properties, and among the four garlic preparations studied, AGE could be the most useful garlic preparation

Indole-3-carbinol modulation of hepatic monooxygenases CYP1A1, CYP1A2 and FMO1 in guinea pig, mouse and rabbit.

Katchamart S, Williams DE.

Comp Biochem Physiol C Toxicol Pharmacol. 2001 Aug; 129(4):377-84.

Indole-3-carbinol (I3C), a major component of cruciferous vegetables, has been shown to be chemoprotective against cancer in a number of animal models and is being evaluated as a potential agent to prevent breast cancer in healthy women. Some concern has been raised related to the long-term use of I3C, as in some models chronic dietary post-initiation exposures promote cancers. I3C administration to rats marked induces several cytochrome P450s (CYPs), especially CYP1A1 (approx. 25-fold), while at the same time inhibiting the expression of FMO1. The consequence is a marked shift in the metabolic profile of drugs such as nicotine and tamoxifen, that are substrates for both monooxygenases. Such an effect could lead to adverse drug reactions in humans. In order to determine if the effect of I3C was manifest in species other than the rat, we fed 2000-ppm I3C to male guinea pigs, mice and rabbits for a period of 4 weeks. In each species, induction of CYP1A1/1A2 expression was observed in the liver but little or no effect on FMO1 was evident, with the possible exception of the rabbit. These data demonstrate that the ability of I3C to both induce CYP1A1 and inhibit FMO1, as observed in the rat, may not be common to other mammals for which FMO1 is the major isoform in the liver

Chemopreventive effect of curcumin, a naturally occurring anti-inflammatory agent, during the promotion/progression stages of colon cancer.

Kawamori T, Lubet R, Steele VE, et al.

Cancer Res. 1999 Feb 1; 59(3):597-601.

Curcumin, derived from the rhizome of Curcuma longa L. and having both antioxidant and anti-inflammatory properties, inhibits chemically induced carcinogenesis in the skin, forestomach, and colon when it is administered during initiation and/or postinitiation stages. This study was designed to investigate the chemopreventive action of curcumin when it is administered (late in the premalignant stage) during the promotion/progression stage of colon carcinogenesis in male F344 rats. We also studied the modulating effect of this agent on apoptosis in the tumors. At 5 weeks of age, groups of male F344 rats were fed a control diet containing no curcumin and an experimental AIN-76A diet with 0.2% synthetically derived curcumin (purity, 99.9%). At 7 and 8 weeks of age, rats intended for carcinogen treatment were given s.c. injections of azoxymethane (AOM) at a dose rate of 15 mg/kg body weight per week. Animals destined for the promotion/progression study received the AIN-76A control diet for 14 weeks after the second AOM treatment and were then switched to diets containing 0.2 and 0.6% curcumin. Premalignant lesions in the colon would have developed by week 14 following AOM treatment. They continued to receive their respective diets until 52 weeks after carcinogen treatment and were then sacrificed. The results confirmed our earlier study in that administration of 0.2% curcumin during both the initiation and postinitiation periods significantly inhibited colon tumorigenesis. In addition, administration of 0.2% and of 0.6% of the synthetic curcumin in the diet during the promotion/progression stage significantly suppressed the incidence and multiplicity of noninvasive adenocarcinomas and also strongly inhibited the multiplicity of invasive adenocarcinomas of the colon. The inhibition of adenocarcinomas of the colon was, in fact, dose dependent. Administration of curcumin to the rats during the initiation and postinitiation stages and throughout the promotion/progression stage increased apoptosis in the colon tumors as compared to colon tumors in the groups receiving AOM and the control diet. Thus, chemopreventive activity of curcumin is observed when it is administered prior to, during, and after carcinogen treatment as well as when it is given only during the promotion/progression phase (starting late in premalignant stage) of colon carcinogenesis

Conceptually new deltanoids (vitamin D analogs) inhibit multistage skin tumorigenesis.

Kensler TW, Dolan PM, Gange SJ, et al.

Carcinogenesis. 2000 Jul; 21(7):1341-5.

Development of vitamin D analogs (deltanoids) as chemopreventive agents requires separation of desirable antiproliferative and pro-differentiating activities from the undesirable calcemic activity also found in the hormone calcitriol (1 alpha, 25-dihydroxyvitamin D(3)). Therefore, several conceptually new deltanoids were synthesized with modifications to the 1alpha- and/or 25-hydroxyl groups, positions traditionally considered essential for stimulating biological responses. In this study, 1 beta-hydroxymethyl-3-epi-25-hydroxyvitamin D(3), a non-calcemic CH(2) homolog of the natural hormone with antiproliferative activity in vitro, was ineffective as an inhibitor of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced induction of ornithine decarboxylase activity in mouse epidermis. However, a hybrid analog incorporating not only the calcemia-ablating 1 beta-hydroxymethyl alteration, but potentiating C,D ring 16-unsaturation and side chain 24,24-fluorination and 26, 27-homologation was found to be as effective as calcitriol. Several non-calcemic 24- or 25-t-butyl sulfones, some containing side chain fluorination but all lacking the 25-hydroxyl group, were also shown to be active in this assay. Three sulfones and the 1 beta-hydroxymethyl hybrid were evaluated as inhibitors of multistage carcinogenesis in mouse skin. Female CD-1 mice were initiated with a single dose of 7,12-dimethylbenz[a]anthracene and then promoted twice weekly for 20 weeks with TPA. Deltanoids were applied topically 30 min before TPA. Unlike calcitriol, none of the atypical deltanoids affected body weight gain in these animals. Minimal effects on urinary calcium excretion were observed following chronic treatment with these analogs. All deltanoids inhibited the incidence and multiplicity of papilloma formation, with the hybrid analog showing the greatest efficacy. With this deltanoid, tumor incidence was significantly reduced by 28% and tumor multiplicity by 63%. These results, coupled with the rich chemical diversity available in side chain sulfur-containing deltanoids, particularly when combined with A ring modifications such as 1 beta-hydroxylalkyl groups, provide important new advances in the fundamental understanding of chemical structure-biological activity relationships as well as more potent and safe vitamin D analogs for cancer chemoprevention and other medicinal uses

Protein intermediate trapped by the simultaneous crystallization process. Crystal structure of an iron-saturated intermediate in the Fe3+ binding pathway of camel lactoferrin at 2.7 a resolution.

Khan JA, Kumar P, Srinivasan A, et al.

J Biol Chem. 2001 Sep 28; 276(39):36817-23.

This is the first protein intermediate obtained in the crystalline state by the simultaneous process of Fe(3+) binding and crystal nucleation and is also the first structure of an intermediate of lactoferrin in the Fe(3+) binding pathway. Lactoferrin is an iron-binding 80-kDa glycoprotein. It binds Fe(3+) very tightly in a closed interdomain cleft in both lobes. The iron-free structure of lactoferrin, on the other hand, adopts an open conformation with domains moving widely apart. These studies imply that initial Fe(3+) binding must be in the open form. The protein intermediate was crystallized by the microdialysis method. The protein solution, with a concentration of 100 mg/ml in 10 mm Tris-HCl, pH 8.0, was loaded in a capillary and dialyzed against the same buffer containing 26% (v/v) ethanol placed in a reservoir. FeCl(3) and CO(3)(2-) in excess molar ratios to that of protein in its solution were added to the reservoir buffer. The crystals appeared after some hours and grew to the optimum size within 36 h. The structure was determined by molecular replacement method and refined to final R- and R-free factors of 0.187 and 0.255, respectively. The present structure showed that the protein molecule adopts an open conformation similar to that of camel apolactoferrin. The electron density map clearly indicated the presence of two iron atoms, one in each lobe with 4-fold coordinations: two by the protein ligands of Tyr-92(433) OH and Tyr-192(526) OH and two other coordination sites occupied by oxygen atoms of bidentate CO(3)(2-) ions leading to a tetrahedral intermediate. The CO(3)(2-) anion is stabilized through hydrogen bonds with the synergistic anion-binding site Arg-121(463) and with Ser-122 Ogamma in the N-lobe and Thr-464 Ogamma in C-lobe. The third oxygen atom of CO(3)(2-) interacts with a water molecule in both lobes

Synergistic effect of genistein and BCNU on growth inhibition and cytotoxicity of glioblastoma cells.

Khoshyomn S, Nathan D, Manske GC, et al.

J Neurooncol. 2002 May; 57(3):193-200.

OBJECTIVE: Recent experiments have shown that dietary soy isoflavones such as genistein can significantly suppress invasiveness and growth of a number of human malignancies. This study examined whether genistein, at a concentration typical of plasma levels following soy diet intake, in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU, carmustine) exhibited an additive or synergistic inhibitory effect on the growth of glioma cells. METHODS: The human glioblastoma multiforme (GBM) cell line U87 and the rodent C6 glioma were treated with genistein at 4 microM, combined with BCNU (0-50 microM). Monolayer cell growth and cytotoxicity, as measured by colonigenic survival in soft agarose, were then compared in control and drug-treated cultures. Presence of apoptosis, using the DNA ladder assay and laser scanning cytometry (LSC), was investigated in all cell lines at those concentrations where an enhancement of antiproliferative effect of BCNU in presence of genistein was observed. RESULTS: A 32-41% increase in monolayer growth inhibition and a 28-42% increase in colony cytotoxicity in the U87 cell line were observed when genistein (4 microM) was added to BCNU in the 0-10 microM dose range. In the C6 cell line, a 30-36% increase in monolayer growth inhibition and a 39-54% increase in colony cytotoxicity were observed with the BCNU dose range of 0-50 microM. All experiments showed a significant increase in growth inhibition and a decrease in colonogenic survival (P < 0.05). We were unable to detect apoptosis in any of the lines when genistein was combined with BCNU. CONCLUSION: These results indicate that genistein at typical adult dietary plasma levels can significantly enhance the antiproliferative and cytotoxic action of BCNU. The implication for treatment of GBM may be a reduction in the chemotherapeutic dose recommendations of these agents and subsequently a decrease in the risk of treatment sequelae for these patients

A new approach to metastatic cancer prevention: modified citrus pectin (MCP), a unique pectin that blocks cell surface lectins.

Kidd P.

Altern Med Rev. 1996;(1):4-10.

Melatonin as Antioxidant 2000.

Kim SJ.

2000

Resveratrol isolated from Polygonum cuspidatum root prevents tumor growth and metastasis to lung and tumor-induced neovascularization in Lewis lung carcinoma-bearing mice.

Kimura Y, Okuda H.

J Nutr. 2001 Jun; 131(6):1844-9.

Resveratrol is a naturally occurring phytoalexine found in medicinal plants. We found that resveratrol, at doses of 2.5 and 10 mg/kg, significantly reduced the tumor volume (42%), tumor weight (44%) and metastasis to the lung (56%) in mice bearing highly metastatic Lewis lung carcinoma (LLC) tumors, but not at a dose of 0.6 mg/kg. Resveratrol did not affect the number of CD4(+), CD8(+) and natural killer (NK)1.1.(+) T cells in the spleen. Therefore, the inhibitory effects of resveratrol on tumor growth and lung metastasis could not be explained by natural killer or cytotoxic T-lymphocyte activation. In addition, resveratrol inhibited DNA synthesis most strongly in LLC cells; its 50% inhibitory concentration (IC(50)) was 6.8 micromol/L. Resveratrol at 100 micromol/L increased apoptosis to 20.6 +/- 1.35% from 12.1 +/- 0.36% (P < 0.05) in LLC cells, and decreased the S phase population to 22.1 +/- 1.03% and 29.2 +/- 0.27% from 35.2 +/- 1.72% (P < 0.05) at concentrations of 50 and 100 micromol/L, respectively. Resveratrol inhibited tumor-induced neovascularization at doses of 2.5 and 10 mg/kg in an in vivo model. Moreover, resveratrol significantly inhibited the formation of capillary-like tube formation from human umbilical vein endothelial cells (HUVEC) at concentrations of 10-100 micromol/L; the degree of the inhibition of capillary-like tube formation by resveratrol was 45.5% at 10 micromol/L, 50.2% at 50 micromol/L and 52.6% at 100 micromol/L. Resveratrol inhibited the binding of vascular endothelial growth factor (VEGF) to HUVEC at concentrations of 10-100 micromol/L, but not at concentrations of 1 and 5 micromol/L. The degree of inhibition of VEGF binding to HUVEC by resveratrol was 16.9% at 10 micromol/L, 53.2% at 50 micromol/L and 47.8% at 100 micromol/L. We suggest that the antitumor and antimetastatic activities of resveratrol might be due to the inhibition of DNA synthesis in LLC cells and the inhibition of LLC-induced neovascularization and tube formation (angiogensis) of HUVEC by resveratrol

Low alpha-linolenic acid content of adipose breast tissue is associated with an increased risk of breast cancer.

Klein V, Chajes V, Germain E, et al.

Eur J Cancer. 2000 Feb; 36(3):335-40.

Data derived from experimental studies suggest that alpha-linolenic acid may have a protective effect in breast cancer. Observations obtained from epidemiological studies have not allowed conclusions to be drawn about a potential protective effect of dietary alpha-linolenic acid on breast cancer, possibly because of methodological issues. This case-control study conducted in an homogeneous population from a central area in France was designed to explore the hypothesis that alpha-linolenic acid inhibits breast cancer, using fatty acid levels in adipose breast tissue as a biomarker of past qualitative dietary intake of fatty acids. Biopsies of adipose breast tissue at the time of diagnosis were obtained from 123 women with invasive non-metastatic breast carcinoma. 59 women with benign breast disease served as controls. Individual fatty acids were analysed by capillary gas chromatography. An unconditional logistic regression model was used to obtain odds ratio estimates whilst adjusting for age, menopausal status and body mass index (BMI). No association was found between fatty acids (saturates, monounsaturates, long-chain polyunsaturates n-6 or n-3) and the disease, except for alpha-linolenic acid which showed an inverse association with the risk of breast cancer. The relative risk of breast cancer for women in the highest quartile of adipose breast tissue alpha-linolenic acid level was 0.36 (95% confidence interval=0.12-1.02) compared with those in the lowest quartile (P trend=0.026), suggesting a protective effect of alpha-linolenic acid in the risk of breast cancer. The effects of dietary alpha-linolenic on the risk of breast cancer warrant further study

Glutamine facilitates chemotherapy while reducing toxicity.

Klimberg VS, Nwokedi E, Hutchins LF, et al.

JPEN J Parenter Enteral Nutr. 1992 Nov; 16(6 Suppl):83S-7S.

Dose intensification of chemotherapy is thought to increase survival. With recent advances in hemopoietic cell modulators such as granulocyte colony stimulating factor, the limiting toxicity of intensifying chemotherapeutic regimens has become the severity of the associated enterocolitis. In animal models, glutamine protects the host from methotrexate-induced enterocolitis. This study evaluates the effects of a glutamine-supplemented diet on the tumoricidal effectiveness of methotrexate. Sarcoma-bearing Fisher 344 rats (n = 30) were pair-fed an isocaloric elemental diet containing 1% glutamine or an isonitrogenous amount of glycine beginning on day 25 of the study. Rats from each group received two intraperitoneal injections of methotrexate (5 mg/kg) or saline on days 26 and 33 of the study. On day 40, rats were killed, tumor volume and weight were recorded, and tumor glutaminase activity and tumor morphometrics were measured. Blood was taken for arterial glutamine content, complete blood count, and blood culture. The gut was processed for glutaminase activity and synthesis phase of the deoxyribonucleic acid. In rats receiving methotrexate, the tumor volume loss was nearly doubled when glutamine was added to the diet. Significant differences in tumor glutaminase activity and morphometrics were not detected. The toxicity to the host was ameliorated. Significantly increased synthesis phase of deoxyribonucleic acid of the whole jejunum, decreased bacteremia, "sepsis," and mortality were demonstrated. Glutamine supplementation enhances the tumoricidal effectiveness of methotrexate while reducing its morbidity and mortality in this sarcoma rat model

Glutamine suppresses PGE2 synthesis and breast cancer growth.

Klimberg VS, Kornbluth J, Cao Y, et al.

J Surg Res. 1996 Jun; 63(1):293-7.

Reduced natural killer (NK) activity found in tumor-bearing hosts has been associated with high levels of prostaglandin E2 (PGE2) produced by monocytes in vitro. We have previously demonstrated a dependence of NK cell activity on glutamine (GLN) levels in vitro and in vivo. Further, glutathione (GSH) is antagonistic to PGE2 synthesis. We hypothesized that GLN, through increased GSH production, leads to decreased PGE2 synthesis and upregulation of NK cytotoxic activity. To test this, we examined the effects of oral GLN on GSH and PGE2 concentrations, NK activity and tumor growth in a rat breast cancer model. Starting on the day of MTF-7 tumor implantation 18 Fisher 344 rats were pair-fed chow and gavaged with 1 g/kg/day GLN (n = 9) or an isonitrogenous amount of Freamine (FA) (n = 9). Seven weeks after tumor implantation rats were sacrificed. Tumors were measured, weighed, and processed for tumor morphometrics. Spleens were removed, lymphocytes isolated and assayed for NK activity. Blood GLN, GSH, and PGE2 concentrations were measured. Over the 7-week study period tumor growth was decreased by approximately 40% in the GLN-supplemented group. This decrease in growth was associated with a 2.5 fold greater NK activity in the GLN-fed rats vs FA-fed rats. This correlated with a 25% rise in GSH concentration and a proportional decrease in PGE2 synthesis. Decreased tumor volume in rats fed GLN was not associated with changes in morphometrics. Oral GLN supplementation enhances NK activity resulting in decreased tumor growth. The enhanced NK activity seen with oral GLN supplementation in the tumor-bearing host is associated with GSH mediated suppression of PGE2 synthesis

Claude H. Organ, Jr. Honorary Lectureship. Glutamine, cancer, and its therapy.

Klimberg VS, McClellan JL.

Am J Surg. 1996 Nov; 172(5):418-24.

OBJECTIVE: This overview on glutamine, cancer and its therapy discusses some of the in vitro and in vivo work on glutamine and tumor growth, and summarizes animal and human data on the potential benefits of glutamine in the tumor-bearing host receiving radiation or chemotherapy. BACKGROUND: Glutamine is the most abundant amino acid in the body. A tumor can act as a "glutamine trap," depleting host glutamine stores and resulting in cachexia. In vitro evidence of the dependence of tumor growth on glutamine has deterred its use in the clinic setting. METHODS: Data from a variety of investigations studying glutamine's interaction with the tumor-bearing host receiving radiation or chemotherapy were compiled and summarized. RESULTS: A large body of evidence in vivo suggests that supplemental glutamine does not make tumors grow but in fact results in decreased growth through stimulation of the immune system. When given with radiation or chemotherapy, glutamine protects the host and actually increases the selectivity of therapy for the tumor. CONCLUSION: Further prospective randomized trials are needed to demonstrate the safety and efficacy in humans undergoing radiation and chemotherapy

Risk of breast cancer among Norwegian women with visual impairment.

Kliukiene J, Tynes T, Andersen A.

Br J Cancer. 2001 Feb 2; 84(3):397-9.

Experimental studies suggest that melatonin has a protective effect against breast cancer. Exposure to light suppresses melatonin secretion, but to a lesser degree in totally blind persons. Breast cancer was investigated in a cohort of 15 412 Norwegian visually impaired women. The risk among totally blind women was 0.64 (95% CI = 0.21-1.49, 5 cases only), and for those who became blind before age of 65, the SIR was 0.51 (95% CI = 0.11-1.49). Our findings give support to the 'melatonin hypothesis'

Vegetables, fruits, legumes and prostate cancer: a multiethnic case-control study.

Kolonel LN, Hankin JH, Whittemore AS, et al.

Cancer Epidemiol Biomarkers Prev. 2000 Aug; 9(8):795-804.

The evidence for a protective effect of vegetables, fruits, and legumes against prostate cancer is weak and inconsistent. We examined the relationship of these food groups and their constituent foods to prostate cancer risk in a multicenter case-control study of African-American, white, Japanese, and Chinese men. Cases (n = 1619) with histologically confirmed prostate cancer were identified through the population-based tumor registries of Hawaii, San Francisco, and Los Angeles in the United States and British Columbia and Ontario in Canada. Controls (n = 1618) were frequency-matched to cases on ethnicity, age, and region of residence of the case, in a ratio of approximately 1:1. Dietary and other information was collected by in-person home interview; a blood sample was obtained from control subjects for prostate-specific antigen determination. Odds ratios (OR) were estimated using logistic regression, adjusting for age, geographic location, education, calories, and when indicated, ethnicity. Intake of legumes (whether total legumes, soyfoods specifically, or other legumes) was inversely related to prostate cancer (OR for highest relative to lowest quintile for total legumes = 0.62; P for trend = 0.0002); results were similar when restricted to prostate-specific antigen-normal controls or to advanced cases. Intakes of yellow-orange and cruciferous vegetables were also inversely related to prostate cancer, especially for advanced cases, among whom the highest quintile OR for yellow-orange vegetables = 0.67 (P for trend = 0.01) and the highest quintile OR for cruciferous vegetables = 0.61 (P for trend = 0.006). Intake of tomatoes and of fruits was not related to risk. Findings were generally consistent across ethnic groups. These results suggest that legumes (not limited to soy products) and certain categories of vegetables may protect against prostate cancer

Clinical conference: Unusual course of chronic colitis.

Konig H, Hermanek P, Rosch W.

Acta Hepatogastroenterol (Stuttg). 1976 Jun; 23(3):227-31.

Case presentation of a 35-year-old patient with a history of chronic colitis of 16 years duration. Crohn's disease in this patient involved the entire colon without skip lesions and without terminal ileitis. The course was complicated by recurrent erythema nodosum and wandering arthritis as well as sclerosing cholangitis and multifocal adenocarcinoma of the large bowel. Sclerosing cholangitis is a rare condition in Crohn's disease (1,8) whereas pericholangitis in liver biopsy specimen was diagnosed in prospective studies in 8 (7) to 30 (2) per cent. The same is true for carcinomas complicating granulomatous enterocolitis. In a recent review 36 cases of small bowel cancer (4) and 20 cases of colon cancer (5) were reported. Weedon et al. (9) calculated the risk of developing carcinoma to be 20 times greater in Crohn's enterocolitis than in a control population. Using life-table methods the 10-year probability of remaining cancer free was 99.7 per cent, the 20-year probability 97.2 per cent. In our patient the long-lasting history of Crohn's colitis with several minor complications and the multiplicity of colonic carcinomas speak in favor of a causal relationship between the chronic inflammation and the development of malignancy

Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the 'French paradox'?

Kopp P.

Eur J Endocrinol. 1998 Jun; 138(6):619-20.

Inhibition of ligand-induced activation of epidermal growth factor receptor tyrosine phosphorylation by curcumin.

Korutla L, Cheung JY, Mendelsohn J, et al.

Carcinogenesis. 1995 Aug; 16(8):1741-5.

We explored the regulation of epidermal growth factor (EGF)-mediated activation of EGF receptor (EGF-R) phosphorylation by curcumin (diferuloyl-methane), a recently identified kinase inhibitor, in cultured NIH 3T3 cells expressing human EGF-R. Treatment of cells with a saturating concentration of EGF for 5-15 min induced increased EGF-R tyrosine phosphorylation by 4- to 11-fold and this was inhibited in a dose- and time-dependent manner by up to 90% by curcumin, which also inhibited the growth of EGF-stimulated cells. There was no effect of curcumin treatment on the amount of surface expression of labeled EGF-R and inhibition of EGF-mediated tyrosine phosphorylation of EGF-R by curcumin was mediated by a reversible mechanism. In addition, curcumin also inhibited EGF-induced, but not bradykinin-induced, calcium release. These findings demonstrate that curcumin is a potent inhibitor of a growth stimulatory pathway, the ligand-induced activation of EGF-R, and may potentially be useful in developing anti-proliferative strategies to control tumor cell growth

Inhibitory effects of carotenoids on the invasion of rat ascites hepatoma cells in culture.

Kozuki Y, Miura Y, Yagasaki K.

Cancer Lett. 2000 Apr 3; 151(1):111-5.

The effects of carotenoids--alpha-carotene, beta-carotene, lycopene, beta-cryptoxanthin, zeaxanthin, lutein, canthaxanthin, astaxanthin--on the invasion of rat ascites hepatoma AH109A cells were investigated by co-culturing the hepatoma cells with rat mesentery-derived mesothelial cells (M-cells). All the carotenoids examined inhibited AH109A invasion in a dose-dependent manner up to 5 microM. Cancer cells previously cultured with hypoxanthine (HX) and xanthine oxidase (XO) showed a highly invasive activity. Carotenoids, 5 microM of beta-carotene and astaxanthin, suppressed this reactive oxygen species-potentiated invasive capacity by simultaneously treating AH109A cells with the carotenoids, HX and XO. These results suggest that the antioxidative property of these carotenoids may be involved in their anti-invasive action

Resveratrol suppresses hepatoma cell invasion independently of its anti-proliferative action.

Kozuki Y, Miura Y, Yagasaki K.

Cancer Lett. 2001 Jun 26; 167(2):151-6.

Resveratrol, found in grapes, is a phytoalexin with antioxidative activity. The compound (100 and 200 microM) inhibited the proliferation of hepatoma cells, although this phytoalexin exerted little influence up to 50 microM. Resveratrol, however, suppressed the invasion of the hepatoma cells even at a concentration of 25 microM. Sera from rats orally given resveratrol restrained only the invasion of AH109A cells. Resveratrol and resveratrol-loaded rat serum suppressed reactive oxygen species-potentiated invasive capacity. These results suggest that the anti-invasive activity of resveratrol is independent of the anti-proliferative activity, and that the antioxidative property of resveratrol may be involved in its anti-invasive action

Cimetidine modulates the antigen presenting capacity of dendritic cells from colorectal cancer patients.

Kubota T, Fujiwara H, Ueda Y, et al.

Br J Cancer. 2002 Apr 22; 86(8):1257-61.

Cimetidine, a H(2) receptor antagonist, has been reported to improve survival in gastrointestinal cancer patients. These effects have largely been attributed to the enhancing effects of cimetidine on the host's antitumour cell-mediated immune response, such as inhibition of suppressor T lymphocyte activity, stimulation of natural killer cell activity and increase of interleukin-2 production from helper T lymphocytes. We conducted an in vitro study on the effects of cimetidine on differentiation and antigen presenting capacity of monocyte-derived dendritic cells from advanced colorectal cancer patients and normal controls. As a result, an investigation of expression of surface molecules associated with dendritic cells by flow cytometric analyses showed that cimetidine had no enhancing effect on differentiation of dendritic cells from cancer patients and normal controls. An investigation of [(3)H]thymidine incorporation by allogeneic mixed lymphocyte reactions revealed that cimetidine increased the antigen presenting capacity of dendritic cells from both materials. Moreover, a higher antigen presenting capacity was observed in advanced cancer patients compared to normal controls. These effects might be mediated via specific action of cimetidine and not via H(2) receptors because famotidine did not show similar effects. Our results suggest that cimetidine may enhance the host's antitumour cell-mediated immunity by improving the suppressed dendritic cells function of advanced cancer patients

Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy.

Kucuk O, Sarkar FH, Sakr W, et al.

Cancer Epidemiol Biomarkers Prev. 2001 Aug; 10(8):861-8.

An inverse association has been observed between dietary intake of lycopene and the risk of prostate cancer. We investigated the effects of lycopene supplementation in patients with prostate cancer. Twenty-six men with newly diagnosed, clinically localized (14 T(1) and 12 T(2)) prostate cancer were randomly assigned to receive 15 mg of lycopene (n = 15) twice daily or no supplementation (n = 11) for 3 weeks before radical prostatectomy. Biomarkers of differentiation and apoptosis were assessed by Western blot analysis on benign and malignant parts of the prostate gland. Prostatectomy specimens were entirely embedded, step-sectioned, and evaluated for pathological stage, Gleason score, volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia. Plasma levels of lycopene, insulin-like growth factor-1 (IGF-1), IGF binding protein-3, and prostate-specific antigen were measured at baseline and after 3 weeks of supplementation or observation. Eleven (73%) subjects in the intervention group and two (18%) subjects in the control group had no involvement of surgical margins and/or extra-prostatic tissues with cancer (P = 0.02). Twelve (84%) subjects in the lycopene group and five (45%) subjects in the control group had tumors <4 ml in size (P = "0.22)." Diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia was present in 10 (67%) subjects in the intervention group and in 11 (100%) subjects in the control group (P = "0.05)." Plasma prostate-specific antigen levels decreased by 18% in the intervention group, whereas they increased by 14% in the control group (P = "0.25)." Expression of connexin 43 in cancerous prostate tissue was 0.63 +/- 0.19 absorbance in the lycopene group compared with 0.25 +/- 0.08 in the control group (P = "0.13)." Expression of bcl-2 and bax did not differ significantly between the two study groups. IGF-1 levels decreased in both groups (P = "0.0002" and P = "0.0003," respectively). The results suggest that lycopene supplementation may decrease the growth of prostate cancer. However, no firm conclusions can be drawn at this time because of the small sample size

Berberine complexes with DNA in the berberine-induced apoptosis in human leukemic HL-60 cells.

Kuo CL, Chou CC, Yung BY.

Cancer Lett. 1995 Jul 13; 93(2):193-200.

Berberine, an alkaloid initially isolated from Chinese herbal medicine exhibited the ability to induce morphological changes and internucleosomal DNA fragmentation, characteristic of apoptosis in promyelocytic leukemia HL-60 cells. Cell cycle studies showed that only about 20% of the cells underwent apoptosis at the early time (6 h) of berberine (25 micrograms/ml) treatment; these appeared to be cells in S phase at the time of berberine treatment. At extended time (6-48 h), cells were cell cycle arrested, the number of cells of each phase, particularly the cells of S phase decreased and much more (> 50%) of the cells appeared with DNA content less than G1. Attempts were also made to isolate possible berberine-DNA complexes from cell cultures treated with berberine (25 micrograms/ml; 2-24 h). Shifts of absorption maxima of berberine in the direction of longer wavelengths were observed in the isolated berberine-DNA complexes. Palmatine, an analog of berberine, which was not able to induce apoptosis, also complexed with DNA in cells treated with palmatine (25 micrograms/ml; 2-24 h). Our results suggest that some important cellular processes other than the intracellular DNA-interacting action of berberine may be involved in the berberine-induced apoptosis in HL-60 cells

Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells.

Kuo ML, Huang TS, Lin JK.

Biochim Biophys Acta. 1996 Nov 15; 1317(2):95-100.

Curcumin, widely used as a spice and coloring agent in food, possesses potent antioxidant, anti-inflammatory and anti-tumor promoting activities. In the present study, curcumin was found to induce apoptotic cell death in promyelocytic leukemia HL-60 cells at concentrations as low as 3.5 micrograms/ml. The apoptosis-inducing activity of curcumin appeared in a dose- and time-dependent manner. Flow cytometric analysis showed that the hypodiploid DNA peak of propidium iodide-stained nuclei appeared at 4 h after 7 micrograms/ml curcumin treatment. The apoptosis-inducing activity of curcumin was not affected by cycloheximide, actinomycin D, EGTA, W7 (calmodulin inhibitor), sodium orthovanadate, or genistein. By contrast, an endonuclease inhibitor ZnSO4 and proteinase inhibitor N-tosyl-L-lysine chloro-methyl ketone (TLCK) could markedly abrogate apoptosis induced by curcumin, whereas 12-O-tetradecanoylphorbol-13-acetate (TPA) had a partial effect. The antioxidants, N-acetyl-L-cysteine (NAC), L-ascorbic acid, alpha-tocopherol, catalase and superoxide dismutase, all effectively prevented curcumin-induced apoptosis. This result suggested that curcumin-induced cell death was mediated by reactive oxygen species. Immunoblot analysis showed that the level of the antiapoptotic protein Bcl-2 was decreased to 30% after 6 h treatment with curcumin, and was subsequently reduced to 20% by a further 6 h treatment. Furthermore, overexpression of bcl-2 in HL-60 cells resulted in a delay of curcumin-treated cells entering into apoptosis, suggesting that bcl-2 plays a crucial role in the early stage of curcumin-triggered apoptotic cell death

Genistein studies in rats: potential for breast cancer prevention and reproductive and developmental toxicity.

Lamartiniere CA, Zhang JX, Cotroneo MS.

Am J Clin Nutr. 1998 Dec; 68(6 Suppl):1400S-5S.

Asian women and men who consume a traditional diet high in soy products have low incidences of breast and prostate cancers, respectively. Yet Asians who immigrate to the United States and adopt a Western diet lose this protection. We investigated the potential of genistein, a component of soy, to protect against breast cancer and to cause reproductive and developmental toxicity. Our study showed that injections of genistein in rats during the prepubertal period resulted in a 50% reduction of chemically induced mammary tumorigenesis. Studies in mammary whole mounts revealed that prepubertal genistein exposure resulted in fewer terminal end buds and more lobules type II. Cell proliferation in the terminal end buds of adult rats treated prepubertally with genistein was less than that in animals treated with the vehicle (dimethyl sulfoxide). Reproductive and developmental toxicity studies did not find significant alterations to fertility, number of male and female offspring, body weight, anogenital distance, vaginal opening, testes descent, estrus cycle, or follicular development. We concluded that pharmacologic doses of genistein given to immature rats enhance mammary gland differentiation, resulting in a significantly less proliferative gland that is not as susceptible to mammary cancer. We speculate that breast cancer protection in Asian women consuming traditional soy-containing diets is, in part, derived from early exposure to genistein-containing soy. We believe that early programming events are essential for cancer protection benefits

Garlic: the new cancer-fighting candidate.

Langer S.

Better Nutrition for Today's Living 1991 Jun. 1991;Jun

Garlic Research Update.

Lau B.

1991;1991a;

Superiority of intralesional immunotherapy with Corynebacterium parvum and Allium sativum in control of murine transitional cell carcinoma.

Lau BH, Woolley JL, Marsh CL, et al.

J Urol. 1986 Sep; 136(3):701-5.

Immunotherapy with bacillus Calmette-Guerin (BCG), Corynebacterium parvum (CP), keyhole limpet hemocyanin (KLH) and an extract of Allium sativum (AS) was studied in a transitional cell carcinoma (MBT-2) in mice. Comparison was made between intraperitoneal (IP) versus intralesional (IL) administration of these agents. C3H/He mice were transplanted subcutaneously in the hind limb with 5 X 10(4) tumor cells. After transplantation, mice were randomized into groups to receive either IP or IL treatments with BCG (2 X 10(6) CFU), CP (250 micrograms.), KLH (50 micrograms.) or AS (25 mg.). At weekly intervals the tumor volume was determined. To assess the local cellular events following these treatments, histopathological studies were performed 10 days after tumor transplant with tissues removed from the injected sites. IL route was much more effective than IP route in inhibiting tumor growth. CP and AS exhibited more significant therapeutic effect than BCG or KLH. No tumor developed in mice which received five IL treatments of CP or AS. The data indicate that CP or AS may serve as effective biological response modifiers in controlling transitional cell carcinoma. The study further emphasizes that route and frequency of administration are crucial variables determining efficacy of immunotherapy

Garlic compounds modulate macrophage and T-lymphocyte functions.

Lau BH, Yamasaki T, Gridley DS.

Mol Biother. 1991 Jun; 3(2):103-7.

Organosulfur compounds of garlic have been shown to inhibit growth of animal tumors and to modulate the activity of diverse chemical carcinogens. There is also evidence that garlic may modulate antitumor immunity. In this study, we determined the effects of an aqueous garlic extract and a protein fraction isolated from the extract on the chemiluminescent oxidative burst of the murine J774 macrophage cell line and thioglycollate-elicited peritoneal macrophages obtained from BALB/c mice. T-lymphocyte activity was determined using mouse splenocytes incubated with phytohemagglutinin, labeled with [3H]-thymidine and assayed for lymphoproliferation. Significant dose-related augmentation of oxidative burst was observed with garlic extract and the protein fraction. The protein fraction also enhanced the T-lymphocyte blastogenesis. The data suggest that garlic compounds may serve as biological response modifiers by augmenting macrophage and T-lymphocyte functions

Expression of estrogen receptor (ER)-alpha and ER-beta in normal and malignant prostatic epithelial cells: regulation by methylation and involvement in growth regulation.

Lau KM, LaSpina M, Long J, et al.

Cancer Res. 2000 Jun 15; 60(12):3175-82.

The aim of the current study is to demonstrate normal and malignant prostatic epithelial cells (PrECs) as targets for receptor-mediated estrogenic and antiestrogenic action. Using an improved protocol, we have successfully isolated and maintained highly enriched populations of normal PrECs from ultrasound-guided peripheral zone biopsies, individually determined to be morphologically normal. Semiquantitative reverse transcription-PCR analyses were used to determine whether transcripts of estrogen receptor (ER)-alpha and those of ER-beta were expressed in our normal PrEC primary cultures, in a commercially available PrEC preparation (PrEC; Clontech), in an immortalized PrEC line established from a benign prostatic hyperplasia specimen (BPH-1), and in three prostatic cancer cell lines (LNCaP, PC-3, and DU145). Expression levels of ER-alpha and ER-beta transcripts were related to those of two estrogen-responsive genes [progesterone receptor (PR) and pS2], at the message levels, to gain insights into the functionality of the ER subtypes in PrECs. Interestingly, only transcripts of ER-beta, but not those of ER-alpha, were found in our primary cultures of normal PrECs, along with both PR and pS2 mRNA. These data strongly suggest that estrogen action was signaled exclusively via ER-beta in normal human PrECs. In contrast, PrEC (Clontech) and BPH-1 cells expressed both ER-alpha and ER-beta transcripts and no PR nor pS2 mRNA in PrEC and only a minimal level of PR mRNA in BPH-1. Among the three prostate cancer cell lines, LNCaP expressed ER-beta mRNA along with transcripts of PR and pS2, DU145 expressed messages of ER-beta and PR, and PC-3 cells exhibited ER-alpha, ER-beta, and pS2 mRNA. Thus, unlike normal PrECs, expression patterns of these genes in malignant PrECs are more variable. Treatment of prostate cancer cells with demethylation agents effectively reactivated the expression of ER-alpha mRNA in LNCaP and DU145 and that of pS2 message in DU145. These findings provide experimental evidence that ER-alpha gene silencing in prostate cancer cells, and perhaps also in normal PrECs, are caused by DNA hypermethylation. To evaluate the potential of using antiestrogens as prostate cancer therapies, we have assessed the growth-inhibitory action of estrogens (estradiol and diethylstilbestrol) and antiestrogens (4-hydroxy-tamoxifen and ICI-182,780) on PC-3 and DU-145 cells. In PC-3 cells, which express both ER subtypes, estrogens as well as antiestrogens are effective inhibitors. In contrast, in DU145 cells, which express only ER-beta, antiestrogens, but not estrogens, are growth inhibitors. By comparison, ICI 182,780 is the more effective cell growth inhibitor. Importantly, the ICI 182,780-induced antiproliferative effects were reversed by cotreatment of DU145 cells with an ER-beta antisense oligonucleotide, hence lending additional support to a central role played by ER-beta in mediating growth-inhibitory action of antiestrogens

Garlic Allium satium.

Leigh E.

7777

Correlation of stress factors with sustained depression of natural killer cell activity and predicted prognosis in patients with breast cancer.

Levy S, Herberman R, Lippman M, et al.

J Clin Oncol. 1987 Mar; 5(3):348-53.

Natural killer (NK) cell activity and psychological status were measured at baseline and at 3 months into treatment, as part of the National Cancer Institute (NCI) Protocol 79-C-111, randomizing breast cancer patients to lumpectomy/radiation v mastectomy. Patients who were found to have positive axillary lymph nodes also received combination chemotherapy (Adriamycin [Adria Laboratories, Columbus, OH], plus Cytoxan [Mead Johnson Pharmaceuticals, Evansville, IN] or methotrexate, plus 5-fluorouracil [5-FU]). Seventy-five patients were entered onto this behavioral immunology protocol at the time of data analysis. We reported in an earlier publication that NK activity was an important predictor of patient baseline prognosis relevant to nodal status. In that study, by using multiple regression analyses, 51% of the baseline NK activity variance could be accounted for by entering three distress indicators into the equation (patient "adjustment," lack of social support, and fatigue/depression symptoms). On reassessment of NK activity after 3 months, it was found that NK activity was not affected by the interim administration of chemotherapy and/or radiotherapy. However, consistent with our earlier findings, NK activity levels remained markedly lower in patients with positive nodes than in patients with negative nodes (at 60 to 1 effector to target cell [E:T] ratio, mean of 18% lytic activity v mean of 31% lytic activity [t = 1.87, P less than .05]). Even though average levels of NK activity were lower for patients with more tumor burden, there was still a substantial range of NK activity levels within the node positive patient group, as well as within the patient group as a whole. We hypothesized that differences in levels of NK activity could be predicted on the basis of baseline distress factors found to be significant in our earlier report. In fact, we found that we could account for 30% of NK activity level variance at 3 months follow-up on the basis of baseline NK activity, fatigue/depression, and lack of social support. Therefore, although neither radiation nor chemotherapy appeared to affect NK activity, tumor burden was again clearly associated with NK activity levels, and a significant amount of baseline and 3-month NK activity could be predicted on the basis of CNS-mediated effects. At the least, such factors provide a psychological marker of host biological status

Bombesin and gastrin releasing peptide increase tyrosine phosphorylation of focal adhesion kinase and paxillin in non-small cell lung cancer cells.

Leyton J, Garcia-Marin LJ, Tapia JA, et al.

Cancer Lett. 2001 Jan 10; 162(1):87-95.

The effects of some oncogenes, growth factors and neuropeptides are mediated by tyrosine phosphorylation of focal adhesion kinase (p125(FAK)) and paxillin cytoskeletal proteins. In this study the ability of bombesin/gastrin releasing peptide (BB/GRP) to stimulate tyrosine phosphorylation of p125(FAK) and paxillin in non-small cell lung cancer (NSCLC) H1299 cells was investigated. BB, 100 nM caused increased p125(FAK) and paxillin tyrosine phosphorylation maximally after 1 min. The effect of BB on p125(FAK) and paxillin tyrosine phosphorylation was concentration-dependent, being half maximal at 4-8 nM. Also, 100 nM GRP, GRP(14-27) but not GRP(1-16) increased p125(FAK) and paxillin tyrosine phosphorylation indicating that the C-terminal of GRP is essential. BW2258U89, a GRP receptor antagonist, caused a dose-dependent inhibition of BB-stimulated p125(FAK) and paxillin tyrosine phosphorylation with an IC50 value of 3 microM. Cytochalasin D (0.3 microM), which inhibits actin polymerization, reduced the ability of BB to stimulate tyrosine phosphorylation of p125(FAK) and paxillin. Genistein (50 microM) and H-7 (50 microM), which are kinase inhibitors, reduced the tyrosine phosphorylation of p125(FAK) and paxillin stimulated by BB. Also, treatment of NCI-H1299 cells with FAK antisense resulted in decreased FAK tyrosine kinase activity and proliferation. These results suggest that p125(FAK) is an important enzyme for NSCLC proliferation

Mechanisms of cancer chemoprevention by curcumin.

Li JK, Lin-Shia SY.

Proc Natl Sci Counc Repub China B. 2001 Apr; 25(2):59-66.

Curcumin is a major component of the Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. Curcumin has shown anti-carcinogenic activity in animals as indicated by its ability to block colon tumor initiation by azoxymethane and skin tumor promotion induced by phorbol ester TPA. Recently, curcumin has been considered by oncologists as a potential third generation cancer chemopreventive agent, and clinical trials using it have been carried out in several laboratories. Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive oxygen-generating enzymes, such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase and inducible nitric oxide synthase. Curcumin is also a potent inhibitor of protein kinase C, EGF-receptor tyrosine kinase and IkappaB kinase. In addition, curcumin inhibits the activation of NFkappaB and the expression of c-jun, c-fos, c-myc and iNOS. It is proposed that curcumin may suppress tumor promotion by blocking signal transduction pathways in the target cells. Curcumin was first biotransformed to dihydrocurcumin and tetrahydrocurcumin, and these compounds were subsequently convened into monoglucuronide conjugates. The experimental results suggest that curcumin-glucuronide, dihydrocurcumin-glucuronide, tetrahydrocurcumin-glucuronide and tetrahydrocurcumin are major metabolites of curcumin in mice

Gene expression profiles of genistein-treated PC3 prostate cancer cells.

Li Y, Sarkar FH.

J Nutr. 2002 Dec; 132(12):3623-31.

Our previous studies have shown that genistein inhibits the growth of PC3 prostate cancer cells and induces apoptosis by inhibiting nuclear factor kappaB (NF-kappaB) and Akt signaling pathways. To better understand the precise molecular mechanism(s) by which genistein exerts its effects on PC3 cells, we utilized cDNA microarray to interrogate 12,558 known genes to determine the gene expression profiles altered by genistein treatment. We found a total of 832 genes that showed a greater than twofold change after genistein treatment from two independent experiments with a high degree of concordance. Among these genes, 774 genes were down-regulated and 58 genes were up-regulated with genistein treatment. Cluster analysis showed nine different types of expression alternations. These genes were also subjected to cluster analysis according to their biological functions. We found that genistein regulated the expression of genes that are critically involved in the regulation of cell growth, cell cycle, apoptosis, cell signaling transduction, angiogenesis, tumor cell invasion and metastasis. Reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to confirm the results of cDNA microarray, and the results of RT-PCR were consistent with the microarray data. We conclude that genistein affected the expression of a large number of genes that are related to the control of cell survival and physiologic behaviors. The gene expression profiles provide comprehensive molecular mechanism(s) by which genistein exerts its pleiotropic effects on cancer cells. Genistein-induced regulation of these genes may be further exploited for devising chemopreventive and/or therapeutic strategies for prostate cancer

Down-regulation of invasion and angiogenesis-related genes identified by cDNA microarray analysis of PC3 prostate cancer cells treated with genistein.

Li Y, Sarkar FH.

Cancer Lett. 2002 Dec 5; 186(2):157-64.

Prostate cancer is the second leading cause of cancer related deaths in men in the United States and for many years the treatment results for metastatic prostate cancer have been disappointing. Our previous studies have shown that genistein elicits pleiotropic effects on prostate cancer cells; however, its role in invasion and metastasis has not been fully elucidated. In order to better understand the precise molecular mechanism(s) by which genistein exerts its effects on PC3 cells, we have utilized cDNA microarray to interrogate 12558 known genes to determine the gene expression profile altered by genistein treatment. We found a total of 832 genes which showed >2-fold change after genistein treatment. Among these genes, we found down-regulation of 11 genes (MMP-9, protease M, uPAR, VEGF, neuropilin, TSP, BPGF, LPA, TGF-beta2, TSP-1, PAR-2) and up-regulation of two genes (connective tissue growth factor, connective tissue activation peptide), which are related to angiogenesis, tumor cell invasion and metastasis. Reverse transcription-polymerase chain reaction, Western blot, and zymographic analysis were conducted to confirm the data of microarray at the level of mRNA, protein, and biological function. The results were in direct agreement with the microarray data. From these results, we conclude that genistein down-regulates the transcription and translation of genes critically involved in the control of angiogenesis, tumor cell invasion and metastasis, suggesting the possible therapeutic role of genistein for metastatic prostate cancer. Thus, genistein-induced alternations of gene expressions may be exploited for devising chemopreventive or therapeutic strategies, particularly for chemosensitization of metastatic prostate cancer to existing chemotherapeutic agents

p53-independent apoptosis induced by genistein in lung cancer cells.

Lian F, Li Y, Bhuiyan M, et al.

Nutr Cancer. 1999; 33(2):125-31.

Lung cancer is the leading cause of cancer-related deaths in the world, with increasing incidence in many developed countries. Epidemiological data suggest that consumption of soy products may be associated with a decreased risk of cancer. Despite the association of nutrition and cancer, the molecular mechanisms by which the active metabolite in the soy diet, genistein, exerts its biological response have not been studied. We previously showed that genistein can inhibit the growth of H460 non-small-cell lung cancer (NSCLC) cells in vitro. To explore the molecular mechanisms by which genistein inhibits the growth of NSCLC cells, we investigated cell growth inhibition, modulation in gene expression, and induction of apoptosis by genistein in H460 cells, which harbor wild-type p53, and H322 cells, which possess mutated p53. Genistein was found to inhibit H460 and H322 cell growth in a dose-dependent manner. Staining with 4,6-diamidino-2-phenylindole, poly(ADP-ribose) polymerase cleavage, and flow cytometric apoptosis analysis were used to investigate apoptotic cell death, and the results show that 30 microM genistein causes cell death via a typical apoptotic pathway. Western blot analysis demonstrated upregulations of p21WAF1 and Bax by genistein in wild-type and mutant p53 cell lines. Furthermore, cells treated with genistein showed an increased expression of endogenous wild-type p53, while the level of the mutant p53 protein remained unchanged. From these results, we conclude that genistein induces apoptosis in NSCLC cells through a p53-independent pathway and, thus, may act as an anticancer agent

ELF magnetic fields, breast cancer, and melatonin: 60 Hz fields block melatonin's oncostatic action on ER+ breast cancer cell proliferation.

Liburdy RP, Sloma TR, Sokolic R, et al.

J Pineal Res. 1993 Mar; 14(2):89-97.

In this study we investigated whether a 60 Hz magnetic field can act at the cellular level to influence the growth of human estrogen-dependent breast cancer cells. Our experimental design assessed cell proliferation of a human breast cancer cell line, MCF-7, in the absence or the presence of melatonin which inhibits growth at a physiological concentration of 10(-9) M. In three experiments, continuous exposure to average sinusoidal 60 Hz magnetic fields of 1.90 +/- 0.01, 2.40 +/- 0.70, and 2.53 +/- 0.50 mG, or simultaneous exposure in matched incubators to average 60 Hz magnetic fields of 10.4 +/- 2.12, 11.95 +/- 2.73, and 11.95 +/- 3.28 mG, respectively, had no effect on cell proliferation in the absence of melatonin. When MCF-7 cells were cultured in the presence of 10(-9) M melatonin, an 18% inhibition of growth was observed for cells in a 2.40 +/- 0.70 mG field. This effect was blocked by a 60 Hz magnetic field of 11.95 +/- 2.75 mG. In a second experiment, a 27% inhibition of MCF-7 cell growth was observed for cells in a 2.53 +/- 0.50 mG magnetic field, and this was blocked by a 60 Hz magnetic field of 11.95 +/- 3.28 mG. These results provide the first evidence that ELF frequency magnetic fields can act at the cellular levels to enhance breast cancer cell proliferation by blocking melatonin's natural oncostatic action. In addition, there appears to be a dose threshold between 2 and 12 mG. The mechanism(s) of action is unknown and may involve modulation of signal transduction events associated with melatonin's regulation of cell growth

How Selenium Fights Disease 1995 Jan 1.

Life Extension Foundation Report.

1995;Jan 1

Life Extension Magazine. CLA and cancer.

Life Extension Magazine 2000 Apr.

Life Extension Magazine 2000 Apr. 2000;2000 Apr 6(4):69-70.

Life Extension Magazine. Newly discovered benefits of gamma tocopherol.

Life Extension Magazine October 2002.

Life Extension Magazine October 2002. 2002;OCt 2002

Effects of berberine on arylamine N-acetyltransferase activity in human colon tumor cells.

Lin JG, Chung JG, Wu LT, et al.

Am J Chin Med. 1999; 27(2):265-75.

Berberine was used to determine loss of viable cells and inhibition of arylamine Nacetyltransferase (NAT) activity in a human colon tumor (adenocarcinoma) cell line. The viable cells were determined by trypan blue exclusion under a light microscope. The NAT activity was measured by high performance liquid chromatography for the amounts of N-acetyl-2-aminofluorene (AAF), N-acetyl-p-aminobenzoic acid (N-Ac-PABA), and the remaining 2-aminofluorene (AF) and p-aminobenzoic acid (PABA). The viability and NAT activity in a human colon tumor cell line was inhibited by berberine in a dose-dependent manner, i.e., the higher the concentration of berberine, the higher the inhibition of NAT activity and cell death. The NAT activities measured in the intact human colon tumor cells were decreased over 50% by AAF and NAc-PABA production from acetylation of AF and PABA. The apparent values of Kmoff and Vmax of NAT from colon tumor cells were also inhibited by berberine in cytosols and in intact cells. This report is the first to show that berberine did affect human colon tumor cell NAT activity

Suppression of protein kinase C and nuclear oncogene expression as possible molecular mechanisms of cancer chemoprevention by apigenin and curcumin.

Lin JK, Chen YC, Huang YT, et al.

J Cell Biochem Suppl. 1997; 28-29:39-48.

Apigenin, a less-toxic and non-mutagenic flavonoid, suppressed 12-0-tetradecanoyl-phorbol-13-acetate-(TPA)-mediated tumor promotion of mouse skin. TPA had the ability to activate protein kinase C (PKC) and induced nuclear proto-oncogene expression. Our study indicates that apigenin inhibited PKC by competing with adenosine triphosphate (ATP). Apigenin also reduced the level of TPA-stimulated phosphorylation of cellular proteins and inhibited TPA-induced c-jun and c-fos expression. Curcumin, a dietary pigment phytopolyphenol, is also a potent inhibitor of tumor promotion induced by TPA in mouse skin. When mouse fibroblast cells were treated with TPA alone, PKC translocated from the cytosolic fraction to the particulate fraction. Treatment with 15 or 20 microM curcumin for 15 min inhibited TPA-induced PKC activity in the particulate fraction by 26-60%. Curcumin also inhibited PKC activity in vitro by competing with phosphatidylserine. Curcumin (10 microM) suppressed the expression of c-jun in TPA-treated cells. Fifteen flavonoids were examined for their effects on morphological changes in soft agar and cellular growth in v-H-ras transformed NIH3T3 cells. The results demonstrated that only apigenin, kaempferol, and genistein exhibited the reverting effect on the transformed morphology of these cells. Based on these findings, it is suggested that the suppression of PKC activity and nuclear oncogene expression might contribute to the molecular mechanisms of inhibition of TPA-induced tumor promotion by apigenin and curcumin

Garlic in Nutrition and Medicine.

Lin R.

1989;

Neuroimmunotherapy of advanced solid neoplasms with single evening subcutaneous injection of low-dose interleukin-2 and melatonin: preliminary results.

Lissoni P, Barni S, Rovelli F, et al.

Eur J Cancer. 1993; 29A(2):185-9.

On the basis of the demonstrated existence of immunoneuroendocrine interactions and on the previously observed synergistic action between the pineal hormone melatonin (MLT) and interleukin-2 (IL-2), we have designed a neuroimmunotherapeutic combination consisting of low-dose IL-2 and MLT in the treatment of advanced solid neoplasms. The study included 24 patients with advanced solid tumours (non-small cell lung cancer 9; colorectal cancer 7; gastric cancer 3; breast cancer 2; cancer of pancreas 1; hepatocarcinoma 1; unknown primary tumour 1), 21 of whom showed distant organ metastases. Not all patients responded to previous chemotherapies, or had tumours for which no standard therapy was available. Moreover, not all patients were able to tolerate IL-2 immunotherapy at the conventional doses. IL-2 was given subcutaneously at a dose of 3 x 10(6) U/day at 8:00 p.m. for 6 days/week for 4 weeks. MLT was given orally at a dose of 50 mg at 8:00 p.m. every day, starting 7 days before IL-2 injection. In non-progressed patients, a second cycle was given after a 21-day rest period. A partial response was seen in 3/24 patients (lung 2; stomach 1; duration: 11, 4, 4 months, respectively). Moreover, a minimal response (duration: 8+ months) was seen in 1 lung cancer patient. Stable disease was obtained in 14/24 patients (median duration: 6+ months), while the remaining 6 patients progressed. An improvement in performance status was seen in 7/24 patients. No important toxicity was observed. Mean eosinophil and lymphocyte levels significantly increased during the immunotherapy, and their rise was significantly higher in patients with response or stable disease than in those with progressive disease. These preliminary results show that neuroimmunotherapy with low-dose IL-2 and the pineal hormone MLT is a biologically active and well tolerated strategy, capable of determining an apparent control of tumour growth in patients with advanced solid neoplasms, for whom no standard effective therapy is available

A randomised study with subcutaneous low-dose interleukin 2 alone vs interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma.

Lissoni P, Barni S, Tancini G, et al.

Br J Cancer. 1994 Jan; 69(1):196-9.

Our previous experimental studies have shown that the best approach to increase the biological anti-tumour activity of interleukin 2 (IL-2) is not co-administration of another cytokine, but the association with immunomodulating neurohormones, in an attempt to reproduce the physiological links between psychoendocrine and immune systems, which play a fundamental role in the regulation of the immune responses. In particular, the association with the pineal neurohormone melatonin (MLT) has been shown to cause tumour regressions in neoplasms that are generally non-responsive to IL-2 alone. To confirm these preliminary results, a clinical trial was performed in locally advanced or metastatic patients with solid tumours other than renal cell cancer and melanoma. The study included 80 consecutive patients, who were randomised to be treated with IL-2 alone subcutaneously (3 million IU day-1 at 8.00 p.m. 6 days a week for 4 weeks) or IL-2 plus MLT (40 mg day-1 orally at 8.00 p.m. every day starting 7 days before IL-2). A complete response was obtained in 3/41 patients treated with IL-2 plus MLT and in none of the patients receiving IL-2 alone. A partial response was achieved in 8/41 patients treated with IL-2 plus MLT and in only 1/39 patients treated with IL-2 alone. Tumour objective regression rate was significantly higher in patients treated with IL-2 and MLT than in those receiving IL-2 alone (11/41 vs 1/39, P < 0.001). The survival at 1 year was significantly higher in patients treated with IL-2 and MLT than in the IL-2 group (19/41 vs 6/39, P < 0.05). Finally, the mean increase in lymphocyte and eosinophil number was significantly higher in the IL-2 plus MLT group than in patients treated with IL-2 alone; on the contrary, the mean increase in the specific marker of macrophage activation neopterin was significantly higher in patients treated with IL-2 alone. The treatment was well tolerated in both groups of patients. This study shows that the concomitant administration of the pineal hormone MLT may increase the efficacy of low-dose IL-2 subcutaneous therapy

A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms.

Lissoni P, Barni S, Ardizzoia A, et al.

Cancer. 1994 Feb 1; 73(3):699-701.

BACKGROUND. Unresectable brain metastases remain an untreatable disease. Because of its antitumor cytostatic action and its anticonvulsant effect, the pineal hormone melatonin could constitute a new effective agent in the treatment of brain metastases. The current study was performed to evaluate the effect of melatonin on the survival time in patients with brain metastases due to solid neoplasms. METHODS. The study included 50 patients, who were randomized to be treated with supportive care alone (steroids plus anticonvulsant agents) or with supportive care plus melatonin (20 mg/day at 8:00 p.m. orally). RESULTS. The survival at 1 year, free-from-brain-progression period, and mean survival time were significantly higher in patients treated with melatonin than in those who received the supportive care alone. Conversely, steroid-induced metabolic and infective complications were significantly more frequent in patients treated with supportive care alone than in those concomitantly treated with melatonin. CONCLUSIONS. The pineal hormone melatonin may be able to improve the survival time and the quality of life in patients with brain metastases due to solid tumors

Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone.

Lissoni P, Meregalli S, Nosetto L, et al.

Oncology. 1996 Jan; 53(1):43-6.

The prognosis of brain glioblastoma is still very poor and the median survival time is generally less than 6 months. At present, no chemotherapy has appeared to influence its prognosis. On the other hand, recent advances in brain tumor biology have suggested that brain tumor growth is at least in part under a neuroendocrine control, mainly realized by opioid peptides and pineal substances. On this basis, we evaluated the influence of a concomitant administration of the pineal hormone melatonin (MLT) in patients with glioblastoma treated with radical or adjuvant radiotherapy (RT). The study included 30 patients with glioblastoma, who were randomized to receive RT alone (60 Gy) or RT plus MLT (20 mg/daily orally) until disease progression. Both the survival curve and the percent of survival at 1 year were significantly higher in patients treated with RT plus MLT than in those receiving RT alone (6/14 vs. 1/16). Moreover, RT or steroid therapy-related toxicities were lower in patients concomitantly treated with MLT. This preliminary study suggests that a radioneuroendocrine approach with RT plus the pineal hormone MLT may prolong the survival time and improve the quality of life of patients affected by glioblastoma

A phase II study of neuroimmunotherapy with subcutaneous low-dose IL-2 plus the pineal hormone melatonin in untreatable advanced hematologic malignancies.

Lissoni P, Bolis S, Brivio F, et al.

Anticancer Res. 2000 May; 20(3B):2103-5.

Interleukin-2 (IL-2) has proven to be able to generate an effective anticancer immunity against both solid and hematologic malignancies. Moreover, recent advances in the knowledge of psychoneuroimmunology have demonstrated that anticancer immunity is under neuroendocrine control and that the pineal hormone melatonin (MLT) may stimulate the IL-2-dependent anticancer reaction. Finally, preliminary clinical studies have already shown that the concommitant administration of MLT may amplify the efficacy of IL-2 in the treatment of advanced solid neoplasms, whereas there are no data about MLT influence on IL-2 activity in hematologic malignancies. The aim of the present study was to evaluate the efficacy and tolerability of a neuroimmunotherapeutic combination of low-dose IL-2 plus MLT in advanced hematologic malignancies which did not respond to previous standard therapies. The study included 12 evaluable patients. Tumor histotypes were as follows: non-Hodgkin's lymphoma (NHL) 6; Hodgkin's disease (HD), 2; multiple myeloma, 2; acute myelogenous leukemia (ALM), 1 and chronic myelomonocytic leukemia (CMML), 1. IL-2 was injected subcutaneously at a dose of 3 million IU/day for 6 days per week for 4 weeks, corresponding to one cycle. MLT was given orally at 20 mg/day in the evening, without interruption. In non-progressing patients, a second IL-2 cycle was planned after a 3 week-rest period. A partial response was achieved in one patient with multiple myeloma. Stable disease occurred in 7 other patients (NHL, 3; HD, 1; AML, 1; CLLM, 1; multiple myeloma, 1), whereas the other 4 patients progressed. Therefore, lack of progression was obtained in 8 out of 12 (67%) patients, with a median duration of 21+ months (14-30+ months). The treatment was well tolerated in all patients. These preliminary results would suggest that the concomitant administration of low-dose IL-2 plus the pineal hormone MLT may prolong the survival time in untreatable advanced hematologic malignancies, with results comparable to those previously reported using a more toxic immunotherapy, consisting of high-dose IL-2 alone

Regulation of pro-inflammatory cytokine expression by curcumin in hyaline membrane disease (HMD).

Literat A, Su F, Norwicki M, et al.

Life Sci. 2001 Dec 7; 70(3):253-67.

Persistent expression of pro-inflammatory cytokines is believed to play a major role in the pathogenesis of chronic lung disease (CLD) in premature infants. Inhibition of pro-inflammatory cytokine production in the lungs of preterm newborns may result in the attenuation of CLD. Curcumin is a naturally occurring phenolic compound derived from the food spice turmeric with broad based in vitro anti-inflammatory properties. In this study lung inflammatory cells from preterm newborns at risk for the development of CLD were derived via modified broncho-alveolar lavage and stimulated ex vivo with lipopolysaccharide (LPS) (10 ng/ml). Curcumin was added to these cultures at 0, 0.5 and 20 uM concentrations. Pro-inflammatory cytokine, TNFalpha, IL-1beta and IL-8 protein was measured from the culture supernatants 12 hours post culture. For control, adult peripheral blood mononuclear cells (PBMC) were cultured under the same conditions. Both neonatal lung inflammatory cells and adult PBMC produced high levels of pro-inflammatory cytokines in response to LPS. Curcumin produced significant inhibition of IL-1beta and IL-8 but minimal inhibition of TNFalpha expression by preterm lung inflammatory cells at 20 uM concentrations. Adult PBMC expression of IL-8 was significantly inhibited by curcumin at 20 uM concentrations. Therefore, curcumin inhibits pro-inflammatory cytokine production (TNFalpha, IL-1beta and IL-8) by lung inflammatory cells ex vivo. Pathways involved with curcumin regulation of these cytokines are developmentally intact and functional in premature infants. Curcumin may be effective as a therapeutic agent in the attenuation of CLD

Apparent partial remission of breast cancer in 'high risk' patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10.

Lockwood K, Moesgaard S, Hanioka T, et al.

Mol Aspects Med. 1994; 15 Suppl:s231-s240.

Thirty-two typical patients with breast cancer, aged 32-81 years and classified 'high risk' because of tumor spread to the lymph nodes in the axilla, were studied for 18 months following an Adjuvant Nutritional Intervention in Cancer protocol (ANICA protocol). The nutritional protocol was added to the surgical and therapeutic treatment of breast cancer, as required by regulations in Denmark. The added treatment was a combination of nutritional antioxidants (Vitamin C: 2850 mg, Vitamin E: 2500 iu, beta-carotene 32.5 iu, selenium 387 micrograms plus secondary vitamins and minerals), essential fatty acids (1.2 g gamma linolenic acid and 3.5 g n-3 fatty acids) and Coenzyme Q10 (90 mg per day). The ANICA protocol is based on the concept of testing the synergistic effect of those categories of nutritional supplements, including vitamin Q10, previously having shown deficiency and/or therapeutic value as single elements in diverse forms of cancer, as cancer may be synergistically related to diverse biochemical dysfunctions and vitamin deficiencies. Biochemical markers, clinical condition, tumor spread, quality of life parameters and survival were followed during the trial. Compliance was excellent. The main observations were: (1) none of the patients died during the study period. (the expected number was four.) (2) none of the patients showed signs of further distant metastases. (3) quality of life was improved (no weight loss, reduced use of pain killers). (4) six patients showed apparent partial remission

Progress on therapy of breast cancer with vitamin Q10 and the regression of metastases.

Lockwood K, Moesgaard S, Yamamoto T, et al.

Biochem Biophys Res Commun. 1995 Jul 6; 212(1):172-7.

Over 35 years, data and knowledge have internationally evolved from biochemical, biomedical and clinical research on vitamin Q10 (coenzyme Q10; CoQ10) and cancer, which led in 1993 to overt complete regression of the tumors in two cases of breast cancer. Continuing this research, three additional breast cancer patients also underwent a conventional protocol of therapy which included a daily oral dosage of 390 mg of vitamin Q10 (Bio-Quinone of Pharma Nord) during the complete trials over 3-5 years. The numerous metastases in the liver of a 44-year-old patient "disappeared," and no signs of metastases were found elsewhere. A 49-year-old patient, on a dosage of 390 mg of vitamin Q10, revealed no signs of tumor in the pleural cavity after six months, and her condition was excellent. A 75-year-old patient with carcinoma in one breast, after lumpectomy and 390 mg of CoQ10, showed no cancer in the tumor bed or metastases. Control blood levels of CoQ10 of 0.83-0.97 and of 0.62 micrograms/ml increased to 3.34-3.64 and to 3.77 micrograms/ml, respectively, on therapy with CoQ10 for patients A-MRH and EEL

Estrogen metabolism and the diet-cancer connection: rationale for assessing the ratio of urinary hydroxylated estrogen metabolites.

Lord RS, Bongiovanni B, Bralley JA.

Altern Med Rev. 2002 Apr; 7(2):112-29.

Estrogens are known for their proliferative effects on estrogen-sensitive tissues resulting in tumorigenesis. Results of experiments in multiple laboratories over the last 20 years have shown that a large part of the cancer-inducing effect of estrogen involves the formation of agonistic metabolites of estrogen, especially 16-alpha-hydroxyestrone. Other metabolites, such as 2-hydroxyestrone and 2-hydroxyestradiol, offer protection against the estrogen-agonist effects of 16-alpha-hydroxyestrone. An ELISA method for measuring 2- and 16-alpha-hydroxylated estrogen (OHE) metabolites in urine is available and the ratio of urinary 2-OHE/16-alpha-OHE (2/16-alpha ratio) is a useful biomarker for estrogen-related cancer risk. The CYP1A1 enzyme that catalyzes 2-hydroxyestrone (2-OHE1) formation is inducible by dietary modification and supplementation with the active components of cruciferous vegetables, indole-3-carbinol (I-3-C), or diindolylmethane (DIM). Other dietary components, especially omega-3 polyunsaturated fatty acids and lignans in foods like flax seed, also exert favorable effects on estrogen metabolism. Thus, there appear to be effective dietary means for reducing cancer risk by improving estrogen metabolism. This review presents the accumulated evidence to help clinicians evaluate the merit of using tests that measure estrogen metabolites and using interventions to modify estrogen metabolism

The Yam Cream Conundrum 2001 Feb.

Lukaczer D.

2001;2001 Feb

Effect of radiation therapy on small-cell lung cancer is reduced by ubiquinone intake.

Lund EL, Quistorff B, Spang-Thomsen M, et al.

Folia Microbiol (Praha). 1998; 43(5):505-6.

The effect of oral ubiquinone (Q10) intake on the in vivo response of tumors to single dose radiotherapy was examined. The human small-cell lung cancer (SCLC) line CPH 054A, which is sensitive to relatively low doses of X-radiation, was grown as subcutaneous transplants in the flanks of nude nu/nu mice. When macroscopical growth was established, groups of mice received either 10, 20 or 40 mg/kg Q10 in 30 mL soy oil intragastrically daily on 4 consecutive days. Controls received either 30 mL of pure soy oil or nothing. Three h after the last dose half of the tumors in each group received a single radiation dose of 5 Gy, using a 300 kV therapeutic unit. The macroscopic growth pre- and posttreatment was analyzed according to a transformed Gompertz algorithm using the software program GROWTH. Treatment with Q10 or soy oil alone had no effect on tumor growth compared with untreated controls. Groups of tumors that received Q10 and radiotherapy had a significantly lower specific growth delay (SGD) than the radiotherapy-only groups. This effect was significant at 40 mg/kg and borderline at 20 mg/kg, whereas at 10 mg/kg no radioprotection was seen. We conclude that systemic Q10 reduces the response to single dose tumor irradiation inxenotransplanted human SCLC tumors

A cost-evaluation of glutamine-supplemented parenteral nutrition in adult bone marrow transplant patients.

MacBurney M, Young LS, Ziegler TR, et al.

J Am Diet Assoc. 1994 Nov; 94(11):1263-6.

OBJECTIVE: In a randomized, double-blind, prospective clinical trial, we evaluated the metabolic effects of glutamine-supplemented parenteral nutrition in patients with bone marrow transplants. We compared hospital charge and cost data for the two groups of patients in the trial. DESIGN: Retrospective review. SETTING: Bone Marrow Transplant Unit, Brigham and Women's Hospital, Boston, Mass. SUBJECTS: Forty-three patients admitted to the Bone Marrow Transplant Unit were assigned randomly to receive either standard parenteral nutrition or an isocaloric, isonitrogenous parenteral nutrition solution containing glutamine starting on day 1 after bone marrow transplant. The two groups were well matched for diagnosis, antineoplastic treatment, and sex. MEASURES: The primary clinical end points evaluated were nitrogen balance, length of hospitalization, incidence of infection, and results of microbial culture. After completion of the study, we compared the hospital charges for the categories of room and board, surgery, laboratory, pharmacy, radiology, ancillary, and miscellaneous between the two groups of patients. STATISTICAL ANALYSIS PERFORMED: The two groups were compared using the unpaired t test or Mann-Whitney test for nonparametric measurements. A P value of < .05 was considered significant. RESULTS: Nitrogen balance improved in the glutamine-supplemented group compared with control subjects (-1.4 +/- 0.5 g/day vs 4.2 +/- 1.2 g/day, respectively; P = ".002)." Length of hospitalization was significantly shorter in the glutamine-supplemented group than in the control group (29 +/- 1 day vs 36 +/- 2 days, respectively; P = ".017)." The incidence of positive microbial cultures and clinical infection was also significantly lower with glutamine supplementation. Hospital charges were $21,095 per patient less in the glutamine-supplemented group compared with charges for patients who received standard therapy. Room and board charges were significantly different: $51,484 +/- 2,647 for the glutamine-supplemented group vs $61,591 +/- 3,588 in the control group (P = ".02)." CONCLUSION: This intervention study using a new therapy demonstrated clinical and nutritional benefits to patients and cost savings to the hospital

In humans, serum polyunsaturated fatty acid levels predict the response of proinflammatory cytokines to psychologic stress.

Maes M, Christophe A, Bosmans E, et al.

Biol Psychiatry. 2000 May 15; 47(10):910-20.

BACKGROUND: Psychologic stress in humans induces the production of proinflammatory cytokines, such as interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6), and that of the negative immunoregulatory cytokine, IL-10. An imbalance of omega6 to omega3 polyunsaturated fatty acids (PUFAs) in the peripheral blood causes an overproduction of proinflammatory cytokines. The omega3 PUFAs reduce the production of proinflammatory cytokines. METHODS: This study examines whether an imbalance in omega6 to omega3 PUFAs in human blood predicts a greater production of proinflammatory cytokines in response to psychologic stress. Twenty-seven university students had serum sampled a few weeks before and after as well as 1 day before a difficult oral examination. We determined the omega6 and omega3 fractions in serum phospholipids as well as the ex vivo production of IFN-gamma, TNF-alpha, IL-6, IL-10, and IL-5 by diluted whole blood stimulated with polyclonal activators. RESULTS: Academic examination stress significantly increased the ex vivo, stimulated production of IFN-gamma, TNF-alpha and IL-10, and the IFN-gamma/IL-5 production ratio. Subjects with lower serum omega3 PUFA levels or with a higher omega6/omega3 ratio had significantly greater stress-induced TNF-alpha and IFN-gamma responses than subjects with higher serum omega3 PUFAs and a lower omega6/omega3 ratio, respectively. Subjects with lower serum omega3 PUFA levels or with a higher omega6/omega3 ratio had a significantly higher stress-induced increase in the IFN-gamma/IL-5 ratio than the remaining subjects. CONCLUSIONS: Psychologic stress induces a Th-1-like or proinflammatory response in some subjects. An imbalance in the omega6 to omega3 PUFA ratio appears to predispose humans toward an exaggerated Th-1-like response and an increased production of monocytic cytokines, such as TNF-alpha, in response to psychologic stress. The results suggest that increased omega3 PUFA levels may attenuate the proinflammatory response to psychologic stress

Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer.

Maestroni GJ.

Adv Exp Med Biol. 1999; 467:217-26.

Maintenance of health depends on the ability to respond appropriately to environmental stressors via reciprocal interactions between the body and the brain. In this context, it is well recognized that the pineal hormone melatonin (MLT) plays an important role. T-helper cells bear G-protein-coupled MLT cell membrane receptors and, perhaps, MLT nuclear receptors. Activation of MLT receptors enhances the release of T-helper cell cytokines, such as gamma-interferon and interleukin-2 (IL-2), as well as activation of novel opioid cytokines which crossreact immunologically with both interleukin-4 and dynorphin B. MLT has been reported also to enhance the production of interleukin-1, interleukin-6 and interleukin-12 in human monocytes. These mediators may counteract secondary immunodeficiencies, protect mice against lethal viral and bacterial diseases, synergize with IL-2 against cancer and influence hematopoiesis. Hematopoiesis is influenced by MLT-induced-opioids (MIO) acting on kappa 1-opioid receptors present on bone marrow macrophages. Clinically, MLT could amplify the anti-tumoral activity of low dose IL-2, induce objective tumor regression, and prolong progression-free time and overall survival. MLT seems to be required for the effectiveness of low dose IL-2 in those neoplasias that are generally resistant to IL-2 alone. Similar findings were obtained in a study in which MLT was combined with gamma-interferon in metastatic renal cell carcinoma. In addition, MLT in combination with low-dose IL-2 was able to neutralize the surgery-induced lymphocytopenia in cancer patients. IL-2 treatment in patients results in activation of the immune system and creates the most suitable biological background for MLT. The finding that MLT stimulates IL-12 production from human monocytes only if incubated in presence of IL-2 further supports this concept. On the other hand, high concentrations of MLT have been found in human breast cancer tissue. The MLT concentration, which was 3 orders of magnitude higher than that present in the plasma, correlated positively with good prognostic markers such as estrogen receptor status and nuclear grade. Whether this relates to the immunoneuroendocrine action of MLT remains to be established. Clinical studies are needed on the effect of MLT in combination with IL-2 or other cytokines in cancer patients and viral diseases including HIV-infected patients

N-3 and N-6 fatty acids in breast adipose tissue and relative risk of breast cancer in a case-control study in Tours, France.

Maillard V, Bougnoux P, Ferrari P, et al.

Int J Cancer. 2002 Mar 1; 98(1):78-83.

Experimental studies have indicated that n-3 fatty acids, including alpha-linolenic acid (18:3 n-3) and long-chain n-3 polyunsaturated fatty acids inhibit mammary tumor growth and metastasis. Earlier epidemiological studies have given inconclusive results about a potential protective effect of dietary n-3 polyunsaturated fatty acids on breast cancer risk, possibly because of methodological issues inherent to nutritional epidemiology. To evaluate the hypothesis that n-3 fatty acids protect against breast cancer, we examined the fatty acid composition in adipose tissue from 241 patients with invasive, nonmetastatic breast carcinoma and from 88 patients with benign breast disease, in a case-control study in Tours, central France. Fatty acid composition in breast adipose tissue was used as a qualitative biomarker of past dietary intake of fatty acids. Biopsies of adipose tissue were obtained at the time of surgery. Individual fatty acids were measured as a percentage of total fatty acids, using capillary gas chromatography. Unconditional logistic regression modeling was used to obtain odds ratio estimates while adjusting for age, height, menopausal status and body mass index. We found inverse associations between breast cancer-risk and n-3 fatty acid levels in breast adipose tissue. Women in the highest tertile of alpha-linolenic acid (18:3 n-3) had an odds ratio of 0.39 (95% confidence intervals [CI] = 0.19-0.78) compared to women in the lowest tertile (trend p = 0.01). In a similar way, women in the highest tertile of docosahexaenoic acid (22:6 n-3) had an odds ratio of 0.31 (95% CI = 0.13-0.75) compared to women in the lowest tertile (trend p = 0.016). Women in the highest tertile of the long-chain n-3/total n-6 ratio had an odds ratio of 0.33 (95% confidence interval = 0.17-0.66) compared to women in the lowest tertile (trend p = 0.0002). In conclusion, our data based on fatty acids levels in breast adipose tissue suggest a protective effect of n-3 fatty acids on breast cancer risk and support the hypothesis that the balance between n-3 and n-6 fatty acids plays a role in breast cancer

Inhibition of angiogenesis and promotion of melanoma dormancy by vitamin E succinate.

Malafa MP, Fokum FD, Smith L, et al.

Ann Surg Oncol. 2002 Dec; 9(10):1023-32.

BACKGROUND: Relapse of melanoma after surgical treatment remains a significant clinical problem in need of novel therapies. Vitamin E succinate (VES) is a promising antitumor micronutrient. We evaluated the effect of VES on melanoma dormancy and angiogenesis. METHODS: B16F10 melanoma cells were allografted in mice. The effect of VES on melanoma dormancy was measured by monitoring tumor volume. Tumor vascularity was quantitated with CD31 immunostaining. The expression of vascular endothelial growth factor (VEGF), VEGF receptor 1, and VEGF receptor 2 in tumors was assessed by the intensity of immunostaining. VES effect on secreted VEGF protein and VEGF promoter activity was measured with enzyme-linked immunosorbent assay and transient transfection assay, respectively. Significance was determined by analysis of variance. RESULTS: VES promoted melanoma dormancy (P =.0019) and inhibited melanoma angiogenesis (P <.0001). VES also significantly suppressed the expression of VEGF, VEGF receptor 1, and VEGF receptor 2 in melanoma tumors (P <.0001). Melanoma VEGF secretion (P =".0077)" and melanoma VEGF promoter activity (P <.05) were significantly inhibited by VES. CONCLUSIONS: VES promotes melanoma dormancy and inhibits melanoma angiogenesis. The mechanism of the VES antiangiogenesis effect involves the inhibition of VEGF gene transcription. These findings support future studies of VES in the prevention of melanoma metastasis

Vitamin E inhibits melanoma growth in mice.

Malafa MP, Fokum FD, Mowlavi A, et al.

Surgery. 2002 Jan; 131(1):85-91.

BACKGROUND: Previous work has demonstrated that vitamin E succinate (VES), an ester analogue of vitamin E, inhibits the growth of melanoma in vitro. However, there is no information about the effect of VES on melanoma in vivo. We investigated the effect of VES on melanoma in vitro and in vivo. METHODS: The effect of VES on the proliferation and apoptosis of the B16F10 murine melanoma cell line was determined by a modified Cell Titer 96 AQ assay and a cell death detection enzyme-linked immunosorbent assay, respectively. The in vivo effect of VES on B16F10 melanoma cells allografted in athymic nude mice was investigated. The mechanism of the in vivo antitumor effect of VES was determined by immunohistochemical detection of proliferation and apoptosis. RESULTS: VES decreased cell proliferation (P =.0001) and increased cell apoptosis (P =.0001) in a dose-dependent manner in vitro. Also, VES significantly inhibited melanoma growth in mice (P =.0013). The VES antitumor effect in vivo was associated with a significant increase in the melanoma apoptosis rate (P =.0256). CONCLUSIONS: This is the first report of the antimelanoma effect of VES in vivo. The mechanism of the antimelanoma effect of VES in vivo involves the promotion of tumor cell apoptosis. These findings support future investigations of VES as a therapeutic micronutrient against melanoma

Prospective study of serum selenium levels and incident esophageal and gastric cancers.

Mark SD, Qiao YL, Dawsey SM, et al.

J Natl Cancer Inst. 2000 Nov 1; 92(21):1753-63.

BACKGROUND: From March 1986 through May 1991, we conducted a randomized nutritional intervention trial, the General Population Trial, in Linxian, China, a region with epidemic rates of squamous esophageal and adenomatous gastric cardia cancers. We found that participants who received selenium, beta-carotene, and vitamin E had significantly lower cancer mortality rates than those who did not. In the current study, we examined the relationship between selenium levels measured in pretrial (1985) sera from participants and the subsequent risk of developing squamous esophageal, gastric cardia, and gastric non-cardia cancers during the trial. METHODS: This study was designed and analyzed in accord with a stratified case-cohort sampling scheme, with the six strata defined by sex and three age categories. We measured serum selenium levels in 590 case subjects with esophageal cancer, 402 with gastric cardia cancers, and 87 with gastric non-cardia cancers as well as in 1062 control subjects. Relative risks (RRs), absolute risks, and population attributable risk for cancers were estimated on the basis of the Cox proportional hazards models. All statistical tests are two-sided. RESULTS: We found highly significant inverse associations of serum selenium levels with the incidence of esophageal (P: for trend <10(-4)) and gastric cardia (P: for trend <10(-6)) cancers. The RR and 95% confidence interval (CI) for comparison of highest to lowest quartile of serum selenium was 0.56 (95% CI = "0.44-0.71)" for esophageal cancer and 0.47 (95% CI = "0.33-0.65)" for gastric cardia cancer. The population proportion of these cancers that is attributable to low selenium levels was 26.4% (95% CI = "14.45-38.36)." We found no evidence for a gradient of serum selenium associated with incidence of gastric non-cardia cancer (P: for trend =".96)," with an RR of 1.07 (95% CI = "0.55-2.08)" for the highest to lowest quartile of serum selenium. CONCLUSIONS: Our study supports findings from previous prospective studies and randomized trials that variations in selenium levels affect the incidence of certain cancers. In the United States, where intervention trials of selenium are in the planning stages, consideration should be given to including populations at high risk for squamous esophageal and gastric cardia cancers

Effects of combinations of therapeutic agents on the proliferation of progenitor cells in chronic myeloid leukaemia.

Marley SB, Davidson RJ, Goldman JM, et al.

Br J Haematol. 2002 Jan; 116(1):162-5.

Combination of STI571, a tyrosine kinase inhibitor, with other drugs may be beneficial in the treatment of chronic myeloid leukaemia (CML). We measured the effects of STI571, AG490, farnesyltransferase inhibitor (FTI), interferon alpha (IFN-alpha), cytosine arabinoside (Ara-C) and all-trans retinoic acid (ATRA), singly and in combination, on clonogenic leukaemic cell proliferation. STI571, IFN-alpha and ATRA each reduced proliferation by 50-60%; AG490, FTI and Ara-C had less effect. Comparing the observed and expected (i.e. additive) effects of drug combinations showed STI571 + FTI, STI571 + AG490 and IFN-alpha + ATRA were additive; STI571 + IFN-alpha, IFN-alpha + Ara-C and STI571 + AG490 + FTI were less than additive. Thus, STI571 + FTI, STI571 + AG490 and IFN-alpha + ATRA may be better combination therapies for CML than STI571 + IFN-alpha, IFN-alpha + Ara-C or STI571 + AG490 + FTI

Suppression by estrogen receptor beta of AP-1 mediated transactivation through estrogen receptor alpha.

Maruyama S, Fujimoto N, Asano K, et al.

J Steroid Biochem Mol Biol. 2001 Aug; 78(2):177-84.

The estrogen receptor (ER) is known to mediate gene transcription from AP-1 enhancer elements as well as the well-documented estrogen responsive elements (EREs). Investigations of AP-1 mediated transactivation through ER have been performed with rather complex promoters such as insulin like growth factor 1 (IGF-1) and collagenase promoters. In the present study, we investigated AP-1 mediated transactivation through ERalpha and ERbeta with a less complicated reporter consisting of only consensus AP-1 motifs. NIH 3T3 cells were transiently transfected with human ERalpha and ERbeta expression plasmids and AP-1-luc and ERE-luc reporters. 17beta-Estradiol failed to activate ERbeta-AP-1 responses while activating ERalpha-AP-1, ERalpha-ERE, ERbeta-ERE mediated transcription. On the other hand, antiestrogens such as tamoxifen enhanced AP-1 mediated transactivation through both ERalpha and ERbeta. An ERalpha positive human breast cancel cell line, MCF-7, also showed the same manner of AP-1 mediated transactivation through ERalpha. When NIH 3T3 with ERalpha and MCF-7 were co-transfected with ERbeta, E2 dependent AP-1 responses decreased in both cell lines depending on the amount of the ERbeta expression plasmid. These results suggest that ERalpha and ERbeta may function in opposition with ERbeta actually suppressing the function of ERalpha in AP-1 mediated transactivation

Determinants of mammographic densities among women of Asian, Native Hawaiian, and Caucasian ancestry.

Maskarinec G, Lyu LC, Meng L, et al.

Ethn Dis. 2001; 11(1):44-50.

This cross-sectional study explored the relation between mammographic densities (a predictor of breast cancer risk), ethnicity, and dietary factors among women in Hawaii. Thirty-nine postmenopausal women with Japanese, Chinese, Caucasian, and Native Hawaiian ancestry who had received a screening mammogram completed a medical, reproductive, and dietary history. Using a computerized method, we determined the total and the dense area of the breast and calculated the ratio between the two. Blood lipids were measured using standard methods. For statistical analysis, we applied analysis of variance and multiple linear regression. Whereas the mean dense area of the breast was one third smaller in Asian than in Caucasian and Native Hawaiian women, the percent of the breast occupied by dense tissue in the Asian women was slightly higher than in the Caucasian/Hawaiian group, possibly a result of the Asian women's smaller breast size. The exploratory analysis indicated inverse relations of body mass index, high-density lipoprotein cholesterol (HDLC), age at menarche, and soy intake with mammographic densities, as well as direct relations of estrogen use and family history with mammographic densities. The results of this study suggest that variations in these factors may be responsible for ethnic differences in mammographic densities and in breast cancer risk

Chemopreventive effects of bovine lactoferrin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced rat bladder carcinogenesis.

Masuda C, Wanibuchi H, Sekine K, et al.

Jpn J Cancer Res. 2000 Jun; 91(6):582-8.

Chemopreventive effects of bovine lactoferrin (bLF), which is found at high concentrations in colostrum, on rat bladder carcinogenesis were investigated using a rat bladder medium-term bioassay. In experiment 1, a total of 80 F344 male rats, 6 weeks old, were divided into 5 groups. Groups 1 and 2 were treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the drinking water for 8 weeks and after a 1-week interval, received dietary supplementation with 2% and 0.2% bLF, respectively. Group 3 received 0.05% BBN for 8 weeks and then no treatment. Group 4 was administered 2% bLF alone from week 9, without prior carcinogen exposure. Group 5 was maintained without any treatment throughout the experiment. All rats were killed at the end of week 36. Group 1 demonstrated a significantly decreased multiplicity of the bladder tumors (carcinomas and papillomas) as compared with group 3. Maximum cut surface areas of bladder tumors were also significantly decreased in groups 1 and 2 compared with group 3. No bladder tumors were observed in groups 4 or 5. In experiment 2, a total of 60 rats were divided into two groups (30 rats each); both were treated with 0.05% BBN for 4 weeks and after a 1-week interval, one received 2% bLF (group 1) and the other, basal diet (group 2) for 4 weeks. Group 1 demonstrated a tendency for decrease of the 5-bromo-2'-deoxyuridine (BrdU) labeling index. bLF was detected in the urine of rats fed bLF by ELISA as well as western blot analysis. The findings indicate that 2% bLF can inhibit BBN-induced rat bladder carcinogenesis, and that this may be due to bLF in the urine

Evaluation of chemoprevention of oral cancer with Spirulina fusiformis.

Mathew B, Sankaranarayanan R, Nair PP, et al.

Nutr Cancer. 1995; 24(2):197-202.

The blue-green microalgae Spirulina, used in daily diets of natives in Africa and America, have been found to be a rich natural source of proteins, carotenoids, and other micronutrients. Experimental studies in animal models have demonstrated an inhibitory effect of Spirulina algae on oral carcinogenesis. Studies among preschool children in India have demonstrated Spirulina fusiformis (SF) to be an effective source of dietary vitamin A. We evaluated the chemopreventive activity of SF (1 g/day for 12 mos) in reversing oral leukoplakia in pan tobacco chewers in Kerala, India. Complete regression of lesions was observed in 20 of 44 (45%) evaluable subjects supplemented with SF, as opposed to 3 of 43 (7%) in the placebo arm (p < 0.0001). When stratified by type of leukoplakia, the response was more pronounced in homogeneous lesions: complete regression was seen in 16 of 28 (57%) subjects with homogeneous leukoplakia, 2 of 8 with erythroplakia, 2 of 4 with verrucous leukoplakia, and 0 of 4 with ulcerated and nodular lesions. Within one year of discontinuing supplements, 9 of 20 (45%) complete responders with SF developed recurrent lesions. Supplementation with SF did not result in increased serum concentration of retinol or beta-carotene, nor was it associated with toxicity. This is the first human study evaluating the chemopreventive potential of SF. More studies in different settings and different populations are needed for further evaluation

Cimetidine and survival with colorectal cancer.

Matsumoto S.

Lancet. 1995 Jul 8; 346(8967):115.

Phytoestrogen content in foods.

Mazur W.

Baillieres Clin Endocrinol Metab. 1998 Dec; 12(4):729-42.

Plants abound in essential phytochemicals produced for their various vital functions. The same compounds seem also to be crucial for human health and disease. Recent human epidemiological and laboratory animal and cell studies on cancer and heart disease have highlighted the phytoestrogens--naturally occurring principles that share with steroidal oestrogens an ability to activate oestrogen receptors. The best known non-steroidal phytoestrogens include the isoflavones daidzein, genistein, formononetin and biochanin A, the coumestan coumestrol, and the lignans secoisolariciresinol and matairesinol. Acknowledging the potentially chemoprotective role of these non-nutrients, we have quantified all biologically important isoflavonoids and lignans in cereals, oilseeds and nuts, legumes, vegetables, fruits, berries and beverages such as tea, coffee and wine. In this chapter, we present a review of our studies on staple plant foods, indicating that plants contain, besides a wide range of chemicals with a number of biological properties, biologically active phytoestrogens--precursors of hormone-like compounds found in mammalian systems

MGN-3: cure or curiosity? The question persists!

McAllister E.

Well Being Journal. 2001;(Special Edition)

Elevated androgens and prolactin in aromatase-deficient mice cause enlargement, but not malignancy, of the prostate gland.

McPherson SJ, Wang H, Jones ME, et al.

Endocrinology. 2001 Jun; 142(6):2458-67.

Although androgens are the main steroids controlling the growth of the mammalian prostate, increasing evidence demonstrates that estrogens also regulate prostate development and growth. This study describes the effects of estrogen deficiency using aromatase knockout mice (ArKO) with targeted disruption of the cyp19 gene. Serum and tissue testosterone and 5alpha-dihydrotestosterone as well as serum PRL levels are significantly (P < 0.05) elevated in mature male ArKO mice. Histological, stereological, and immunohistochemical studies demonstrated enlargement of the ventral, anterior, and dorsolateral lobes of the prostate in young and older ArKO mice. Hyperplasia of the epithelial, interstitial, and luminal compartments was identified and associated with up-regulation of androgen receptors. There was no evidence of malignancy as the animals aged (up to 56 weeks). The changes observed in the prostates of ArKO mice were unaffected by maintaining mice on regular or soy-free diets. It is concluded in ArKO mice that, despite the long-term elevation of androgens and PRL, the absence of estrogen in these animals does not result in induction of malignancy in the prostate gland

Garlic and gastric cancer.

Mei X.

Acta Nutr Sinica. 1982;(4):53-8.

How You Can Beat Prostate and Breast Cancer Nutritionally 2000b.

Mercola J.

2000;2000b

Omega-3 Fats Prevent Breast Cancer.

Mercola J.

2002;2002a

Modulation of arachidonic acid distribution by conjugated linoleic acid isomers and linoleic acid in MCF-7 and SW480 cancer cells.

Miller A, Stanton C, Devery R.

Lipids. 2001 Oct; 36(10):1161-8.

The relationship between growth and alterations in arachidonic acid (AA) metabolism in human breast (MCF-7) and colon (SW480) cancer cells was studied. Four different fatty acid preparations were evaluated: a mixture of conjugated linoleic acid (CLA) isomers (c9,t11, t10,c12, c11,t13, and minor amounts of other isomers), the pure c9,t11-CLA isomer, the pure t10,c12-CLA isomer, and linoleic acid (LA) (all at a lipid concentration of 16 microg/mL). 14C-AA uptake into the monoglyceride fraction of MCF-7 cells was significantly increased following 24 h incubation with the CLA mixture (P < 0.05) and c9,t11-CLA (P < 0.02). In contrast to the MCF-7 cells, 14C-AA uptake into the triglyceride fraction of the SW480 cells was increased while uptake into the phospholipids was reduced following treatment with the CLA mixture (P < 0.02) and c9,t11-CLA (P < 0.05). Distribution of 14C-AA among phospholipid classes was altered by CLA treatments in both cell lines. The c9,t11-CLA isomer decreased (P < 0.05) uptake of 14C-AA into phosphatidylcholine while increasing (P < 0.05) uptake into phosphatidylethanolamine in both cell lines. Both the CLA mixture and the t10,c12-CLA isomer increased (P < 0.01) uptake of 14C-AA into phosphatidylserine in the SW480 cells but had no effect on this phospholipid in the MCF-7 cells. Release of 14C-AA derivatives was not altered by CLA treatments but was increased (P < 0.05) by LA in the SW480 cell line. The CLA mixture of isomers and c9,t11-CLA isomer inhibited 14C-AA conversion to 14C-prostaglandin E2 (PGE2) by 20-30% (P < 0.05) while increasing 14C-PGF2alpha by 17-44% relative to controls in both cell lines. LA significantly (P < 0.05) increased 14C-PGD2 by 13-19% in both cell lines and increased 14C-PGE2 by 20% in the SW480 cell line only. LA significantly (P < 0.05) increased 5-hydroperoxyeicosatetraenoate by 27% in the MCF-7 cell line. Lipid peroxidation, as determined by increased levels of 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha), was observed following treatment with c9,t11-CLA isomer in both cell lines (P < 0.02) and with t10,c12-CLA isomer in the MCF-7 cell line only (P < 0.05). These data indicate that the growth-promoting effects of LA in the SW480 cell line may be associated with enhanced conversion of AA to PGE2 but that the growth-suppressing effects of CLA isomers in both cell lines may be due to changes in AA distribution among cellular lipids and an altered prostaglandin profile

Involvement of up-regulation of 17beta-hydroxysteroid dehydrogenase type 1 in maintenance of intratumoral high estradiol levels in postmenopausal breast cancers.

Miyoshi Y, Ando A, Shiba E, et al.

Int J Cancer. 2001 Dec 1; 94(5):685-9.

Estradiol (E2) and estrone (E1) levels as well as mRNA expression levels of aromatase, sulfatase and 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) in breast cancer tissues were studied to elucidate the mechanism involved in the maintenance of the intratumoral high E2 levels in postmenopausal patients with very low serum E2 levels. Intratumoral E2 levels of postmenopausal patients (127.2 +/- 17.5 pg/g) (mean +/- SE) were not significantly different from those of premenopausal patients (110.1 +/- 10.1 pg/g) (p = 0.36). The mRNA expression levels of aromatase and sulfatase, determined by a quantitative real-time PCR, were not significantly different between premenopausal and postmenopausal breast cancers, but 17beta-HSD1 mRNA expression levels were significantly higher in postmenopausal than premenopausal breast cancers (p < 0.05). Intratumoral E2/E1 ratios were significantly higher in postmenopausal than premenopausal breast cancers (p < 0.01). These results demonstrate that the increased conversion from E1 to E2 catalyzed by 17beta-HSD1 may play an important role in the maintenance of the intratumoral high E2 levels in postmenopausal patients

A protein fraction from aged garlic extract enhances cytotoxicity and proliferation of human lymphocytes mediated by interleukin-2 and concanavalin A.

Morioka N, Sze LL, Morton DL, et al.

Cancer Immunol Immunother. 1993 Oct; 37(5):316-22.

Fraction 4 (F4), a protein fraction isolated from aged garlic extract, enhanced cytotoxicity of human peripheral blood lymphocytes (PBL) against both natural-killer (NK)-sensitive K562 and NK-resistant M14 cell lines. Although F4 treatment alone increased cytotoxicity, the effect was more remarkable when F4 was administered together with suboptimal doses of interleukin-2 (IL-2); combination treatment of 5 micrograms/ml F4 plus 10 U/ml IL-2 for 72 h generated lymphokine-activated killer activity equivalent to that produced by 100 U/ml IL-2 alone against M14. F4 enhanced IL-2-induced proliferation and IL-2 receptor (Tac) expression of PBL without significant increase of IL-2 production. The enhancement of cytotoxicity both by F4 alone and by F4 plus IL-2 was abolished by anti-IL-2 antibody. F4 also enhanced concanavalin-A(ConA)-induced proliferation of PBL. Radiolabeled-ConA binding assays revealed that F4 treatment greatly augmented the affinity and slightly increased the number of ConA binding sites in PBL. F4 also enhanced ConA-induced IL-2 receptor (Tac) expression and IL-2 production of PBL. Anti- IL-2 antibody inhibited the effect of F4 on ConA-induced proliferation. These data suggest that IL-2 is involved in augmentative effects of F4. Our results indicate that F4 is a very efficient immunopotentiator and may be used for immunotherapy

Melatonin vs. cancer.

Moss R.

Cancer Chronicles #27. 1995; 1995 May

Antioxidants Against Cancer 2000.

Moss R.

2000;

S-allylcysteine ameliorates doxorubicin toxicity in the heart and liver in mice.

Mostafa MG, Mima T, Ohnishi ST, et al.

Planta Med. 2000 Mar; 66(2):148-51.

Doxorubicin, a potent anticancer drug, is effective against a wide range of human neoplasms. However, the clinical uses of doxorubicin have been limited due to its serious cardiotoxic effects, which are likely the result of generation of free radicals and lipid peroxidation. S-Allylcysteine (SAC), an organosulfur compound purified from garlic, has been reported to have antioxidant and radical scavenging effects. Thus, we examined the effect of SAC on doxorubicin toxicity in mice. Severe doxorubicin toxicity was induced in mice by a single intraperitoneal injection (15 mg/kg body weight). SAC (30 mg/kg) was injected intraperitoneally daily for 5 days, starting two days prior to the administration of doxorubicin. Body weight was measured every alternate day. A measurement of serum creatine phosphokinase (CPK) and a histopathological analysis of the heart and liver was performed 6 days after the administration of doxorubicin. Death of any of the animals was recorded during the observation period. Doxorubicin injection induced a mortality rate of 58%, with SAC treatment reducing the doxorubicin-induced mortality rate to 30%. The severe body weight loss caused by doxorubicin (13%) was also significantly attenuated by SAC treatment (9%). Although an elevation of the level of serum CPK was observed following doxorubicin injection (5472 +/- 570 i.u./L), treatment with SAC significantly reduced the level of CPK (1923 +/- 635 i.u./L). Histological analysis demonstrated that heart and liver damage was significantly less severe in SAC treated mice than in mice receiving only doxorubicin. These results suggest that SAC research may ultimately lead to a resolution of the adverse effects of doxorubicin treatment in cancer chemotherapy

Arginine induces apoptosis and gene expression of pancreatitis-associated protein (PAP) in rat pancreatic acinar AR4-2J cells.

Motoo Y, Taga K, Su SB, et al.

Pancreas. 2000 Jan; 20(1):61-6.

Arginine-induced pancreatic acinar cell injury has been reported in vivo, but the mechanism involved is unknown. In this study we investigated the effects of arginine on the cell morphology and pancreatitis-associated protein (PAP) gene expression in rat pancreatic acinar AR4-2J cells in vitro. Arginine inhibited the proliferation of AR4-2J cells in a dose-dependent manner. This decrease in proliferation was due to an increase in apoptosis, as assessed by cell morphology and DNA fragmentation. PAP messenger RNA (mRNA) was expressed at doses of 2.5 and 5.0 mg/ml of arginine, and a time-course study showed that the expression started 2 h after arginine addition and peaked at 6 h. Apoptosis was rarely seen when PAP mRNA was highly expressed, but occurred when PAP mRNA expression was decreased. These results suggest that arginine induces apoptosis and PAP gene expression in pancreatic acinar cells and that PAP might inhibit the induction of apoptosis

Vitamin E, alpha- and gamma-tocopherol, and prostate cancer.

Moyad MA, Brumfield SK, Pienta KJ.

Semin Urol Oncol. 1999 May; 17(2):85-90.

Vitamin E is one of the most researched compounds in medicine. Vitamin E is actually a general name for potentially eight different compounds, so supplements can contain several forms and vitamin E in the diet also differs from the form found over the counter. There has been a strong interest in this supplement in the prostate cancer arena primarily because of a Finnish study that demonstrated a lower morbidity and mortality from this disease in men taking 50 mg of synthetic (alpha-tocopherol) vitamin E daily. In addition, observations from laboratory and clinical studies dealing with heart disease have found that gamma-tocopherol may also play a significant role in prevention; therefore, we decided to test the ability of this compound (versus synthetic vitamin E) to control the growth of a human prostate cancer cell line. Gamma-tocopherol was found to be superior to alpha-tocopherol in terms of cell inhibition in vitro. Both forms of vitamin E (and others) should be thoroughly evaluated in the future to provide the most effective chemoprevention information to the patient

Effects of arginine, L-alanyl-L-glutamine or taurine on neutrophil (PMN) free amino acid profiles and immune functions in vitro.

Muhling J, Fuchs M, Fleck C, et al.

Amino Acids. 2002; 22(1):39-53.

The objective of this study was to determine the effects of arginine, L-alanyl-L-glutamine (Ala-Gln) or taurine on polymorphonuclear leucocyte (PMN) free amino acid profiles, superoxide anion (O2-) generation, hydrogen peroxide (H2O2) formation and released myeloperoxidase activity (MPO). Arginine led to significant increases in PMN arginine, ornithine, citrulline, aspartate, glutamate and alanine concentrations as well as increased H2O2-generation and MPO activity while O(2-)-formation was decreased. Ala-Gln caused significant increases in PMN free glutamine, alanine, asparagine, aspartate, glutamate, ornithine, arginine, serine and glycine concentrations and increased PMN immune functions. Taurine significantly increased PMN free taurine profiles, reduced PMN neutral amino acid content and decreased

Pyrrolidine dithiocarbamate inhibits the production of interleukin-6, interleukin-8, and granulocyte-macrophage colony-stimulating factor by human endothelial cells in response to inflammatory mediators: modulation of NF-kappa B and AP-1 transcription factors activity.

Munoz C, Pascual-Salcedo D, Castellanos MC, et al.

Blood. 1996 Nov 1; 88(9):3482-90.

Endothelial cells (EC) play a key role in the inflammatory response, both by the production of proinflammatory cytokines and by their interaction with leukocytes. Molecular genetic analysis has demonstrated that functional NF-kappa B sites are involved in the transcription of interleukin-6 (IL-6), IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) genes in response to inflammatory mediators. Thus, we have explored the effect of two inhibitors of the NF-kappa B activation, pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), on the production of these cytokines by EC. Both PDTC and NAC inhibited, in a dose-dependent manner, the synthesis of IL-6, IL-8, and GM-CSF induced by tumor necrosis factor (TNF)-alpha or bacterial lipopolysaccharides (LPS) in human umbilical vein endothelial cells (HUVEC). PDTC appeared to prevent IL-6, IL-8, and GM-CSF gene transcription, as it blocked the induction of specific mRNA by TNF-alpha or LPS. The TNF-alpha mediated transcriptional activation of a chloramphenicol acetyltransferase (CAT) plasmid containing three copies of the -72 kappa B binding site from the IL-6 promoter was abrogated by PDTC. According to transfection experiments, electrophoretic mobility shift assays (EMSA) demonstrated that the antioxidant prevented the induction of NF-kappa B DNA-binding activity by TNF-alpha. Under the same conditions, PDTC by itself or in combination with TNF-alpha, enhanced the DNA-binding activity of AP-1, as well as c-fos and c-jun mRNA levels. Altogether, these results indicate that the antioxidant PDTC specifically inhibits the transcription of IL-6, IL-8, and GM-CSF genes through the inhibition of the NF-kappa B activation, while increasing the expression of AP-1. Our data make evident the antiinflammatory and immunoregulatory potential of the pharmacological inhibition of the NF-kappa B activation. In addition, PDTC and related molecules may be a useful tool to explore the expression of genes involved in the inflammatory response

A secreted/shed product of Helicobacter pylori activates transcription factor nuclear factor-kappa B.

Munzenmaier A, Lange C, Glocker E, et al.

J Immunol. 1997 Dec 15; 159(12):6140-7.

Helicobacter pylori is an etiologic agent in the development of chronic gastritis, duodenal ulceration, and gastric adenocarcinoma. Exposure of gastric epithelial cells to H. pylori induces secretion of the cytokine IL-8, which plays a pivotal role in the immunopathogenesis of H. pylori infections. Isolated Helicobacter strains differ in their virulence and in their ability to induce cytokine production. High degrees of virulence correlate with enhanced IL-8 production. However, the molecular mechanism of this variance in Helicobacter pathogenicity remains poorly understood. Here we show that H. pylori-mediated IL-8 secretion requires activation of the transcription factor nuclear factor-kappaB (NF-kappaB) in a gastric epithelial cell line. Several H. pylori strains which fail to induce IL-8 secretion do not activate NF-kappaB, while all IL-8-inducing strains activate the transcription factor. Moreover, the antioxidant curcumin, which inhibits NF-kappaB activation, also completely suppresses IL-8 induction by H. pylori. NF-kappaB activation is not mediated by LPSs, since purified H. pylori LPS had no effect on gastric epithelial cells. In contrast, both IL-8 secretion and NF-kappaB activation require a secreted H. pylori product, which is not secreted by strains mutated in picB/cagE, a recently identified putative transport protein

Melatonin in feverfew and other medicinal plants.

Murch SJ, Simmons CB, Saxena PK.

Lancet. 1997 Nov 29; 350(9091):1598-9.

Encyclopedia of Nutritional Supplements 1996.

Murray M.

1996;

Telomerase inhibition, telomere shortening, and senescence of cancer cells by tea catechins.

Naasani I, Seimiya H, Tsuruo T.

Biochem Biophys Res Commun. 1998 Aug 19; 249(2):391-6.

Animal in vivo studies and human epidemiological observations indicated potent anticancer effects for tea. Here we demonstrate that epigallocatechin gallate (EGCG), a major tea catechin, strongly and directly inhibits telomerase, an enzyme essential for unlocking the proliferative capacity of cancer cells by maintaining the tips of their chromosomes. Telomerase inhibition was elaborated in a cell-free system (cell extract) as well as in living cells. In addition, the continued growth of two representative human cancer cell lines, U937 monoblastoid leukemia cells and HT29 colon adenocarcinoma cells, in the presence of nontoxic concentrations of EGCG showed life span limitations accompanied with telomere shortening, chromosomal abnormalities, and expression of the senescence-associated beta-galactosidase. It is suggested that telomerase inhibition could be one of the major mechanisms underlying the anticancer effects of tea

Transport mechanism of anthracycline derivatives in human leukemia cell lines: uptake and efflux of pirarubicin in HL60 and pirarubicin-resistant HL60 cells.

Nagasawa K, Natazuka T, Chihara K, et al.

Cancer Chemother Pharmacol. 1996; 37(4):297-304.

We studied the transport mechanism of pirarubicin (THP) in HL60 and its THP-resistant (HL60/THP) cells, which showed no expression of mdr1 mRNA on Northern blot analysis. Under physiological conditions, the uptake of THP by both types of cell was time- and temperature-dependent. The amount of drug transport in the resistant cells was significantly less than that in the parent cells within 3 min of incubation. THP uptake was significantly higher in the presence than in the absence of 4 mM 2,4-dinitrophenol (DNP) in glucose-free Hanks' balanced salt solution in both HL60 and HL60/THP cells and the increases were approximately equal. In the presence of DNP, the uptake of THP by both types of cell was concentration-dependent, and there were no significant differences in the apparent kinetic constants (Michaelis constant (Km), maximum velocity (Vmax) and Vmax/Km) for THP uptake between HL60 and HL60/THP cells. Additionally, THP transport was competitively inhibited by its analogue doxorubicin. The efflux of THP from HL60/THP cells was significantly greater than that from HL60 cells, and the release from both types of cell was completely inhibited by decreasing the incubation temperature to 0 degrees C and by treatment with DNP in glucose-free medium. In contrast, the P-glycoprotein inhibitors verapamil and cyclosporin A did not inhibit THP efflux. However, genistein, which is a specific inhibitor of multidrug resistance-associated protein (MRP), increased the THP remaining in the resistant cells, and the value was approximately equal to that of the control group in the sensitive cells. These results suggest that THP is taken up into HL60 and HL60/THP cells via a common carrier by facilitated diffusion, and then pumped out in an energy-dependent manner. Furthermore, the accelerated efflux of THP by a specific mechanism, probably involving MRP, other than the expression of P-glycoprotein, resulted in decreased drug accumulation in the resistant cells, and was responsible, at least in part, for the development of resistance in HL60/THP cells

Effect of soymilk consumption on serum estrogen concentrations in premenopausal Japanese women.

Nagata C, Takatsuka N, Inaba S, et al.

J Natl Cancer Inst. 1998 Dec 2; 90(23):1830-5.

BACKGROUND: Estrogens have been implicated in the development of breast cancer. Preliminary evidence suggests that consumption of soy products, which contain isoflavones (phytoestrogens), can reduce serum estrogen levels. Our purpose was to determine the effect of soy consumption on serum estrogen levels in premenopausal women by use of a dietary intervention approach. METHODS: Premenopausal Japanese women were randomly assigned to receive either a soymilk-supplemented diet (n = 31) or a normal (control) diet (n = 29). The women in the soymilk-supplemented group were asked to consume about 400 mL of soymilk (containing about 109 mg of isoflavones) daily during a study period that involved three consecutive menstrual cycles. Follicular-phase blood samples were to be obtained in the menstrual cycles preceding (cycle 1) and following (cycle 3) the 2-month dietary intervention. All statistical tests were two-sided. RESULTS: At the end of the study period, estrone and estradiol levels were decreased by 23% and 27%, respectively, in the soymilk-supplemented group and were increased by 0.6% and 4%, respectively, in the control group. The changes for each hormone between the two groups were not statistically significantly different. In the soymilk-supplemented group, menstrual cycle length was increased by nearly 2 days, and, in the control group, it was decreased by approximately 1 day, a difference that was not statistically significant. A subgroup analysis restricted to subjects who provided follicular-phase blood samples on the same day or 1 day apart in menstrual cycles 1 and 3 showed a reduction in serum estrone levels in the soymilk-supplemented group that was of borderline statistical significance (P = .07 for change in serum estrone level in soymilk-supplemented group versus control group). CONCLUSION: Much larger studies will be required to confirm the ability of soy products to reduce serum estrogen levels

Inhibition of in vitro tumor cell-endothelial adhesion by modified citrus pectin: a pH modified natural complex carbohydrate.

Naik H.

Proc Am Assoc Cancer Res. 1995; 36

377

Serum and colon mucosa micronutrient antioxidants: differences between adenomatous polyp patients and controls.

Nair S, Norkus EP, Hertan H, et al.

Am J Gastroenterol. 2001 Dec; 96(12):3400-5.

OBJECTIVES: Micronutrient antioxidants, by virtue of their free radical scavenging properties, are potential chemopreventive agents against colon cancer. Yet, little is known about the actual concentration of these antioxidants in colonic mucosa. It is also not known whether a relationship exists between serum and mucosal tissue antioxidant levels. Previous studies evaluating the occurrence of polyps after supplementation with vitamin E and beta-carotene have yielded mixed results. The aim of this study was to determine the concentrations of seven micronutrient antioxidants (alpha- and gamma-tocopherol, lutein, beta-cryptoxanthin, lycopene, and alpha- and beta-carotene) in colonic mucosa and to determine whether serum levels of each antioxidant could predict levels of that antioxidant in the right and left colon of patients with normal mucosa or in those with adenomatous polyps. METHODS: Mucosal tissue concentrations and serum levels of antioxidants were determined in 10 patients with adenomatous polyps and 15 control subjects (GI patients with normal colonic mucosa). Mucosal tissue samples were obtained from both the right and left colon in all patients. RESULTS: Patients with polyps similar serum antioxidant status similar to that of control. However, polyp patients had significantly lower concentrations of all seven antioxidants in both the right (p < 0.0070) and left colon (p < 0.0026) than did controls. Finally, serum antioxidant levels predict right and left colon antioxidant levels in controls but not in patients with polyps. CONCLUSIONS: Patients with adenomatous polyps have low levels of micronutrient antioxidants in their colon mucosa. Because the serum levels of these antioxidants were similar in controls and polyp patients, our findings suggest an increased level of free radical activity in patients with polyps compared to normal subjects

Resveratrol inhibits human breast cancer cell growth and may mitigate the effect of linoleic acid, a potent breast cancer cell stimulator.

Nakagawa H, Kiyozuka Y, Uemura Y, et al.

J Cancer Res Clin Oncol. 2001 Apr; 127(4):258-64.

Resveratrol is a naturally occurring product found in grapes and wine. The effect of synthetic resveratrol on the growth of estrogen receptor (ER)-positive (KPL-1 and MCF-7) and -negative (MKL-F) human breast cancer cell lines was examined. Resveratrol at low concentrations caused cell proliferation in ER-positive lines (KPL-1, < or = "22" microM; MCF-7, or = 44 microM) it caused suppression of cell growth in all three cell lines examined. Growth suppression was due to apoptosis as seen by the appearance of a sub-G1 fraction. The apoptosis cascade up-regulated Bax and Bak protein, down-regulated Bcl-xL protein, and activated caspase-3. Resveratrol (52-74 microM) antagonized the effect of linoleic acid, a potent breast cancer cell stimulator, and suppressed the growth of both ER-positive and -negative cell lines. Thus, resveratrol could be a promising anticancer agent for both hormone-dependent and hormone-independent breast cancers, and may mitigate the growth stimulatory effect of linoleic acid in the Western-style diet

Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin.

Nangia-Makker P, Hogan V, Honjo Y, et al.

J Natl Cancer Inst. 2002 Dec 18; 94(24):1854-62.

BACKGROUND: The role of dietary components in cancer progression and metastasis is an emerging field of clinical importance. Many stages of cancer progression involve carbohydrate-mediated recognition processes. We therefore studied the effects of high pH- and temperature-modified citrus pectin (MCP), a nondigestible, water-soluble polysaccharide fiber derived from citrus fruit that specifically inhibits the carbohydrate-binding protein galectin-3, on tumor growth and metastasis in vivo and on galectin-3-mediated functions in vitro. METHODS: In vivo tumor growth, angiogenesis, and metastasis were studied in athymic mice that had been fed with MCP in their drinking water and then injected orthotopically with human breast carcinoma cells (MDA-MB-435) into the mammary fat pad region or with human colon carcinoma cells (LSLiM6) into the cecum. Galectin-3-mediated functions during tumor angiogenesis in vitro were studied by assessing the effect of MCP on capillary tube formation by human umbilical vein endothelial cells (HUVECs) in Matrigel. The effects of MCP on galectin-3-induced HUVEC chemotaxis and on HUVEC binding to MDA-MB-435 cells in vitro were studied using Boyden chamber and labeling assays, respectively. The data were analyzed by two-sided Student's t test or Fisher's protected least-significant-difference test. RESULTS: Tumor growth, angiogenesis, and spontaneous metastasis in vivo were statistically significantly reduced in mice fed MCP. In vitro, MCP inhibited HUVEC morphogenesis (capillary tube formation) in a dose-dependent manner. In vitro, MCP inhibited the binding of galectin-3 to HUVECs: At concentrations of 0.1% and 0.25%, MCP inhibited the binding of galectin-3 (10 micro g/mL) to HUVECs by 72.1% (P =.038) and 95.8% (P =.025), respectively, and at a concentration of 0.25% it inhibited the binding of galectin-3 (1 micro g/mL) to HUVECs by 100% (P =.032). MCP blocked chemotaxis of HUVECs toward galectin-3 in a dose-dependent manner, reducing it by 68% at 0.005% (P<.001) and inhibiting it completely at 0.1% (P<.001). Finally, MCP also inhibited adhesion of MDA-MB-435 cells, which express galectin-3, to HUVECs in a dose-dependent manner. CONCLUSIONS: MCP, given orally, inhibits carbohydrate-mediated tumor growth, angiogenesis, and metastasis in vivo, presumably via its effects on galectin-3 function. These data stress the importance of dietary carbohydrate compounds as agents for the prevention and/or treatment of cancer

Colon cancer prevention with a small amount of dietary perilla oil high in alpha-linolenic acid in an animal model.

Narisawa T, Fukaura Y, Yazawa K, et al.

Cancer. 1994 Apr 15; 73(8):2069-75.

BACKGROUND. Epidemiologic and experimental studies suggest that dietary fish oil and vegetable oil high in omega-3 polyunsaturated fatty acids (PUFAs) suppress the risk of colon cancer. The optimal amount to prevent colon carcinogenesis with perilla oil high in omega-3 PUFA alpha-linolenic acid in a 12% medium-fat diet was investigated in female F344 rats. For comparison, safflower oil high in omega-6 PUFA linoleic acid was used. METHODS. Thirty or 25 rats at 7 weeks of age in each group received an intrarectal dose of 2 mg N-methyl-N-nitrosourea 3 times weekly in weeks 1 and 2 and were fed the diets with various levels of perilla oil and safflower oil throughout the experiment. RESULTS. The incidence of colon cancer at the termination of the experiment at week 35 was 40%, 48% and 32% in the rats fed the diets with 3% perilla oil plus 9% safflower oil, 6% perilla oil plus 6% safflower oil, and 12% perilla oil plus 0% safflower oil, respectively, whereas it was 67% in the rats fed the control diet with 0% perilla oil plus 12% safflower oil. The amount of diet consumed and the body weight gain were identical in all of the dietary groups. The ratios of omega-3 PUFA to omega-6 PUFA in the serum and the colonic mucosa at week 35 were increased in parallel to the increased intake of perilla oil. CONCLUSIONS. The results suggest that a relatively small fraction of perilla oil, 25% of total dietary fat, may provide an appreciable beneficial effect in lowering the risk of colon cancer

Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status.

Nesaretnam K, Stephen R, Dils R, et al.

Lipids. 1998 May; 33(5):461-9.

Potential antiproliferative effects of tocotrienols, the major vitamin E component in palm oil, were investigated on the growth of both estrogen-responsive (ER+) MCF7 human breast cancer cells and estrogen-unresponsive (ER-) MDA-MB-231 human breast cancer cells, and effects were compared with those of alpha-tocopherol (alphaT). The tocotrienol-rich fraction (TRF) of palm oil inhibited growth of MCF7 cells in both the presence and absence of estradiol with a nonlinear dose-response but such that complete suppression of growth was achieved at 8 microg/mL. MDA-MB-231 cells were also inhibited by TRF but with a linear dose-response such that 20 microg/mL TRF was needed for complete growth suppression. Separation of the TRF into individual tocotrienols revealed that all fractions could inhibit growth of both ER+ and ER- cells and of ER+ cells in both the presence and absence of estradiol. However, the gamma- and delta-fractions were the most inhibitory. Complete inhibition of MCF7 cell growth was achieved at 6 microg/mL of gamma-tocotrienol/delta-tocotrienol (gammaT3/deltaT3) in the absence of estradiol and 10 microg/mL of deltaT3 in the presence of estradiol, whereas complete suppression of MDA-MB-231 cell growth was not achieved even at concentrations of 10 microg/mL of deltaT3. By contrast to these inhibitory effects of tocotrienols, alphaT had no inhibitory effect on MCF7 cell growth in either the presence or the absence of estradiol, nor on MDA-MB-231 cell growth. These results confirm studies using other sublines of human breast cancer cells and demonstrate that tocotrienols can exert direct inhibitory effects on the growth of breast cancer cells. In searching for the mechanism of inhibition, studies of the effects of TRF on estrogen-regulated pS2 gene expression in MCF7 cells showed that tocotrienols do not act via an estrogen receptor-mediated pathway and must therefore act differently from estrogen antagonists. Furthermore, tocotrienols did not increase levels of growth-inhibitory insulin-like growth factor binding proteins (IGFBP) in MCF7 cells, implying also a different mechanism from that proposed for retinoic acid inhibition of estrogen-responsive breast cancer cell growth. Inhibition of the growth of breast cancer cells by tocotrienols could have important clinical implications not only because tocotrienols are able to inhibit the growth of both ER+ and ER- phenotypes but also because ER+ cells could be growth-inhibited in the presence as well as in the absence of estradiol. Future clinical applications of TRF could come from potential growth suppression of ER+ breast cancer cells otherwise resistant to growth inhibition by antiestrogens and retinoic acid

Beyond Aspirin.

Newmark T.

2000;

Cell growth inhibition by a novel vitamin K is associated with induction of protein tyrosine phosphorylation.

Ni R, Nishikawa Y, Carr BI.

J Biol Chem. 1998 Apr 17; 273(16):9906-11.

We have shown that a synthetic vitamin K analog, 2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone or compound 5 (Cpd 5), potently inhibits cell growth and suggested that the analog exerts its effects mainly via sulfhydryl arylation rather than redox cycling. Since protein-tyrosine phosphatases (PTPases), which have pivotal roles in many cellular functions, have a critical cysteine in their active site, we have proposed PTPases as likely targets for Cpd 5. To test this hypothesis, we examined the effects of Cpd 5 on protein tyrosine phosphorylation of cellular proteins and on the activity of PTPases. We found that Cpd 5 rapidly induced protein tyrosine phosphorylation in a human hepatocellular carcinoma cell line (Hep3B) at growth inhibitory doses, and the effect was blocked by thiols but not by non-thiol antioxidants or tyrosine kinase inhibitors. Cpd 5 inhibited PTPase activity, which was also significantly antagonized by reduced glutathione. Furthermore, the well studied PTPase inhibitor orthovanadate also induced protein tyrosine phosphorylation and growth inhibition in Hep3B cells. These results suggest that inhibition of cellular PTPases by sulfhydryl arylation and subsequent perturbation of protein tyrosine phosphorylation may be involved in the mechanisms of Cpd 5-induced cell growth inhibition

Thromboxane A(2) regulation of endothelial cell migration, angiogenesis, and tumor metastasis.

Nie D, Lamberti M, Zacharek A, et al.

Biochem Biophys Res Commun. 2000 Jan 7; 267(1):245-51.

Prostaglandin endoperoxide H synthases and their arachidonate products have been implicated in modulating angiogenesis during tumor growth and chronic inflammation. Here we report the involvement of thromboxane A(2), a downstream metabolite of prostaglandin H synthase, in angiogenesis. A TXA(2) mimetic, U46619, stimulated endothelial cell migration. Angiogenic basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) increased TXA(2) synthesis in endothelial cells three- to fivefold. Inhibition of TXA(2) synthesis with furegrelate or CI reduced HUVEC migration stimulated by VEGF or bFGF. A TXA(2) receptor antagonist, SQ29,548, inhibited

Antitumor-promoting activity of allixin, a stress compound produced by garlic.

Nishino H.

Cancer J. 1990;(3):20-1.

Berberine sulfate inhibits tumor-promoting activity of teleocidin in two-stage carcinogenesis on mouse skin.

Nishino H, Kitagawa K, Fujiki H, et al.

Oncology. 1986; 43(2):131-4.

Berberine sulfate, an isoquinoline alkaloid isolated from Hydrastis canadensis L., inhibited the effects of the tumor promoters 12-O-tetradecanoylphorbol-13-acetate and teleocidin, such as increased 32Pi-incorporation into phospholipids of cell membrane and hexose transport. Berberine sulfate also markedly suppressed the promoting effect of teleocidin on skin tumor formation in mice initiated with 7,12-dimethylbenz[a]anthracene

Development of a radiochemical cyclooxygenase-1 and -2 in vitro assay for identification of natural products as inhibitors of prostaglandin biosynthesis.

Noreen Y, Ringbom T, Perera P, et al.

J Nat Prod. 1998 Jan; 61(1):2-7.

A radiochemical enzyme assay for studying cyclooxygenase (COX)-catalyzed prostaglandin biosynthesis in vitro was optimized with respect to both COX-1 and COX-2 activity. The assay can be used to assess the relative selectivity of plant-derived inhibitors on COX-1 and COX-2 Assay conditions were optimized for both enzymes with respect to concentration of cofactors (l-epinephrine, reduced glutathione, and hematin), activation time (enzyme and cofactors), reaction time, and pH. Moreover, the kinetic parameters, Km and Kcat, of both enzymes were estimated. Five COX inhibitors were used to validate the assay, indomethacin, aspirin, naproxen, ibuprofen, and the arylsulfonamide NS-398, all with different COX selectivity and time dependency. Time-dependent inhibition was determined by comparing the inhibition, with and without preincubation of enzyme and inhibitor. Two flavonoids, (+)-catechin and quercitrin, were examined with respect to inhibition of COX-catalyzed prostaglandin biosynthesis. (+)-Catechin showed equal inhibitory effects on the two enzymes. Quercitrin was found to be inactive toward both COX-1- and COX-2-catalyzed prostaglandin biosynthesis. The optimization procedure resulted in a considerable reduction of the amount of enzyme required for adequate prostglandin biosynthesis and a reliable method suited to evaluate natural products on inhibition of COX-2-catalyzed prostaglandin biosynthesis, as well as on COX-1

Nutrition Science News. Vitamin D Is for Cancer Defense 2000 Mar.

NSN.

2000;2000 Mar

Effect of fish oil, arginine, and doxorubicin chemotherapy on remission and survival time for dogs with lymphoma: a double-blind, randomized placebo-controlled study.

Ogilvie GK, Fettman MJ, Mallinckrodt CH, et al.

Cancer. 2000 Apr 15; 88(8):1916-28.

BACKGROUND: Polyunsaturated n-3 fatty acids have been shown to inhibit the growth and metastasis of tumors. This double-blind, randomized study was designed to evaluate the hypothesis that polyunsaturated n-3 fatty acids can improve metabolic parameters, decrease chemical indices of inflammation, enhance quality of life, and extend disease free interval and survival time for dogs treated for lymphoblastic lymphoma with doxorubicin chemotherapy. METHODS: Thirty-two dogs with lymphoma were randomized to receive one of two diets supplemented with menhaden fish oil and arginine (experimental diet) or an otherwise identical diet supplemented with soybean oil (control diet). Diets were fed before and after remission was attained with up to five dosages of doxorubicin. Parameters examined included blood concentrations of glucose, lactic acid, and insulin in response to glucose and diet tolerance tests; alpha-1 acid glycoprotein; tumor necrosis factor; interleukin-6; body weight; amino acid profiles; resting energy expenditure; disease free interval (DFI); survival time (ST); and clinical performance scores. RESULTS: Dogs fed the experimental diet had significantly (P < 0.05) higher mean serum levels of the n-3 fatty acids docosahexaenoic acid (C22:6) and eicosapentaenoic acid (C20:5) compared with controls. Higher serum levels of C22:6 and C20:5 were associated with lesser (P < 0.05) plasma lactic acid responses to intravenous glucose and diet tolerance testing. Increasing C22:6 levels were significantly (P < 0.05) associated with longer DFI and ST for dogs with Stage III lymphoma fed the experimental diet. CONCLUSIONS: Fatty acids of the n-3 series normalize elevated blood lactic acid in a dose-dependent manner, resulting in an increase in DFI and ST for dogs with lymphoma

Nitric-oxide production by murine mammary adenocarcinoma cells promotes tumor-cell invasiveness.

Orucevic A, Bechberger J, Green AM, et al.

Int J Cancer. 1999 Jun 11; 81(6):889-96.

The role of nitric oxide (NO) in tumor biology remains controversial and poorly understood. While a few reports indicate that the presence of NO in tumor cells or their micro-environment is detrimental for tumor-cell survival, and consequently their metastatic ability, a large body of data suggests that NO promotes tumor progression. The purpose of this study was to identify the source of NO in the spontaneously metastasizing C3-L5 murine mammary-adenocarcinoma model, the role of tumor-derived NO in tumor-cell invasiveness, and the mechanisms underlying the invasion-stimulating effects of tumor-derived NO. The source of NO was established by immunocytochemical localization of NO synthase (NOS) enzymes in C3-L5 cells in vitro and transplanted tumors in vivo. An in vitro transwell Matrigel invasion assay was used to test the invasiveness of C3-L5 cells in the presence or the absence of NO blocking agents or iNOS inducers (IFN-gamma and LPS). The mechanisms underlying the invasion-stimulating effects of tumor-derived NO were examined by measuring mRNA expression of matrix metalloproteinases (MMP)-2 and -9, and tissue inhibitors of metalloproteinases (TIMP) 1, 2 and 3 in C3-L5 cells in various experimental conditions. Results showed that C3-L5 cells expressed high level of eNOS protein in vitro, and in vivo, both in primary and in metastatic tumors. C3-L5 cells also expressed iNOS mRNA and protein when cultured in the presence of IFN-gamma and LPS. Constitutively produced NO promoted tumor-cell invasiveness in vitro by down-regulating TIMP 2 and TIMP 3. In addition, there was up-regulation of MMP-2, when extra NO was induced by IFN-gamma and LPS. In conclusion, NO produced by C3-L5 cells promoted tumor-cell invasiveness by altering the balance between MMP-2 and its inhibitors TIMP-2 and 3. Thus, our earlier observations of anti-tumor and anti-metastatic effects of NO inhibitors in vivo in this tumor model can be explained, at least in part, by reduced tumor-cell invasiveness

Differential effects of the antioxidant alpha-lipoic acid on the proliferation of mitogen-stimulated peripheral blood lymphocytes and leukaemic T cells.

Pack RA, Hardy K, Madigan MC, et al.

Mol Immunol. 2002 Feb; 38(10):733-45.

The effects of the antioxidant alpha-lipoic acid (LA) on the proliferation of mitogen-stimulated human peripheral blood lymphocytes (HPBL) were investigated in comparison to its effects on the proliferation of two leukaemic T cell lines, Jurkat and CCRF-CEM. At low mM concentrations, LA inhibited in a dose-dependent manner DNA synthesis of HPBL stimulated with either phorbol myristate acetate (PMA) in combination with ionomycin (IoM), or phytohaemagglutinin (PHA). At similar concentrations, LA inhibited the proliferation of Jurkat and CCRF-CEM cells. However, LA was preferentially cytotoxic to the leukaemic cell lines. The selective toxicity of LA to Jurkat cells was shown by electron microscopy (EM) to be due to the induction of apoptosis. Furthermore, LA had different effects on the secretion of interleukin-2 (IL-2) and steady-state levels of IL-2 mRNA in mitogen-stimulated HPBL depending on the mitogens used. LA dramatically increased the induction of IL-2 mRNA and IL-2 protein secretion in PMA/IoM-stimulated HPBL, whereas it inhibited these in HPBL stimulated with PHA. The differential effects of LA on normal and leukaemic T lymphocytes may indicate a new route towards development of therapeutic agents

The Antioxidant Miracle 1999.

Packer LCC.

1999;

Canthaxanthin induces apoptosis in human cancer cell lines.

Palozza P, Maggiano N, Calviello G, et al.

Carcinogenesis. 1998 Feb; 19(2):373-6.

To investigate the possibility that canthaxanthin inhibits cancer cell growth by inducing apoptosis, human WiDr colon adenocarcinoma and SK-MEL-2 melanoma cells were treated with two different doses of the carotenoid for 48 h. Canthaxanthin was incorporated and/or associated to cells. The treatment with the carotenoid caused growth inhibition in both cell types. Concomitantly, apoptosis was induced. Increasing time of exposure and carotenoid concentration, this effect was more pronounced. At 48 h, the percentages of apoptotic cells were 13 and 15, using 1 microM canthaxanthin, and 18 and 20, using 10 microM canthaxanthin in WiDr and SK-MEL-2 cells, respectively. This study represents the first demonstration that canthaxanthin is able to induce apoptosis in tumour cells

Induction of apoptosis in prostate cancer cell lines by the green tea component, (-)-epigallocatechin-3-gallate.

Paschka AG, Butler R, Young CY.

Cancer Lett. 1998 Aug 14; 130(1-2):1-7.

Green tea components exert many biological effects, including antitumor and cancer preventive activities. In the search for anticancer agents for prostate cancer the inhibitory effects of green tea components were tested on the prostate cancer cell lines LNCaP, PC-3 and DU145. (-)-Epigallocatechin-3-gallate (EGCG) proved to be the most potent catechin at inhibiting cell growth. The inhibition induced by EGCG was found to occur via apoptotic cell death as shown by changes in nuclear morphology and DNA fragmentation. Thus, we report the first evidence that EGCG is the active component in green tea and induces apoptosis in human prostate cancer cells

Coenzyme Q10.

Pepping J.

Am J Health Syst Pharm. 1999 Mar 15; 56(6):519-21.

Estrogen receptor beta acts as a dominant regulator of estrogen signaling.

Pettersson K, Delaunay F, Gustafsson JA.

Oncogene. 2000 Oct 12; 19(43):4970-8.

The physiological effects of estrogens are mediated by two intracellular transcription factors, the estrogen receptors (ERs), that regulate transcription of target genes through binding to specific DNA target sequences. Here we describe alterations in cellular responses to different ER agonists and to the anti-estrogenic compound tamoxifen resulting from co-expression of the two ERs in transient co-transfection experiments. Our results demonstrate that ERbeta can act as a negative or positive dominant regulator of ER activity. This is manifested through reduced transcriptional activity at low concentrations of estradiol (E2); increased antagonistic effects of tamoxifen on E2 stimulated activity; and enhanced agonistic action of the phytoestrogenic compound genistein. Furthermore, using chimeric proteins lacking the N-terminal activation function 1 (AF-1), we show that the differential responses of ERalpha and ERbeta to different agonists and antagonists are primarily dictated by inherent differences in the C-terminal ligand-binding domains of the receptors, whereas the magnitude of transcriptional activity is influenced by ERalpha AF-1, but not ERbeta AF-1. The ERalpha AF-1 activity appears to be modulated upon co-expression of both ERs. The alterations in transcriptional activity resulting from co-expression of ERalpha and ERbeta are probably due to the formation of alpha/beta heterodimeric complexes. This study demonstrates that co-localization and subsequent heterodimerization of ERalpha and ERbeta may result in receptor activity distinct from that of ER homodimers

Functional Foods for Health. Resveratrol in Grapes Fights Cancer 1997.

Pezzuto J.

1997;

Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin.

Pienta KJ, Naik H, Akhtar A, et al.

J Natl Cancer Inst. 1995 Mar 1; 87(5):348-53.

BACKGROUND: Prostate cancer is the most common cancer diagnosed in U.S. men and remains incurable once it has metastasized. Many stages of the metastatic cascade involve cellular interactions mediated by cell surface components, such as carbohydrate-binding proteins, including galactoside-binding lectins (galectins). Modified citrus pectin (pH-modified), a soluble component of plant fiber derived from citrus fruit, has been shown to interfere with cell-cell interactions mediated by cell surface carbohydrate-binding galectin-3 molecules. PURPOSE: The aim of this study was to determine whether modified citrus pectin, a complex polysaccharide rich in galactosyl residues, could inhibit spontaneous metastasis of prostate adenocarcinoma cells in the rat. METHODS: The ability of modified citrus pectin to inhibit the adhesion of Dunning rat prostate cancer MAT-LyLu cells to rat endothelial cells was measured by 51Cr-labeling. Modified citrus pectin inhibition of MAT-LyLu cell anchorage-independent growth was measured by colony formation in agarose. The presence of galectin-3 in rat MAT-LyLu cells and human prostate carcinoma was demonstrated by immunoblotting and immunohistochemistry. One million MAT-LyLu cells were injected subcutaneously into the hind limb of male Copenhagen rats on day 0. Rats were given 0.0%, 0.01%, 0.1%, or 1.0% (wt/vol) modified citrus pectin continuously in their drinking water (from day 4 until necropsy on day 30). The number of MAT-LyLu tumor colonies in the lungs were counted. RESULTS: Compared with 15 or 16 control rats that had lung metastases on day 30, seven of 14 rats in the 0.1% and nine of 16 rats in the 1.0% modified citrus-pectin group had statistically significant (two-sided; P < .03 and P < .001, respectively) reductions in lung metastases. The lungs of the 1.0% modified citrus pectin-treated rats had significantly (two-sided; P < .05) fewer metastatic colonies than control groups (9 colonies +/- 4 [mean +/- SE] in the control group compared with 1 colony +/- 1 in the treated group). Modified citrus pectin had no effect on the growth of the primary tumors. In vitro, modified citrus pectin inhibited MAT-LyLu cell adhesion to rat endothelial cells in a time- and dose-dependent manner as well as their colony formation in semisolid medium. CONCLUSIONS: We present a novel therapy in which oral intake of modified citrus pectin acts as a potent inhibitor of spontaneous prostate carcinoma metastasis in the Copenhagen rat. IMPLICATIONS: Further investigations are warranted to determine the following: 1) the role of galectin-3 in normal and cancerous prostate tissues and 2) the ability of modified citrus pectin to inhibit human prostate metastasis in nude mice

Combination of phenylbutyrate and 13-cis retinoic acid inhibits prostate tumor growth and angiogenesis.

Pili R, Kruszewski MP, Hager BW, et al.

Cancer Res. 2001 Feb 15; 61(4):1477-85.

Differentiation-inducing agents, such as retinoids and short-chain fatty acids, have an inhibitory effect on tumor cell proliferation and tumor growth in preclinical studies. Clinical trials involving these compounds as single agents have been suboptimal in terms of clinical benefit. Our study evaluated the combination of phenylbutyrate (PB) and 13-cis retinoic acid (CRA) as a differentiation and antiangiogenesis strategy for prostate cancer. On the basis of previous evidence, common signal transduction pathways and possible modulation of retinoid receptors and retinoid response elements by PB could be responsible for such activities. We assessed the effect of the combination of PB and CRA on human and rodent prostate carcinoma cell lines. The combination of PB and CRA inhibited cell proliferation and increased apoptosis in vitro in an additive fashion as compared with single agents (P < 0.014). Prostate tumor cells treated with both PB and CRA revealed an increased expression of a subtype of retinoic acid receptor (retinoic acid receptor-beta), suggesting a molecular mechanism for the biological additive effect. The combination of PB and CRA also inhibited prostate tumor growth in vivo (up to 82-92%) as compared with single agents (P < 0.025). Histological examination of tumor xenografts revealed decreased in vivo tumor cell proliferation, an increased apoptosis rate, and a reduced microvessel density in the animals treated with combined drugs, suggesting an antiangiogenesis effect of this combination. Thus, endothelial cell treatment with both PB and CRA resulted in reduced in vitro cell proliferation. In vivo testing using the Matrigel angiogenesis assay showed an additive inhibitory effect in the animals treated with a combination of PB + CRA (P < 0.004 versus single agents). In summary, this study showed an additive inhibitory effect of combination of differentiation agents PB and CRA on prostate tumor growth through a direct effect on both tumor and endothelial cells

Omega 3-fatty acids: a key nutrient in cancer care. Presented at Comprehensive Cancer Care 2001, Arlington, VA, October 17-21, 2001.

Pizzorno J.

2001;October 17-21, 2001

Modulation of the lung colonization of B16-F1 melanoma cells by citrus pectin.

Platt D, Raz A.

J Natl Cancer Inst. 1992 Mar 18; 84(6):438-42.

CONTEXT: Studies have shown that the galactoside-containing simple sugars and anti-galactoside-binding lectin antibodies may affect experimental tumor cell metastasis. However, the limited number of reagents used thus far necessitate further observations. PURPOSE: Natural citrus pectin (CP) and pH-modified CP (MCP), rich in galactose residues, were used to study the involvement of carbohydrates containing galactoside residues in cellular interaction in vitro and in lung colonization in vivo of B16-F1 melanoma cells. METHODS: B16-F1 melanoma cells were incubated with various concentrations of CP and MCP. Their ability to form homotypic aggregation in vitro and tumor lung colonization in vivo in 8-week-old female C57BL/6 mice was then analyzed. RESULTS: The CP binds to the surface of B16-F1 melanoma cells; this binding can be inhibited by lactose at a concentration of 0.15 M. Intravenous injection of the murine B16-F1 melanoma cells with the natural CP resulted in a significant increase (up to threefold) in the appearance of tumor colonies in the lung and in increased homotypic aggregation properties of the cells, while injection of MCP significantly decreased B16-F1 experimental metastasis (greater than 90%). CONCLUSIONS: Tumor galactoside-binding proteins mediate cellular recognition by linking oligosaccharides with terminal D-galactoside residues on adjacent cells. Successful interference with such a process with MCP may lead to a reduced ability to form tumor cell emboli and metastasis. IMPLICATIONS: These findings imply that the galactose-containing carbohydrate side chains of CP might mimic or compete with the natural ligand(s) of the tumor galactoside-binding protein (gal-lectin) and thus affect cellular interactions relevant for metastasis

Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex.

Plummer SM, Holloway KA, Manson MM, et al.

Oncogene. 1999 Oct 28; 18(44):6013-20.

Colorectal cancer is a major cause of cancer deaths in Western countries, but epidemiological data suggest that dietary modification might reduce these by as much as 90%. Cyclo-oxygenase 2 (COX2), an inducible isoform of prostaglandin H synthase, which mediates prostaglandin synthesis during inflammation, and which is selectively overexpressed in colon tumours, is thought to play an important role in colon carcinogenesis. Curcumin, a constituent of turmeric, possesses potent anti-inflammatory activity and prevents colon cancer in animal models. However, its mechanism of action is not fully understood. We found that in human colon epithelial cells, curcumin inhibits COX2 induction by the colon tumour promoters, tumour necrosis factor alpha or fecapentaene-12. Induction of COX2 by inflammatory cytokines or hypoxia-induced oxidative stress can be mediated by nuclear factor kappa B (NF-kappaB). Since curcumin inhibits NF-kappaB activation, we examined whether its chemopreventive activity is related to modulation of the signalling pathway which regulates the stability of the NF-kappaB-sequestering protein, IkappaB. Recently components of this pathway, NF-kappaB-inducing kinase and IkappaB kinases, IKKalpha and beta, which phosphorylate IkappaB to release NF-kappaB, have been characterised. Curcumin prevents phosphorylation of IkappaB by inhibiting the activity of the IKKs. This property, together with a long history of consumption without adverse health effects, makes curcumin an important candidate for consideration in colon cancer prevention

Molecular Architects Create New Cancer Preventives 2000.

Posner G.

2000

Doses of multiple antioxidant vitamins: essential ingredients in proving the efficacy of standard cancer therapy.

Prasad KN.

J Am Coll Nutr. 1999; 18(1):13-25.

Genistein modulates drug resistance in non P-glycoprotein multidrug resistant human colon carcinoma cells (meeting abstract).

Rabindran SK.

Proc Annu Meet Am Assoc Cancer Res. 1995; 36(A1928)

Endogenous galactoside-binding lectins: a new class of functional tumor cell surface molecules related to metastasis.

Raz A, Lotan R.

Cancer Metastasis Rev. 1987; 6(3):433-52.

The formation of secondary tumors by circulating cancer cells (blood-borne metastasis) correlates with an increased tendency of the cells to form emboli by aggregation with other tumor cells or with host cells. Although it is evident that cell-cell recognition and adhesion are mediated by cell surface components, the identity of these molecules is only now being unraveled. Over the last decade an increasing number of studies have demonstrated the presence of endogenous carbohydrate-binding proteins on the surface of various normal cells, and it has been proposed that such lectin-like molecules might be involved in intercellular adhesion. We have shown that various tumor cell lines contain endogenous galactose-specific lectins. Lectin activity was detected at the cell surface by the binding of asialofetuin. This glycoprotein also enhanced the aggregation of the tumor cells. After purification by affinity chromatography on immobilized asialofetuin the lectin activity was associated with two proteins of Mr 14,500 and 34,000. By using polyclonal and monoclonal antilectin antibodies in conjunction with various immunologic techniques we have demonstrated that the endogenous lectins are present on the surface of different tumor cells. Quantitation of cell surface lectins by flow cytometric analyses of antilectin antibody binding revealed that among related tumor cells those exhibiting a higher metastatic potential expressed more lectin on their surface. The binding of monoclonal antilectin antibodies to metastatic cells decreased asialofetuin-induced homotypic aggregation in vitro and suppressed the ability of the cells to form lung metastases after intravenous injection in the tail vein of syngeneic mice. These results strongly implicate the tumor cell surface lectins in cell adhesion and metastasis. We propose that such lectins can increase the ability of tumor cells that enter the blood stream to form aggregates with other tumor cells, or to adhere to host cells or the extracellular matrix and thereby increase their metastatic potential. Other contributing components to tumor cell-host cell interactions are cell surface carbohydrate-binding proteins that have been detected on lymphocytes, platelets, macrophages, hepatocytes, and endothelial cells. These lectin-like molecules might recognize and bind carbohydrates expressed on the surface of tumor cells and enhance emboli formation and organ colonization

Genistein inhibits growth of B16 melanoma cells in vivo and in vitro and promotes differentiation in vitro.

Record IR, Broadbent JL, King RA, et al.

Int J Cancer. 1997 Sep 4; 72(5):860-4.

Consumption of soy products has been linked to a reduced mortality and morbidity from a number of cancers. Genistein, one of the principal soy isoflavones, has been shown to inhibit the growth of a number of tumour cell lines in vitro; however, a role of genistein in retarding tumour growth in vivo is less well documented. In this study, in addition to examining the effects of genistein on the growth of murine B16 melanoma cells in vitro, we have examined the effects of feeding a genistein-rich diet on s.c. growth of these tumour cells in mice. In vitro, the melanoma cells showed an increase in sensitivity to genistein with increasing time of exposure, culminating in a 50% growth inhibition (IC50) at 12.5 microM after 7 days. Genistein at 25 microM induced micronucleus formation after 24 hr and at concentrations as low as 2.5 microM induced morphological changes indicative of differentiation. Growth of solid tumours implanted into female C57BL/6J mice was inhibited by 50% when mice were fed genistein for 1 week before and for 1 week after inoculation with B16 melanoma cells. Plasma genistein concentrations at the time of tumour removal were 1.1 microM, which is similar to levels reported in humans consuming diets high in soybeans or soybean products, while control animals had no detectable genistein in plasma. Our results provide additional in vivo evidence suggesting that genistein retards the growth of implanted tumours, adding further to studies suggesting that this isoflavonoid is a biologically active component of soy foods

Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds.

Reddi K, Henderson B, Meghji S, et al.

Cytokine. 1995 Apr; 7(3):287-90.

Naphthoquinone vitamins (vitamins K) are widely recognized for their role in the gamma-carboxylation of specific glutamyl residues in coagulation, anti-coagulation and extra-hepatic proteins. Recently, however, there have been reports that these compounds can exert actions other than those normally associated with protein gamma-carboxylation. These observations suggest that naphthoquinones may have effects on the production of inflammatory mediators including cytokines. Fibroblasts are now recognized as a rich source of cytokines and we have examined the effect of various naphthoquinones on the production of interleukin 6 (IL-6) by lipopolysaccharide-stimulated human gingival fibroblasts. Compounds examined in this study include: phylloquinone (K1), menaquinone-4 (K2), menadione (K3), 2,3-dimethoxy-1,4-naphthoquinone (DMK) and a synthetic product of vitamin K catabolism, 2-methyl, 3-(2'methyl)-hexanoic acid-1,4-naphthoquinone (KCAT). All of these compounds are capable of inhibiting IL-6 production with a rank order of potency: KCAT > K3 > DMK > K2 > K1. The most potent compound, KCAT, inhibited IL-6 production with an IC50 of 3 x 10(-7)M. The mechanism of action of these naphthoquinones on fibroblast IL-6 production is unknown. Given that K3 and KCAT are inactive in the gamma-carboxylation reaction, we suggest that this activity is not essential for the inhibition of IL-6 production and that activity may be related to the redox capacity of these naphthoquinones

Vitamin A inhibits radiation-induced pneumonitis in rats.

Redlich CA, Rockwell S, Chung JS, et al.

J Nutr. 1998 Oct; 128(10):1661-4.

Radiation-induced lung injury frequently limits the total dose of thoracic radiotherapy that can be delivered, and the determinants of host susceptibility are poorly understood. To test the hypothesis that vitamin A status may be an important, modifiable host determinant of radiation-induced lung injury, we determined the effect of altered vitamin A status on radiation-induced lung inflammation in rats. WAG-Rij Y rats were fed a diet deficient in or supplemented with vitamin A (0 units/kg or 80,000 units/kg diet). After 5 wk of consuming the prescribed diet, rats were irradiated with 15 Gy of 250 kV X-rays to the whole thorax. At 4-5 wk post-irradiation, there were significantly fewer neutrophils on bronchoalveolar lavage in rats fed the vitamin A-supplemented diet (8.8 +/- 1.2% neutrophils) compared with those fed the vitamin A-deficient diet (20.8 +/- 3.4% neutrophils, P < 0.01). At the termination of the experiment, 4-5 wk postradiation, lung retinol levels of the vitamin A-supplemented group were 19.6 +/- 1.8 nmol/g, whereas those in the vitamin A-deficient group were significantly lower, 1.7 +/- 0.5 nmol/g (P < 0.01). These findings suggest that supplemental vitamin A may reduce lung inflammation after thoracic radiation and be an important modifiable radioprotective agent in the lung

Melatonin in plants.

Reiter RJ, Tan DX, Burkhardt S, et al.

Nutr Rev. 2001 Sep; 59(9):286-90.

Once thought to be exclusively a molecule of the animal kingdom, melatonin has now been found to exist in plants as well. Among a number of actions, melatonin is a direct free radical scavenger and an indirect antioxidant. Melatonin directly detoxifies the hydroxyl radical (OH), hydrogen peroxide, nitric oxide, peroxynitrite anion, peroxynitrous acid, and hypochlorous acid. The products from each of these reactions have been identified in pure chemical systems and in at least one case in vivo; the interaction product of melatonin with the OH, ie., cyclic 3-hydroxymelatonin, is found in the urine of humans and rats. Some of the products that are produced when melatonin detoxifies reactive species are also highly efficient scavengers. As a result, a cascade of scavenging reactions may enhance the antioxidant capacity of melatonin. Additionally, melatonin increases the activity of several antioxidative enzymes, thereby improving its ability to protect macromolecules from oxidative stress. Melatonin is endogenously produced and is also consumed in edible plants. In animal experiments, feeding melatonin-containing foods raised blood levels of the indole. Because physiologic concentrations of melatonin in the blood are known to correlate with the total antioxidant capacity of the serum, consuming food-stuffs containing melatonin may be helpful in lowering oxidative stress

Hypocholesterolemia in acute myelogenous leukemia.

Reverter JC, Sierra J, Marti-Tutusaus JM, et al.

Eur J Haematol. 1988 Oct; 41(4):317-20.

Plasma-cholesterol concentrations were determined in 85 acute myelogenous leukemia patients. Measurements were repeated in 28 cases during remission. Mean plasma-cholesterol concentration (+/- SD) at diagnosis was 3.95 mmol/l (+/- 1.29). 47 patients (55.3%) had hypocholesterolemia (less than 3.87 mmol/l). Among the main clinical, hematologic and biochemical parameters, only high leukocyte counts were correlated with hypocholesterolemia. As far the FAB subtypes are concerned, the lowest cholesterol levels were observed in leukemias with monocytic component. However, although the same FAB subtypes showed significantly higher leucocytes counts than the other subtypes, both parameters were independently related to low cholesterol levels. Remission was associated with a significant increase in cholesterol levels in those patients with low cholesterol concentrations or high leukocyte counts at diagnosis. These results support the idea that initial hypocholesterolemia in acute myelogenous leukemia is related to the tumoral mass present at diagnosis

Complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology.

Richardson MA, Sanders T, Palmer JL, et al.

J Clin Oncol. 2000 Jul; 18(13):2505-14.

PURPOSE: Oncologists are aware that their patients use complementary/alternative medicine (CAM). As cancer incidence rates and survival time increase, use of CAM will likely increase. This study assessed the prevalence and predictors of CAM use in a comprehensive cancer center. SUBJECTS AND METHODS: Subjects were English-speaking cancer patients at least 18 years of age, attending one of eight outpatient clinics at The University of Texas M.D. Anderson Cancer Center, Houston, TX, between December 1997 and June 1998. After giving written informed consent, participants completed a self-administered questionnaire. Differences between CAM users and nonusers were assessed by chi(2) and univariate logistic regression analysis. A multivariate logistic regression model identified the simultaneous impact of demographic, clinical, and treatment variables on CAM use; P values were two-sided. RESULTS: Of the 453 participants (response rate, 51.4%), 99.3% had heard of CAM. Of those, 83.3% had used at least one CAM approach. Use was greatest for spiritual practices (80.5%), vitamins and herbs (62.6%), and movement and physical therapies (59.2%) and predicted (P <.001) by sex (female), younger age, indigent pay status, and surgery. After excluding spiritual practices and psychotherapy, 95.8% of participants were aware of CAM and 68.7% of those had used CAM. Use was predicted (P <.0001) by sex (female), education, and chemotherapy. CONCLUSION: In most categories, CAM use was common among outpatients. Given the number of patients combining vitamins and herbs with conventional treatments, the oncology community must improve patient-provider communication, offer reliable information to patients, and initiate research to determine possible drug-herb-vitamin interactions

Stress hormone may contribute to breast cancer deaths. Stanford Online Report 2000 Jun 28.

Richter R.

2000;2000 Jun 28

Cox-2 inhibitory effects of naturally occurring and modified fatty acids.

Ringbom T, Huss U, Stenholm A, et al.

J Nat Prod. 2001 Jun; 64(6):745-9.

In the search for new cyclooxygenase-2 (COX-2) selective inhibitors, the inhibitory effects of naturally occurring fatty acids and some of their structural derivatives on COX-2-catalyzed prostaglandin biosynthesis were investigated. Among these fatty acids, linoleic acid (LA), alpha-linolenic acid (alpha-LNA), myristic acid, and palmitic acid were isolated from a CH(2)Cl(2) extract of the plant Plantago major by bioassay-guided fractionation. Inhibitory effects of other natural, structurally related fatty acids were also investigated: stearic acid, oleic acid, pentadecanoic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Further, the inhibitory effects of these compounds on COX-2- and COX-1-catalyzed prostaglandin biosynthesis was compared with the inhibition of some synthesized analogues of EPA and DHA with ether or thioether functions. The most potent COX-2-catalyzed prostaglandin biosynthesis inhibitor was all-(Z)-5-thia-8,11,14,17-eicosatetraenoic acid (2), followed by EPA, DHA, alpha-LNA, LA, (7E,11Z,14Z,17Z)-5-thiaeicosa-7,11,14,17-tetraenoic acid, all-(Z)-3-thia-6,9,12,15-octadecatetraenoic acid, and (5E,9Z,12Z,15Z,18Z)-3-oxaheneicosa-5,9,12,15,18-pentaenoic acid, with IC(50) values ranging from 3.9 to180 microM. The modified compound 2 and alpha-LNA were most selective toward COX-2, with COX-2/COX-1 ratios of 0.2 and 0.1, respectively. This study shows that several of the natural fatty acids as well as all of the semisynthetic thioether-containing fatty acids inhibited COX-2-catalyzed prostaglandin biosynthesis, where alpha-LNA and compound 2 showed selectivity toward COX-2

Intravenous ascorbic acid: protocol for its application and use.

Riordan HD, Hunninghake RB, Riordan NH, et al.

P R Health Sci J. 2003 Sep; 22(3):287-90.

High dose intravenous(i.v.) ascorbic acid (AA) has been used as therapy for infectious disease from bacterial and viral origin and adjuvant therapy for cancer. In this publication we describe a clinical protocol that has been developed over the past twenty years utilizing high dose i.v. AA as therapy for cancer. This includes principles of treatment, rationale, baseline workup, infusion protocol, precautions and side effects

Clinical and experimental experiences with intravenous vitamin C: potentiation of preferential toxicity of vitamin C. Proceedings from Vitamin C as Cancer Therapy Workshop, Montreal.

Riordan N.

J Orthomol Med. 2000; 15(4):201-13.

5' CpG island hypermethylation is associated with transcriptional silencing of the p21(CIP1/WAF1/SDI1) gene and confers poor prognosis in acute lymphoblastic leukemia.

Roman-Gomez J, Castillejo JA, Jimenez A, et al.

Blood. 2002 Apr 1; 99(7):2291-6.

The p21 is a downstream effector of p53/p73 and belongs to the CIP/KIP family of cyclin-dependent kinase inhibitors (CDKIs). It is, therefore, a potential tumor suppressor gene and probably plays an important role in tumor development. Moreover, reduced expression of p21 has been reported to have prognostic value in several human malignancies. In contrast with other CDKIs, mutational inactivation of p21 is infrequent, but gene inactivation by an alternative mechanism seems to be the general pathway. In this study, we analyzed the methylation status of the p21 promoter region using semiquantitative polymerase chain reaction in 124 patients with acute lymphoblastic leukemia (ALL). We observed p21 hypermethylation in bone marrow cells from 41% (51 of 124) of ALL patients. Hypermethylation within promoter strongly correlated with decreased p21 messenger RNA expression in tumoral cells. Clinical, molecular, and laboratory features and complete remission rate did not differ significantly between hypermethylated and normally methylated patients. Estimated disease-free survival (DFS) and overall survival at 7 and 9 years, respectively, were 59% and 65% for healthy patients and 6% and 8% for hypermethylated patients (P =.00001 and P =.006). Multivariate analysis of potential prognostic factors demonstrated that p21 methylation status was an independent prognostic factor in predicting DFS (P =.0001). Our results indicate that the p21 gene is subject to methylation regulation at the transcription level in ALL and seems to be an important factor in predicting the clinical outcome of these patients

The HER-2/neu Oncogene in Breast Cancer: Prognostic Factor, Predictive Factor, and Target for Therapy.

Ross JS, Fletcher JA.

Oncologist. 1998; 3(4):237-52.

The HER-2/neu oncogene encodes a transmembrane tyrosine kinase receptor with extensive homology to the epidermal growth factor receptor. HER-2/neu has been widely studied in breast cancer. In this review, the association of HER-2/neu gene and protein abnormalities studied by Southern and slot blotting, immunohistochemistry, enzyme immunoassays, and fluorescence in situ hybridization with prognosis in breast cancer is studied in depth by review of a series of 47 published studies encompassing more than 15,000 patients. The relative advantages of gene amplification assays and frozen/fresh tissue immunohistochemistry over paraffin section immunohistochemistry are discussed. The significance of HER-2/neu overexpression in ductal carcinoma in situ and the HER-2/neu status in uncommon female breast conditions and male breast cancer are also considered. The potential value of HER-2/neu status for the prediction of response to therapy in breast cancer is presented in the light of a series of recently published studies showing a range of impact on the outcome of patients treated with hormonal, cytotoxic, and radiation therapies. The evidence that HER-2/neu gene and protein abnormalities in breast cancer predict resistance to tamoxifen therapy and relative sensitivity to chemotherapy regimens including adriamycin is presented. The review will also evaluate the status of serum-based testing for circulating the HER-2/neu receptor protein and its ability to predict disease outcome and therapy response. In the final section, the review will briefly present preliminary data concerning the use of antibody-based therapies directed against the HER-2/neu protein and their potential to become a new modality for breast cancer treatment. The recently presented phase III clinical trial evidence that systemic administration of anti-HER2 antibodies (Herceptin®), alone and in combination with cytotoxic chemotherapy in patients with HER-2/neu overexpressing primary tumors, can increase the time to recurrence and overall response rates in metastatic breast cancer is reviewed

Cimetidine use and risk of prostate and breast cancer.

Rossing MA, Scholes D, Cushing-Haugen KL, et al.

Cancer Epidemiol Biomarkers Prev. 2000 Mar; 9(3):319-23.

Histamine (H2) receptor antagonists, such as cimetidine and ranitidine, became available in the late 1970s and presently number among the most commonly used drugs. Cimetidine has been hypothesized to exert a cancer preventive effect on the prostate due to its ability to inhibit the binding of dihydrotestosterone to androgen receptors. Other hormonal effects of this drug include increases in serum prolactin levels and inhibition of 2-hydroxylation of estradiol. We assessed risk of prostate and breast cancers in a cohort of 48,512 members of the Group Health Cooperative of Puget Sound prescribed cimetidine or another H2 blocker between 1977 and 1995. Standardized incidence ratios were calculated comparing the observed numbers of cancers to those expected based on population rates in western Washington State. Because cimetidine, but not other H2 blockers, influences hormonal activity and metabolism, we conducted nested case-control studies comparing cancer risk among individuals treated with cimetidine to individuals who used other H2 blockers. Risks of breast and prostate cancers were identical among users of cimetidine and users of other H2 blockers (relative risk, 1.0 for both cancers). We observed no trend in risk of breast cancer according to time since first or last cimetidine prescription or number of cimetidine prescriptions filled. For prostate cancer, our findings were similar save for a modest increase in risk among men who had filled > or =21 cimetidine prescriptions (relative risk, 1.4; 95% confidence interval, 1.0-1.9). Our results suggest that use of cimetidine does not influence risk of female breast cancer. Further, these data provide little evidence to support the previously hypothesized preventive effect of cimetidine on risk of prostate cancer

Anti-tumour and antioxidant activity of natural curcuminoids.

Ruby AJ, Kuttan G, Babu KD, et al.

Cancer Lett. 1995 Jul 20; 94(1):79-83.

Matural curcuminoids, curcumin, I, II and III isolated from turmeric (Curcuma longa) were compared for their cytotoxic, tumour reducing and antioxidant activities. Curcumin III was found to be more active than the other two as a cytotoxic agent and in the inhibition of Ehrlich ascites tumour in mice (ILS 74.1%). These compounds were also checked for their antioxidant activity which possibly indicates their potential use as anti-promoters. The amount of curcuminoids (I, II and III) needed for 50% inhibition of lipid peroxidation was 20, 14 and 11 g/m. Concentrations needed for 50% inhibition of superoxides were 6.25, 4.25 and 1.9 micrograms/ml and those for hydroxyl radical were 2.3, 1.8 and 1.8 micrograms/ml, respectively. The ability of these compounds to suppress the superoxide production by macrophages activated with phorbol-12-myristate-13-acetate (PMA) indicated that all the three curcuminoids inhibited superoxide production and curcumin III produced maximum effect. These results indicate that curcumin III is the most active of the curcuminoids present in turmeric. Synthetic curcumin I and III had similar activity to natural curcumins

Dose dependent protection by lipoic acid against cisplatin-induced ototoxicity in rats: antioxidant defense system.

Rybak LP, Husain K, Whitworth C, et al.

Toxicol Sci. 1999 Feb; 47(2):195-202.

This study investigated the alterations that occur in auditory brainstem-evoked responses (ABRs) concurrent with changes in cochlear concentrations of glutathione (GSH), lipid peroxidation, and antioxidant enzyme activity in cisplatin-induced ototoxicity and in dose-dependent otoprotection by an antioxidant lipoate. Male Wistar rats were divided into different groups and were treated as follows, with: (1) vehicle (saline) control; (2) cisplatin (16 mg/kg, i.p.); (3) lipoate (100 mg/kg, i.p.) plus saline; (4) cisplatin plus lipoate (25 mg/kg); (5) cisplatin plus lipoate (50 mg/kg), and (6) cisplatin plus lipoate (100 mg/kg). Post-treatment ABRs were evaluated after three days, the rats were sacrificed, and cochleae were harvested and analyzed. The cisplatin-injected rats showed ABR threshold elevations above the pre-treatment thresholds. Rats treated with lipoate plus cisplatin did not show significant elevation of hearing thresholds. Cisplatin administration resulted in a depletion of cochlear GSH concentration (69% of control), whereas, cisplatin-plus-lipoate treatment increased GSH concentration close to control value. Cisplatin-treated rats showed a decrease in cochlear superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activities (57, 78, 59, and 58% of control, respectively), and an increase in malondialdehyde (MDA) concentration (196% of control). Cochlear SOD, CAT, GSH-Px, and GR activities and MDA concentrations were restored in the rats injected with cisplatin plus graded doses of lipoate than those with cisplatin alone. It is concluded that cisplatin-induced ototoxicity is related to impairment of the cochlear antioxidant defense system, and the dose-dependent otoprotection conferred by an antioxidant lipoate against cisplatin ototoxicity is associated with sparing of the cochlear antioxidant defense system

The effects of theanine, as a novel biochemical modulator, on the antitumor activity of adriamycin.

Sadzuka Y, Sugiyama T, Miyagishima A, et al.

Cancer Lett. 1996 Aug 2; 105(2):203-9.

We studied the effects of theanine, a component of green tea leaves, on the antitumor activity of adriamycin (ADR) from the biochemical modulation view point. In vitro, theanine inhibited the ADR efflux from Ehrlich ascites carcinoma cells and maintained the ADR concentration in tumor cells. Theanine enhanced the inhibitory effect of ADR on tumor growth by 2.1-fold in vivo, and increased 2.9-fold the ADR concentration in the tumor, compared to the ADR alone group. An increase in ADR concentration was not observed in normal tissues, such as the heart and liver. Theanine did not enhance, rather tended to normalize the increase of lipid peroxide level and reduction of glutathione peroxidase activity as indicators of the ADR-induced side toxicity

Improvement of idarubicin induced antitumor activity and bone marrow suppression by theanine, a component of tea.

Sadzuka Y, Sugiyama T, Sonobe T.

Cancer Lett. 2000 Oct 1; 158(2):119-24.

We have examined the effect of theanine, a specific amino acid in green tea, on idarubicin (IDA)-induced antitumor activity and toxicity. In combination with theanine, IDA (0.25 mg/kg per day x4 days, a dose that does not show antitumor activity) had significant antitumor activity in P388-bearing mice. The IDA concentration in the tumors in the theanine plus IDA group increased to twice the level in the IDA alone group. Furthermore, the decrease in tumor weight caused by IDA at 1.0 mg/kg per day x4 days (at this dose IDA exhibits antitumor activity) was significantly amplified by theanine. The numbers of leukocyte and bone marrow cells decreased significantly on IDA injection. Theanine significantly reversed these changes. These results suggest that theanine selectively moderates the IDA-induced toxicities. Until recently, the antitumor activity and related toxicities of this chemotherapeutic agent in leukemia could not be distinguished. Theanine increases the IDA-induced antitumor activity and ameliorates the toxicities

Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance.

Sadzuka Y, Sugiyama T, Sonobe T.

Toxicol Lett. 2000 Apr 3; 114(1-3):155-62.

Considering of novel biochemical modulation by some foods and beverages, we have performed screening for green tea components that have enhancing effects on doxorubicin (DOX) induced antitumor activity. Components, such as caffeine, theanine, (-)-epigallocatechin gallate (EGCG) and flavonoids have inhibitory effects on the DOX efflux from Ehrlich ascites carcinoma cells. Thus, it is suggested that EGCG and flavonoids may enhance DOX induced antitumor activity and increase the DOX concentrations in tumors through the inhibition of DOX efflux. It is expected that these components in green tea exhibit low toxicity and that there are few side effects of drinking green tea in combination with an antitumor agent. We think that the intake of a favorite beverage favors a positive mental attitude of a patient and increases the efficacy of the chemotherapeutic index, and that this efficacy is useful for improving the quality of life on cancer chemotherapy. In DOX resistant P388 leukemia cell bearing mice theanine increased the DOX induced efficacy through an increase in the DOX concentrations in the tumors. Theanine attacked the same transport process for DOX in both types of cells, elevated the DOX concentration and increased the DOX induced antitumor activity

Enhancement of the activity of doxorubicin by inhibition of glutamate transporter.

Sadzuka Y, Sugiyama T, Suzuki T, et al.

Toxicol Lett. 2001 Sep 15; 123(2-3):159-67.

Theanine enhanced doxorubicin (DOX) induced antitumor activity by increasing the concentration of DOX in the tumor through the inhibition of efflux of DOX from tumor cells. As theanine reduced the level of glutamate via suppression of the glutamate transporter in tumor cells, we studied the change in the intracellular concentration of glutathione (GSH) and the correlation with the GSH S-conjugate export (GS-X) pump. The reduction in the concentration of glutamate in tumor cells caused by theanine, induced decreases in the intracellular GSH and GS-DOX levels. The expression of MRP5 in M5076 cells, was confirmed. We concluded that the GS-DOX conjugate was transported extracellularly via the MRP5/GS-X pump in M5076 cells and that theanine affected this route. Namely, theanine increases the concentration of DOX in a tumor in vivo through inhibition of the glutamate transporter via the GS-X pump

Up-regulation of the tumor suppressor gene p53 and WAF1 gene expression by IP6 in HT-29 human colon carcinoma cell line.

Saied IT, Shamsuddin AM.

Anticancer Res. 1998 May; 18(3A):1479-84.

Inositol hexaphosphate (InsP6 or IP6) ubiquitous in various cells has a novel anti-cancer action both in vivo and in vitro. IP6 inhibits cell growth, decreases cell proliferation and also causes differentiation of various cell lines, including HT-29 human colon carcinoma cell. We hypothesize that the tumor suppressor genes such as p53 and WAF1/CIP1 may be involved in mediating the anti-neoplastic action of IP6 p53 acts as a molecular policeman prevention of genetically damaged cells; it causes the cells to arrest in the G1 phase of cell cycle, and regulates the level of p21waf1/cip1 which acts as a growth inhibitor. We therefore investigated the effects of IP6 on the expression of p53 and WAF1/p21 in HT-29 human colon carcinoma by immunocytochemistry and quantitative ELISA. Our immunocytochemical studies with anti p53 antibodies (wild type-PAb246 and PAb1620) and anti p21waf1/cip1 (EA10) antibodies demonstrated an increased level of p53 and p21waf1/cip1 after 3 and 6 days of treatment with 3.3 and 5 mM IP6. Quantitative assay for p53 and p21waf1/cip1 by ELISA did not show detectable levels in untreated control cells, while strong expression of p53 and p21waf1/cip1 protein by 3.3 and 5 mM IP6 was seen on day 3 and day 6 of treatment. This increase was dose-dependent; however, a definite time-dependent increase was not observed. These data demonstrate that IP6 up-regulates the expression of the tumor suppressor gene p53 and p21WAF1/CIP1 gene and their modulation may be one of the mechanisms of the anti-neoplastic action of IP6. Since loss of p53 function enhances cancer cells' resistance to chemotherapeutic agents, the stimulating function of IP6 on p53 makes it an attractive adjuvant chemotherapeutic agent as well

Expression of estrogen receptor (ER) (beta)cx protein in ER(alpha)-positive breast cancer: specific correlation with progesterone receptor.

Saji S, Omoto Y, Shimizu C, et al.

Cancer Res. 2002 Sep 1; 62(17):4849-53.

Estrogen receptor (ER) (beta)cx, a splice variant of ERbeta, is a dominant repressor of ER(alpha) function. In this study we investigated the possibility that because the progesterone receptor (PR) gene is a downstream target of activated ER(alpha), in ER(alpha)-positive breast cancers, expression of ER(beta)cx would result in repression of PR. In ER(alpha)-positive MCF-7 cells, stable transfection of an ER(beta)cx expression vector resulted in reduced expression of PR without affecting ER(alpha) expression. In breast cancers, immunohistochemical evaluation of ER(alpha)-positive foci for the expression of PR and ER(beta)cx revealed a significant correlation between a PR-negative phenotype and the presence of ER(beta)cx within the foci. However, when entire lesions were evaluated by Allred scoring in 115 ER(alpha)-positive breast cancer specimens, the presence of two distinct groups of patients could be discerned. One group expressed ER(beta)cx and had very reduced levels of PR expression, as expected. The second group showed both ER(beta)cx and high levels of PR. To evaluate the role of ER(beta)cx in sensitivity to tamoxifen, 18 core needle biopsies, obtained before preoperative treatment with tamoxifen, were investigated. The results show that expression of ER(beta)cx in primary lesions correlated with a poor response to tamoxifen, especially in cancers with a low PR expression in Allred score. This is the first evidence that evaluation of ER(beta)cx along with PR may contribute to a better characterization of ER(alpha)-positive breast cancers

Growth inhibition and differentiation of HT-29 cells in vitro by inositol hexaphosphate (phytic acid).

Sakamoto K, Venkatraman G, Shamsuddin AM.

Carcinogenesis. 1993 Sep; 14(9):1815-9.

Inositol hexaphosphate (InsP6 or phytic acid) has been shown to have antineoplastic action in in vivo models of colon carcinogenesis. We therefore investigated its effect on proliferation and differentiation of the human colon cancer cell line HT-29 in vitro. Proliferation was evaluated by neutral red incorporation assay, and differentiation was assessed by expression of the markers, cytokeratin, carcinoembryonic antigen (CEA) and beta-D-galactose-[1-->3]-N-acetyl-galactosamine (Gal-GalNAc). InsP6 in the culture media (0.66-10 mM) inhibited cell proliferation in a dose-dependent manner (P < 0.001), while inositol or inositol hexasulfate used as controls or media without InsP6 did not show any suppressive effect. The expression of the tumor marker, Gal-GalNac, was augmented (100.7% increase) by low dose (0.66 mM) of InsP6 but was subsequently suppressed with higher concentrations of InsP6. The expression of cytokeratin and CEA were both augmented by either InsP6 or inositol at all concentrations tested, although the degree of augmentation was milder with inositol than with InsP6. The combination of InsP6 and inositol (both 0.66 mm) resulted in augmentation (P < 0.001) of cytokeratin expression, while that of CEA remained unchanged. The inhibitory effect of InsP6 on cell proliferation was not altered by combination with additional inositol at any concentrations tested. Our results show that InsP6 inhibits cell proliferation and concomitantly increases differentiation and is therefore a candidate chemopreventive and chemotherapeutic agent for human large intestinal cancer

Synergistic effects of thearubigin and genistein on human prostate tumor cell (PC-3) growth via cell cycle arrest.

Sakamoto K.

Cancer Lett. 2000 Apr 3; 151(1):103-9.

There is evidence that habitual consumption of green tea by Japanese men is correlated with a reduction in cancers, including prostate; soybean isoflavones are also associated with increased protection. The present study compared the anti-proliferative effect of black tea (Camellia sinensis) polyphenol, thearubigin (TR), alone or combined with the isoflavone genistein, on human prostate (PC-3) carcinoma cells. TR administered alone did not result in any alteration of cell growth. When combined with genistein, however, TR significantly inhibited cell growth and induced a G2/M phase cell cycle arrest in a dose dependent manner. These findings indicate the potential use of combined phytochemicals to provide protection against prostate cancer

Selective inhibition of NF-kappaB activation by the flavonoid hepatoprotector silymarin in HepG2. Evidence for different activating pathways.

Saliou C, Rihn B, Cillard J, et al.

FEBS Lett. 1998 Nov 27; 440(1-2):8-12.

The bioflavonoid silymarin is found to potently suppress both nuclear factor kappa-B (NF-kappaB)-DNA binding activity and its dependent gene expression induced by okadaic acid in the hepatoma cell line HepG2. Surprisingly, tumor necrosis factor-alpha-induced NF-kappaB activation was not affected by silymarin, thus demonstrating a pathway-dependent inhibition by silymarin. Many genes encoding the proteins of the hepatic acute phase response are under the control of the transcription factor NF-kappaB, a key regulator in the inflammatory and immune reactions. Thus, the inhibitory effect of silymarin on NF-kappaB activation could be involved in its hepatoprotective property

Cyr61, a member of the CCN family, is required for MCF-7 cell proliferation: regulation by 17beta-estradiol and overexpression in human breast cancer.

Sampath D, Winneker RC, Zhang Z.

Endocrinology. 2001 Jun; 142(6):2540-8.

Cyr61, a member of the CCN (CTGF/Cyr61/NOV) family of growth regulators, is a secreted cysteine-rich proangiogenic factor that has been implicated in tumorigenesis. Previous studies have also demonstrated that Cyr61 is regulated by 17beta-estradiol (E(2)) in the uterus. Therefore, we hypothesized that hormonal regulation of Cyr61 may be important in estrogen-dependent pathogenic processes such as breast tumorigenesis. Our study demonstrates that both Cyr61 messenger RNA and protein are induced by E(2) in MCF-7 mammary adenocarcinoma cells that primarily overexpress estrogen receptor alpha (ERalpha) in a dose-dependent and immediate early fashion. Cyr61 gene induction by E(2) is transcriptionally regulated by ERalpha as the antiestrogen, ICI 182,780, and actinomycin D blocked induction completely. In addition, Cyr61 is up-regulated in MCF-7 cells by epidermal growth factor (EGF) in an immediate early fashion as well. The functional relevance of steroid induction of Cyr61 in breast cancer cell growth is demonstrated by anti-Cyr61 neutralizing antibodies, which diminished E(2) and EGF-dependent DNA synthesis and dramatically reduced E(2)-driven cell proliferation by more than 70%. Most importantly, Cyr61 is overexpressed in 70% (28 of 40) of breast cancer patients with infiltrating ductal carcinoma and is localized exclusively to hyperplastic ductal epithelial cells. Moreover, the levels of Cyr61 protein are higher in breast tumors that are ER(+)/EGF receptor(+) than those that are ER(-)/EGF receptor(+), suggesting that estrogens may mediate Cyr61 expression in vivo. Collectively, our data suggest that Cyr61 may play a critical role in estrogen- as well as growth factor-dependent breast tumor growth

Genistein inhibits growth of estrogen-independent human breast cancer cells in culture but not in athymic mice.

Santell RC, Kieu N, Helferich WG.

J Nutr. 2000 Jul; 130(7):1665-9.

The studies presented were conducted to assess the effect of the soy isoflavone genistein on proliferation of estrogen-independent human breast cancer cells (MDA-MB-231) in vitro and in vivo. Genistein (20 mcmol/L) inhibited cell proliferation in vitro by approximately 50%. Cell cycle progression was blocked in G(2)/M with 40 and 80 mcmol/L genistein. To evaluate the effect of dietary genistein on tumor growth in vivo, genistein was fed to female athymic mice inoculated with MDA-MB-231 cells. After solid tumor masses had formed, mice were fed genistein at a dose (750 mcg/g AIN-93G diet), shown to produce a total plasma genistein concentration of approximately 1 mcmol/L. This dose of genistein did not significantly (P > 0.05) alter tumor growth. Studies were then conducted to assess the effect of dietary genistein on initial tumor development and growth. Genistein (750 mcg/g AIN-93G diet), fed 3 d before cells were inoculated into mice, did not significantly (P > 0.05) inhibit tumor formation or growth. The plasma concentration of genistein in mice fed this dose of dietary genistein (750 mcg/g AIN-93G diet) does not appear sufficient to inhibit tumor formation or growth. Dietary genistein at 750 mcg/g AIN-93G diet does not inhibit tumor formation or growth. Additional studies were conducted to determine the effect of dietary dosages ranging from 0 to 6000 mcg/g AIN-93G diet on plasma genistein concentration. Plasma genistein concentration increased in a dose-dependent manner up to 7 mcmol/L at 6000 mcg/g AIN-93G diet. These data suggest that although genistein inhibits cancer cell growth in vitro, it is unlikely that the plasma concentration required to inhibit cancer cell growth in vivo can be achieved from a dietary dosage of genistein

Vitamin D is for cancer defense.

Sardi B.

Nutrition Science News 2000 Mar. 2000;2000 Mar

Antiproliferative effect of silybin on gynaecological malignancies: synergism with cisplatin and doxorubicin.

Scambia G, De Vincenzo R, Ranelletti FO, et al.

Eur J Cancer. 1996 May; 32A(5):877-82.

The aim of this study was to test the antiproliferative activity of silybin, a flavonoid, on human ovarian and breast cancer cell lines. Since flavonoids are thought to act through Type II oestrogen binding sites (Type II EBS), silybin binding to Type II EBS was also examined. Silybin, used in concentrations from 0.1 to 20 microM, exerted a dose-dependent growth inhibitory effect on OVCA 433, A2780 parental and drug-resistant ovarian cancer cells, and MCF-7 doxorubicin (DOX)-resistant breast cancer cells (IC50 = 4.8-24 microM). Both L and D diastereoisomers of silybin were effective in inhibiting A2780 WT cell growth (IC50 = 14 and 20 microM, respectively). Flow cytometry revealed that silybin decreased the percentage of cells in the S and G2-M phases of the cell cycle with a concomitant increase in cells in the G0-G1 phase. Silybin was able to compete with [3H]E2 for nuclear but not cytosolic Type II EBS. Its affinity parallels its efficacy in inhibiting cell proliferation. Furthermore, silybin (0.1 and 1 microM) potentiates the effect of cisplatin (CDDP) (0.1-1 micrograms/ml) in inhibiting A2780 WT and CDDP-resistant cell growth. Similar results were obtained on MCF-7 DOX-resistant cells when silybin (0.1 microM) was associated with doxorubicin (0.1-10 micrograms/ml). As assessed by the Berembaum isobole method, the effect of silybin-CDDP and silybin-DOX combinations results in a synergistic action. Using the 'stem cell assay' described by Hamburger and Salmon [Science 1977, 197, 461-463], we found that silybin exerted a dose-dependent inhibition of clonogenic efficiency of cells derived from three ovarian tumours (IC50 = 7.4, 4 and 6.4 microM, respectively). Since CDDP and DOX are the two most commonly used drugs for gynaecological tumours, the clinical application of silybin is currently under investigation in our institute

Lymphocyte proliferation is associated with gender, caregiving, and psychosocial variables in older adults.

Scanlan JM, Vitaliano PP, Zhang J, et al.

J Behav Med. 2001 Dec; 24(6):537-59.

We examined lymphocyte responses to mitogens [phytohemagglutinin (PHA), concanavalin A, pokeweed] in spouse caregivers of persons with Alzheimer's disease (n = 82; mean age = 69.4) and noncaregiver spouses (n = 83) group matched on age and gender. Data were collected at study entry (T1) and 15-18 months later (T2). In men (n = 52), a depressed mood factor was negatively related to all mitogen responses at T1 and PHA at T2. Loneliness was the most important variable in the depressed mood factor. No relationships occurred in women (n = 113). At T2 an anger expression factor (anger-out--anger-control) was negatively related to all mitogen responses in caregivers. Anger-out was the most important variable for anger expression. Depressed mood at T1 predicted residualized changes in PHA at T2 in men. In conclusion, men with higher depressed mood and caregivers with higher anger expression may be at risk for lower proliferation responses

Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Study.

Schatz I.

Lancet. 2001; 358(9279):351.

Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study.

Schatz IJ, Masaki K, Yano K, et al.

Lancet. 2001 Aug 4; 358(9279):351-5.

BACKGROUND: A generally held belief is that cholesterol concentrations should be kept low to lessen the risk of cardiovascular disease. However, studies of the relation between serum cholesterol and all-cause mortality in elderly people have shown contrasting results. To investigate these discrepancies, we did a longitudinal assessment of changes in both lipid and serum cholesterol concentrations over 20 years, and compared them with mortality. METHODS: Lipid and serum cholesterol concentrations were measured in 3572 Japanese/American men (aged 71-93 years) as part of the Honolulu Heart Program. We compared changes in these concentrations over 20 years with all-cause mortality using three different Cox proportional hazards models. FINDINGS: Mean cholesterol fell significantly with increasing age. Age-adjusted mortality rates were 68.3, 48.9, 41.1, and 43.3 for the first to fourth quartiles of cholesterol concentrations, respectively. Relative risks for mortality were 0.72 (95% CI 0.60-0.87), 0.60 (0.49-0.74), and 0.65 (0.53-0.80), in the second, third, and fourth quartiles, respectively, with quartile 1 as reference. A Cox proportional hazard model assessed changes in cholesterol concentrations between examinations three and four. Only the group with low cholesterol concentration at both examinations had a significant association with mortality (risk ratio 1.64, 95% CI 1.13-2.36). INTERPRETATION: We have been unable to explain our results. These data cast doubt on the scientific justification for lowering cholesterol to very low concentrations (<4.65 mmol/L) in elderly people

The inhibitory effect of genistein on the growth and metastasis of a transplantable rat accessory sex gland carcinoma.

Schleicher RL, Lamartiniere CA, Zheng M, et al.

Cancer Lett. 1999 Mar 1; 136(2):195-201.

BACKGROUND: A cell line (K1) derived from a carcinogen-induced accessory sex gland carcinoma was used to examine the effects of the soybean extract, genistein, on tumor growth and metastasis. METHODS: Male Lobund-Wistar rats were injected s.c. with 20 million K1 cells; genistein (50 mg/kg BW) or the vehicle was administered s.c. every 12 h for 31 days. RESULTS: Genistein significantly inhibited tumor growth. Compared with controls, fewer genistein-treated rats developed invasive tumors (11% vs. 44%) or lymph node metastases (44% vs. 89%). No lung metastases were found in genistein-treated animals in contrast to controls (0% vs. 44%). Estrogenic side effects were precipitated in genistein-treated rats, including decreased accessory sex gland complex weight, increased pituitary weight, decreased testis weight, and decreased (BW). Serum testosterone was undetectable and serum prostate-specific acid phosphatase activity was 38% lower in genistein-treated rats compared with controls. Genistein concentrations in the solid tumors (2 nmol/g) were one-third those in blood. CONCLUSIONS: These data suggest that genistein may be a useful chemotherapeutic agent to inhibit the growth and metastasis of accessory sex gland cancers, such as those derived from the prostate

Breast Cancer 1993 Jul 3.

Science News.

Science News. 1993;1993 Jul 3

How EMFs may cause cancer.

Science News.

Spectrum Magazine. 1998;1998 Feb 21

Effects of oxidative stress on phospholipid signaling in rat cultured astrocytes and brain slices.

Servitja JM, Masgrau R, Pardo R, et al.

J Neurochem. 2000 Aug; 75(2):788-94.

Although reactive oxygen species (ROS) are conventionally viewed as toxic by-products of cellular metabolism, a growing body of evidence suggests that they may act as signaling molecules. We have studied the effects of hydrogen peroxide (H(2)O(2))-induced oxidative stress on phospholipid signaling in cultured rat cortical astrocytes. H(2)O(2) stimulated the formation of phosphatidic acid and the accumulation of phosphatidylbutanol, a product of the phospholipase D (PLD)-catalyzed transphosphatidylation reaction. The effect of exogenous H(2)O(2) on the PLD response was mimicked by menadione-induced production of endogenous H(2)O(2). Oxidative stress also elicited inositol phosphate accumulation resulting from phosphoinositide phospholipase C (PLC) activation. The PLD response to H(2)O(2) was totally suppressed by chelation of both extracellular and cytosolic Ca(2+) with EGTA and BAPTA/AM, respectively. Furthermore, H(2)O(2)-induced PLD stimulation was completely abolished by the protein kinase C (PKC) inhibitors bisindolylmaleimide and chelerythrine and by PKC down-regulation. Activation of PLD by H(2)O(2) was also inhibited by the protein-tyrosine kinase inhibitor genistein. Finally, H(2)O(2) also stimulated both PLC and PLD in rat brain cortical slices. These results show for the first time that oxidative stress elicits phospholipid breakdown by both PLC and PLD in rat cultured astrocytes and brain slices

Dietary isoflavones: biological effects and relevance to human health.

Setchell KD, Cassidy A.

J Nutr. 1999 Mar; 129(3):758S-67S.

Substantial evidence indicates that diets high in plant-based foods may explain the epidemiologic variance of many hormone-dependent diseases that are a major cause of mortality and morbidity in Western populations. There is now an increased awareness that plants contain many phytoprotectants. Lignans and isoflavones represent two of the main classes of phytoestrogens of current interest in clinical nutrition. Although ubiquitous in their occurrence in the plant kingdom, these bioactive nonnutrients are found in particularly high concentrations in flaxseeds and soybeans and have been found to have a wide range of hormonal and nonhormonal activities that serve to provide plausible mechanisms for the potential health benefits of diets rich in phytoestrogens. Data from animal and in vitro studies provide convincing evidence for the potential of phytoestrogens in influencing hormone-dependent states; although the clinical application of diets rich in these estrogen mimics is in its infancy, data from preliminary studies suggest beneficial effects of importance to health. This review focuses on the more recent studies pertinent to this field and includes, where appropriate, the landmark and historical literature that has led to the exponential increase in interest in phytoestrogens from a clinical nutrition perspective

Protective effect of green tea on the risks of chronic gastritis and stomach cancer.

Setiawan VW, Zhang ZF, Yu GP, et al.

Int J Cancer. 2001 May 15; 92(4):600-4.

Despite the declining trend, stomach cancer remains the second most common cancer worldwide. We examined the role of green tea consumption on chronic gastritis and stomach cancer risks. A population-based case-control study was conducted in Yangzhong, China, with 133 stomach cancer cases, 166 chronic gastritis cases, and 433 healthy controls. Epidemiologic data were collected by standard questionnaire and odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models in SAS. Inverse association was observed between green tea drinking and chronic gastritis and stomach cancer risks. After adjusting for age, gender, education, body mass index, pack-years of smoking and alcohol drinking, ORs of green tea drinking were 0.52 (95% CI: 0.29-0.94) and 0.49 (95% CI: 0.31-0.77) for stomach cancer and chronic gastritis, respectively. In addition, dose-response relationships were observed with years of green tea drinking in both diseases. The results provide further support on the protective effect of green tea against stomach cancer. This is the first time that green tea drinking was found to be protective against chronic gastritis, which may be of importance when designing intervention strategies for stomach cancer and its pre-malignant lesions in the high-risk population

Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor- and arachidonic acid-mediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling.

Shah BH, Nawaz Z, Pertani SA, et al.

Biochem Pharmacol. 1999 Oct 1; 58(7):1167-72.

Curcumin, a dietary spice from turmeric, is known to be anti-inflammatory, anticarcinogenic, and antithrombotic. Here, we studied the mechanism of the antiplatelet action of curcumin. We show that curcumin inhibited platelet aggregation mediated by the platelet agonists epinephrine (200 microM), ADP (4 microM), platelet-activating factor (PAF; 800 nM), collagen (20 microg/mL), and arachidonic acid (AA: 0.75 mM). Curcumin preferentially inhibited PAF- and AA-induced aggregation (IC50; 25-20 microM), whereas much higher concentrations of curcumin were required to inhibit aggregation induced by other platelet agonists. Pretreatment of platelets with curcumin resulted in inhibition of platelet aggregation induced by calcium ionophore A-23187 (IC50; 100 microM), but curcumin up to 250 microM had no inhibitory effect on aggregation induced by the protein kinase C (PKC) activator phorbol myrsitate acetate (1 microM). Curcumin (100 microM) inhibited the A-23187-induced mobilization of intracellular Ca2+ as determined by using fura-2 acetoxymethyl ester. Curcumin also inhibited the formation of thromboxane A2 (TXA2) by platelets (IC50; 70 microM). These results suggest that the curcumin-mediated preferential inhibition of PAF- and AA-induced platelet aggregation involves inhibitory effects on TXA2 synthesis and Ca2+ signaling, but without the involvement of PKC

Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor- and arachidonic acid-mediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling.

Shah BH, Nawaz Z, Pertani SA, et al.

Biochem Pharmacol. 1999 Oct 1; 58(7):1167-72.

Curcumin, a dietary spice from turmeric, is known to be anti-inflammatory, anticarcinogenic, and antithrombotic. Here, we studied the mechanism of the antiplatelet action of curcumin. We show that curcumin inhibited platelet aggregation mediated by the platelet agonists epinephrine (200 microM), ADP (4 microM), platelet-activating factor (PAF; 800 nM), collagen (20 microg/mL), and arachidonic acid (AA: 0.75 mM). Curcumin preferentially inhibited PAF- and AA-induced aggregation (IC50; 25-20 microM), whereas much higher concentrations of curcumin were required to inhibit aggregation induced by other platelet agonists. Pretreatment of platelets with curcumin resulted in inhibition of platelet aggregation induced by calcium ionophore A-23187 (IC50; 100 microM), but curcumin up to 250 microM had no inhibitory effect on aggregation induced by the protein kinase C (PKC) activator phorbol myrsitate acetate (1 microM). Curcumin (100 microM) inhibited the A-23187-induced mobilization of intracellular Ca2+ as determined by using fura-2 acetoxymethyl ester. Curcumin also inhibited the formation of thromboxane A2 (TXA2) by platelets (IC50; 70 microM). These results suggest that the curcumin-mediated preferential inhibition of PAF- and AA-induced platelet aggregation involves inhibitory effects on TXA2 synthesis and Ca2+ signaling, but without the involvement of PKC

Inositol and inositol hexaphosphate suppress cell proliferation and tumor formation in CD-1 mice.

Shamsuddin AM, Ullah A, Chakravarthy AK.

Carcinogenesis. 1989 Aug; 10(8):1461-3.

In previous studies, we have shown that inositol hexaphosphate (InsP6), a constituent of cereal diet, inhibited azoxymethane-induced experimental large intestinal cancer (LIC) in Fischer 344 rats. We now report a similar antineoplastic action of InsP6 in CD-1 mice injected with 1,2-dimethylhydrazine (DMH). We had hypothesized that InsP6 may bring about this effect by undergoing dephosphorylation to lower phosphorylated forms; the ready availability of Ins, to react with phosphates, may increase the total amount of the lower phosphorylated Ins and potentiate the action of InsP6. LIC induced by DMH (15 mg/kg/week x 13) in mice given a mixture of 1% InsP6 + 1% Ins show a significant reduction (P less than 0.005) in LIC prevalence over InsP6 treatment. Surprisingly, Ins, an in vitro growth promoting agent also caused a significant (P less than 0.001) suppression of LIC. InsP6 +/- Ins also showed a concomitant reduction in the mitotic rate in the non-neoplastic epithelium. Body weight data did not suggest any overt toxic effect of long-term administration of InsP6, Ins or InsP6 + Ins. Since InsP6 is antineoplastic in two species of experimental animals, it should, in combination with Ins, be considered in our strategies for prevention of large intestinal cancer

Inositol and inositol hexaphosphate suppress cell proliferation and tumor formation in CD-1 mice.

Shamsuddin AM, Ullah A, Chakravarthy AK.

Carcinogenesis. 1989 Aug; 10(8):1461-3.

In previous studies, we have shown that inositol hexaphosphate (InsP6), a constituent of cereal diet, inhibited azoxymethane-induced experimental large intestinal cancer (LIC) in Fischer 344 rats. We now report a similar antineoplastic action of InsP6 in CD-1 mice injected with 1,2-dimethylhydrazine (DMH). We had hypothesized that InsP6 may bring about this effect by undergoing dephosphorylation to lower phosphorylated forms; the ready availability of Ins, to react with phosphates, may increase the total amount of the lower phosphorylated Ins and potentiate the action of InsP6. LIC induced by DMH (15 mg/kg/week x 13) in mice given a mixture of 1% InsP6 + 1% Ins show a significant reduction (P less than 0.005) in LIC prevalence over InsP6 treatment. Surprisingly, Ins, an in vitro growth promoting agent also caused a significant (P less than 0.001) suppression of LIC. InsP6 +/- Ins also showed a concomitant reduction in the mitotic rate in the non-neoplastic epithelium. Body weight data did not suggest any overt toxic effect of long-term administration of InsP6, Ins or InsP6 + Ins. Since InsP6 is antineoplastic in two species of experimental animals, it should, in combination with Ins, be considered in our strategies for prevention of large intestinal cancer

Inositol hexaphosphate inhibits large intestinal cancer in F344 rats 5 months after induction by azoxymethane.

Shamsuddin AM, Ullah A.

Carcinogenesis. 1989 Mar; 10(3):625-6.

A treatment regimen of 2% Na-InsP6 in drinking water was effective in significantly reducing large intestinal cancer in F344 rats even when the treatment was begun 5 months after carcinogenic induction with azoxymethane (AOM 8 mg/kg/wk X 6). Compared to untreated (AOM-only) rats, animals on InsP6 had 27% fewer tumors (P less than 0.02). The tumors were approximately two-thirds smaller in size (P less than 0.01) and percentage mitotic rate in the non-neoplastic epithelium was less than half (1.0 +/- 0.1, compared to 2.3 +/- 0.2 of AOM-only animals, significant at P less than 0.001). We postulate that InsP6 may exert its antineoplastic effect by way of regulating cellular proliferation even after effective carcinogenic stimuli and thus may be an important candidate for chemointervention

Inositol hexaphosphate inhibits growth and induces differentiation of PC-3 human prostate cancer cells.

Shamsuddin AM, Yang GY.

Carcinogenesis. 1995 Aug; 16(8):1975-9.

We investigated the effects of inositol hexaphosphate (InsP6) on growth inhibition and differentiation of human prostate cancer cells PC-3 in vitro. A significant dose- and time-dependent growth inhibition was observed as tested by the MTT-incorporation assay (P < 0.05 at 1 mM InsP6 after 24 h treatment, P < 0.01 at 0.1 mM after 3 days). DNA synthesis as determined by [3H]thymidine incorporation assay was also suppressed by InsP6 in a dose-dependent manner, occurring as early as 3 h after treatment and continuing up to 48 h (P < 0.01 at 1 mM InsP6). A 9- to 10-fold increase (P < 0.01) in expression of HLA class I molecule associated with tumor immunosurveillance and cell differentiation was induced by InsP6. The marker for prostatic cell differentiation, prostate acid phosphatase, was significantly (P < 0.05) increased after 48 h treatment at 0.5-5 mM InsP6. Since InsP6 strongly inhibits growth and induces differentiation in human prostate cancer cells in vitro, in vivo studies using a tumor xenograft model and a prostate carcinogenesis model are warranted to validate the efficacy of InsP6 in the treatment and prevention of prostate cancer

IP6: a novel anti-cancer agent.

Shamsuddin AM, Vucenik I, Cole KE.

Life Sci. 1997; 61(4):343-54.

Inositol hexaphosphate (InsP6 or IP6) is ubiquitous. At 10 microM to 1 mM concentrations, IP6 and its lower phosphorylated forms (IP(1-5)) as well as inositol (Ins) are contained in most mammalian cells, wherein they are important in regulating vital cellular functions such as signal transduction, cell proliferation and differentiation. A striking anti-cancer action of IP6 has been demonstrated both in vivo and in vitro, which is based on the hypotheses that exogenously administered IP6 may be internalized, dephosphorylated to IP(1-5), and inhibit cell growth. There is additional evidence that Ins alone may further enhance the anti-cancer effect of IP6. Besides decreasing cellular proliferation, IP6 also causes differentiation of malignant cells often resulting in a reversion to normal phenotype. These data strongly point towards the involvement of signal transduction pathways, cell cycle regulatory genes, differentiation genes, oncogenes and perhaps, tumor suppressor genes in bringing about the observed anti-neoplastic action of IP6

Genistein exerts multiple suppressive effects on human breast carcinoma cells.

Shao ZM, Wu J, Shen ZZ, et al.

Cancer Res. 1998 Nov 1; 58(21):4851-7.

Dietary genistein, a natural flavone compound found in soy, has been proposed to be responsible for the low rate of breast cancer in Asian women. The cellular mechanisms of genistein's chemopreventive effects in vio have been largely unexplored. In our previous studies, we found that genistein exerted pronounced antiproliferative effects on both estrogen receptor-positive and -negative human breast carcinoma cells through G2-M arrest, induction of p21WAF1/CIP1 expression, and apoptosis. Because chemopreventive effects need not be limited to antiproliferation, we decided to examine whether genistein exerted other suppressive effects on breast carcinoma progression. Genistein inhibited invasion in vitro of MCF-7 and MDA-MB-231 cells. This inhibition was characterized by down-regulation of MMP (matrix metalloproteinase)-9 and up-regulation of tissue inhibitor of metalloproteinase-1, the former of which was transcriptionally regulated at activation protein-1 sites in the MMP-9 promoter. Genistein's in vitro effects on MMP-9 and tissue inhibitor of metalloproteinase-1 were also demonstrated in in vivo studies in nude mouse xenografts of MDA-MB-231 and MCF-7 cells. In these xenograft studies, genistein inhibited tumor growth, stimulated apoptosis, and upregulated p21WAF1/CIP1 expression. In the MDA-MB-231 xenograft, genistein also inhibited angiogenesis by decreasing vessel density and decreasing the levels of vascular endothelial growth factor and transforming growth factor-beta1. These in vitro and in vivo studies demonstrate that genistein exerts multiple suppressive effects on breast carcinoma cells, suggesting that its mechanism of chemoprevention is pleiotropic

Genistein's "ER-dependent and independent" actions are mediated through ER pathways in ER-positive breast carcinoma cell lines.

Shao ZM, Shen ZZ, Fontana JA, et al.

Anticancer Res. 2000 Jul; 20(4):2409-16.

Genistein, a natural flavone found in soy has been postulated to be responsible for lowering the rate of breast cancer in Asian women. Our previous studies have shown that genistein exerts multiple suppressive effects on both estrogen receptor positive (ER+) as well as estrogen receptor negative (ER-) human breast carcinoma lines suggesting that the mechanisms of these effects may be independent of ER pathways. In the present study however we provide evidence that in the ER+ MCF-7, T47D and 549 lines but not in the ER-MDA-MB-231 and MDA-MB-468 lines both presumed "ER-dependent" and "ER-independent" actions of genistein are mediated through ER pathways. Genistein's antiproliferative effects are estrogen dependent in these ER+ lines, being more pronounced in estrogen-containing media and in the presence of exogenous 17-beta estradiol. Genistein also inhibits the expression of ER-downstream genes including pS2 and TGF-beta in these ER+ lines and this inhibition is also dependent on the presence of estrogen. Genistein inhibits estrogen-induced protein tyrosine kinase (PTK) activity. Genistein is only a weak transcriptional activator and actually decreases ERE-CAT levels induced by 17-beta estradiol in the ER+ lines. Genistein also decreases steady state ER mRNA only in the presence of estrogen in the ER+ lines thereby manifesting another suppression of and through the ER pathway. Our observations resurrect the hypothesis that genistein functions as a "good estrogen" in ER+ breast carcinomas. Since chemopreventive effects of genistein would be targeted to normal ER-positive ductal-lobular cells of the breast, this "good estrogen" action of genistein is most relevant to our understanding of chemoprevention

Parthenolide, an inhibitor of the nuclear factor-kappaB pathway, ameliorates cardiovascular derangement and outcome in endotoxic shock in rodents.

Sheehan M, Wong HR, Hake PW, et al.

Mol Pharmacol. 2002 May; 61(5):953-63.

Parthenolide is a sesquiterpene lactone used in folk medicine for its anti-inflammatory activity. Recent in vitro studies have shown that this compound inhibits the nuclear factor (NF)-kappaB pathway. This study examines the effect of parthenolide in endotoxic shock in rodents. Endotoxic shock was induced by administration of Escherichia coli endotoxin in rats. Three groups of rats received parthenolide (0.25, 0.5, or 1 mg/kg) 15 min before endotoxin; another group received parthenolide (1 mg/kg) 3 h after endotoxin. In vehicle-treated rats, administration of endotoxin caused severe hypotension, which was associated with a marked hyporeactivity to norepinephrine in ex vivo thoracic aortas. Immunohistochemistry showed positive staining for nitrotyrosine, poly(ADP-ribose) synthetase (PARS) and apoptosis, whereas Northern blot analysis showed increased mRNA expression of inducible nitric-oxide synthase (iNOS) in thoracic aortas. Elevated levels of plasma nitrate/nitrite were also found. Elevated lung levels of myeloperoxidase activity were indicative of infiltration of neutrophils. These inflammatory events were preceded by cytosolic degradation of inhibitor kappaBalpha (IkappaBalpha) and activation of nuclear NF-kappaB in the lung. In vivo pretreatment and post-treatment with parthenolide improved the hemodynamic profile and reduced plasma nitrate/nitrite and lung neutrophil infiltration in a dose-dependent fashion. Vascular hyporeactivity of ex vivo aortas was ameliorated. Treatment with parthenolide also abolished nitrotyrosine formation, PARS expression, and apoptosis and reduced iNOS mRNA content in thoracic aortas. DNA binding of NF-kappaB was inhibited by parthenolide in the lung, whereas degradation of IkappaBalpha was unchanged. In a separate set of experiments, pretreatment or post-treatment with parthenolide significantly improved survival in mice challenged with endotoxin. We conclude that parthenolide exerts beneficial effects during endotoxic shock through inhibition of NF-kappaB

Low-dose genistein induces cyclin-dependent kinase inhibitors and G(1) cell-cycle arrest in human prostate cancer cells.

Shen JC, Klein RD, Wei Q, et al.

Mol Carcinog. 2000 Oct; 29(2):92-102.

Genistein, a naturally occurring isoflavone found chiefly in soy products, reportedly has antiprostate cancer effects, but the mechanisms underlying these effects are unknown. We studied the antiproliferative and apoptosis-inducing effects of genistein in the androgen-sensitive human prostate cancer cell line LNCaP. Viable cell number was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay; cell-cycle progression and apoptosis were evaluated by flow cytometry; apoptosis was also assessed by a histone enzyme-linked immunosorbent assay; and the expression of several cell-cycle- and apoptosis-related genes and their gene products was determined by northern blot analysis, western blot analysis, and/or assays based on polymerase chain reaction. Physiologic concentrations of genistein ( 20 microM) did induce apoptosis. We conclude that genistein (at physiologic concentrations) exerts potent antiproliferative effects on LNCaP cells by inducing a G(1) cell-cycle block. The antiproliferative effects of genistein may be mediated by increased levels of p27(KIP1) and p21(WAF1), which are negative cell-cycle regulators that act as cyclin-dependent kinase inhibitors and that have been recently linked with prostate carcinogenesis. These findings may provide insights into the mechanisms underlying the apparent antiprostate cancer effects of soy consumption observed in epidemiologic studies

Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers.

Shoba G, Joy D, Joseph T, et al.

Planta Med. 1998 May; 64(4):353-6.

The medicinal properties of curcumin obtained from Curcuma longa L. cannot be utilised because of poor bioavailability due to its rapid metabolism in the liver and intestinal wall. In this study, the effect of combining piperine, a known inhibitor of hepatic and intestinal glucuronidation, was evaluated on the bioavailability of curcumin in rats and healthy human volunteers. When curcumin was given alone, in the dose 2 g/kg to rats, moderate serum concentrations were achieved over a period of 4 h. Concomitant administration of piperine 20 mg/kg increased the serum concentration of curcumin for a short period of 1-2 h post drug. Time to maximum was significantly increased (P < 0.02) while elimination half life and clearance significantly decreased (P < 0.02), and the bioavailability was increased by 154%. On the other hand in humans after a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in bioavailability was 2000%. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects

Does cimetidine improve prospects for cancer patients?. A reappraisal of the evidence to date.

Siegers CP, Andresen S, Keogh JP.

Digestion. 1999 Sep; 60(5):415-21.

BACKGROUND: Evidence first appeared in 1988 that cimetidine as an adjuvant may improve the survival of severely ill gastro-intestinal cancer patients when given peri- or postoperatively. Since then, several studies have appeared which suggest an anticancer activity for cimetidine, although few attempts have been made to corroborate their findings in large, placebo-controlled, double-blind studies. METHOD: We reviewed the literature concerning cimetidine's potential anticancer activity, particularly with regard to gastro-intestinal cancers. RESULTS: Most studies suggest that cimetidine may improve the outcome in cancer patients by a three-pronged mechanism involving (1) inhibition of cancer cell proliferation; (2) stimulation of the lymphocyte activity by inhibition of T cell suppressor function, and (3) inhibition of histamine's activity as a growth factor in tumours. CONCLUSION: Bearing in mind the experimental evidence, as well as the potential and excellent safety profile of cimetidine, more studies are required and justified to clarify cimetidine's protherapeutic activity

Serum HDL cholesterol concentration in patients with squamous cell and small cell lung cancer.

Siemianowicz K, Gminski J, Stajszczyk M, et al.

Int J Mol Med. 2000 Sep; 6(3):307-11.

Cancer patients often present altered serum lipid profile including changes of HDL cholesterol level. The aim of our work was to evaluate serum level of HDL cholesterol in patients with squamous cell and small cell lung cancer and its dependence on histological type and clinical stage of lung cancer. Fasting serum level of HDL cholesterol was analysed in 135 patients with newly diagnosed lung cancer and compared to a control group of healthy men. All lung cancer patients, as well as subgroups of squamous cell and small cell lung cancer had statistically significantly lower HDL cholesterol concentration than controls. There were no statistically significant differences of HDL cholesterol level between the histological types or between clinical stages of each histological type of lung cancer

Potentiation of the antiproliferative effect in vitro of doxorubicin, cisplatin and genistein by new analogues of vitamin D.

Siwinska A, Opolski A, Chrobak A, et al.

Anticancer Res. 2001 May; 21(3B):1925-9.

Numerous vitamin D3 analogues have been synthesised in recent years in order to obtain compounds with a favourable biological and therapeutic (antipsoriatic and/or antitumour) activity. Our results showed that pre-treatment for 72 hours of HL-60 human promyelocytic leukaemia cells with calcitriol or its new analogues significantly potentiated their sensitivity to the antiproliferative effect in vitro of cisplatin, doxorubicin or genistein. Moreover, for all cytotoxic agents tested a synergistic antiproliferative effect was observed. This effect was expressed as a significant decrease of the ID50 (inhibitory dose 50%) values for each cytotoxic agent applied after pretreatment with calcitriol or its analogues of HL-60 cells in comparison with the effect of cytotoxic agent applied alone. The observed in vitro potentiated antiproliferative effect of cytotoxic drugs used in combination with vitamin D or its analogues may raise the question as to whether such an effect could be expected in the in vivo situation

Metabolism of N-acetyl-L-cysteine. Some structural requirements for the deacetylation and consequences for the oral bioavailability.

Sjodin K, Nilsson E, Hallberg A, et al.

Biochem Pharmacol. 1989 Nov 15; 38(22):3981-5.

Rat liver, lung and intestine homogenates deacetylated N-acetyl-L-cysteine. Nearly stoichiometric amounts of L-cysteine were recovered. In rat liver, the enzyme activity was associated with the cytosolic fraction. Liver cytosol was much less active. N-Acetyl-D-cysteine or the disulphide of N-acetyl-L-cysteine were not deacetylated or in other ways consumed in vitro. Isolated, perfused rat liver did not retain or metabolize N-acetyl-L-cysteine to any measurable extent during single-pass experiments. N-Acetyl-L-cysteine or N-acetyl-D-cysteine were injected into a ligated segment of rat intestine in situ. After 1 hr 2% of the L-isomer and 35% of the D-isomer remained in the intestinal lumen. Systemic plasma levels were less than 3 microM of the L-form and congruent to 40 microM of the D-form. We conclude that deacetylation in the intestinal mucosa and possibly in the intestinal lumen is the major factor determining the low oral bioavailability of N-acetyl-L-cysteine. The deacetylation is discussed on the basis of the subcellular localization and the structural requirement of the reaction

Carotenoids and colon cancer.

Slattery ML, Benson J, Curtin K, et al.

Am J Clin Nutr. 2000 Feb; 71(2):575-82.

BACKGROUND: Carotenoids have numerous biological properties that may underpin a role for them as chemopreventive agents. However, except for beta-carotene, little is known about how dietary carotenoids are associated with common cancers, including colon cancer. OBJECTIVE: The objective of this study was to evaluate associations between dietary alpha-carotene, beta-carotene, lycopene, lutein, zeaxanthin, and beta-cryptoxanthin and the risk of colon cancer. DESIGN: Data were collected from 1993 case subjects with first primary incident adenocarcinoma of the colon and from 2410 population-based control subjects. Dietary data were collected from a detailed diet-history questionnaire and nutrient values for dietary carotenoids were obtained from the US Department of Agriculture-Nutrition Coordinating Center carotenoid database (1998 updated version). RESULTS: Lutein was inversely associated with colon cancer in both men and women [odds ratio (OR) for upper quintile of intake relative to lowest quintile of intake: 0.83; 95% CI: 0.66, 1.04; P = 0.04 for linear trend]. The greatest inverse association was observed among subjects in whom colon cancer was diagnosed when they were young (OR: 0.66; 95% CI: 0.48, 0.92; P = 0.02 for linear trend) and among those with tumors located in the proximal segment of the colon (OR: 0.65; 95% CI: 0.51, 0.91; P < 0.01 for linear trend). The associations with other carotenoids were unremarkable. CONCLUSION: The major dietary sources of lutein in subjects with colon cancer and in control subjects were spinach, broccoli, lettuce, tomatoes, oranges and orange juice, carrots, celery, and greens. These data suggest that incorporating these foods into the diet may help reduce the risk of developing colon cancer

Induction of the differentiation of HL-60 promyelocytic leukemia cells by vitamin E and other antioxidants in combination with low levels of vitamin D3: possible relationship to NF-kappaB.

Sokoloski JA, Hodnick WF, Mayne ST, et al.

Leukemia. 1997 Sep; 11(9):1546-53.

Epidemiological studies have provided evidence that diets rich in antioxidant nutrients may reduce the risk of cancer. To evaluate the possibility that dietary phytochemicals with antioxidant potential would create an environment capable of affecting the differentiation of HL-60 leukemia cells, we measured the effects of vitamin E and other dietary antioxidants on the differentiation produced by low levels of vitamin D3 and analogs thereof. Vitamin E succinate and other antioxidant compounds (ie butylated hydroxyanisole, beta-carotene and lipoic acid) used alone had no significant effect on the differentiation of HL-60 cells; however, these agents markedly increased the differentiation produced by vitamin D3. Previous studies from this laboratory have shown that a sequence-specific antisense phosphorothioate oligonucleotide to the Rel A subunit of NF-kappaB enhanced the differentiation of HL-60 cells produced by several inducing agents. Consistent with these observations, vitamin E succinate caused a marked reduction in the nuclear content of NF-kappaB both in the presence and absence of vitamin D3. These findings suggest that NF-kappaB may be a factor in regulating the differentiation of myeloid leukemia cells. The results also indicate that combinations of vitamin D3 and analogs thereof with dietary antioxidants may be useful in overcoming the differentiation block present in acute promyelocytic leukemia cells

Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer.

Somasundaram S, Edmund NA, Moore DT, et al.

Cancer Res. 2002 Jul 1; 62(13):3868-75.

Curcumin, the major component of the spice turmeric, is used as a coloring and flavoring additive in many foods and has attracted interest because of its anti-inflammatory and chemopreventive activities. However, this agent also inhibits the generation of reactive oxygen species (ROS) and the c-Jun NH(2)-terminal kinase (JNK) pathway, and because many chemotherapeutic drugs generate ROS and activate JNK in the course of inducing apoptosis, we considered the possibility that curcumin might antagonize their antitumor efficacy. Studies in tissue culture revealed that curcumin inhibited camptothecin-, mechlorethamine-, and doxorubicin-induced apoptosis of MCF-7, MDA-MB-231, and BT-474 human breast cancer cells by up to 70%. Inhibition of programmed cell death was time and concentration dependent, but occurred after relatively brief 3-h exposures, or at curcumin concentrations of 1 microM that have been documented in Phase I chemoprevention trials. Under these conditions, curcumin exhibited antioxidant properties and inhibited both JNK activation and mitochondrial release of cytochrome c in a concentration-dependent manner. Using an in vivo model of human breast cancer, dietary supplementation with curcumin was found to significantly inhibit cyclophosphamide-induced tumor regression. Such dietary supplementation was accompanied by a decrease in the activation of apoptosis by cyclophosphamide, as well as decreased JNK activation. These findings support the hypothesis that dietary curcumin can inhibit chemotherapy-induced apoptosis through inhibition of ROS generation and blockade of JNK function, and suggest that additional studies are needed to determine whether breast cancer patients undergoing chemotherapy should avoid curcumin supplementation, and possibly even limit their exposure to curcumin-containing foods

The effect of soy isoflavones on the development of intestinal neoplasia in ApcMin mouse.

Sorensen IK, Kristiansen E, Mortensen A, et al.

Cancer Lett. 1998 Aug 14; 130(1-2):217-25.

Data from epidemiological studies suggest that isoflavones in soy may have a protective effect on the development of colon cancer in humans. Therefore, we have investigated whether soy isoflavones will inhibit intestinal tumour development in Apc(Min) mice. The mice were fed a Western-type high risk diet (high fat, low fibre and calcium) containing two different isolates of soy protein as a protein source. For the control and test groups this resulted in the administration of about 16 and 475 mg of total isoflavones per kg diet, respectively. As a positive control. a third group of mice was administered a low isoflavone diet supplemented with 300 ppm sulindac. No significant differences in the incidence, multiplicity, size and distribution of intestinal tumours were observed between Min mice fed low and high isoflavone-containing diets. However, a clear reduction in the number of small intestinal tumours was observed for the sulindac diet. Thus, in contrast to epidemiological studies, our results demonstrate that high amounts of soy isoflavones present in a Western-type high risk diet do not protect against intestinal tumour development in a relevant animal model such as the Min mice

Distinct expression patterns of ER alpha and ER beta in normal human mammary gland.

Speirs V, Skliris GP, Burdall SE, et al.

J Clin Pathol. 2002 May; 55(5):371-4.

AIM: Two oestrogen receptors (ERs) have been identified to date-the "classic" ER alpha and the more recently described ER beta. Although much is known about ER alpha at the mRNA and protein levels, our knowledge of the expression and distribution of ER beta protein is much more limited. The aim of this study was to compare the cellular distribution of ER alpha and ER beta in normal human mammary gland. METHODS: Formalin fixed, paraffin wax embedded material was obtained from reduction mammoplasty specimens, normal tissue adjacent to breast tumour, or fibroadenoma. Sections were immunohistochemically stained for ER alpha, ER beta, and the progesterone receptor. The staining pattern for each antibody was evaluated and compared. RESULTS: ER alpha was restricted to the cell nuclei of epithelial cells lining ducts and lobules. Although ER beta was also seen in these cells, additional strong staining was detected specifically in the cell nuclei of myoepithelial cells. Occasional staining was seen in surrounding stromal and endothelial cell nuclei and in lymphocytes. CONCLUSIONS: ER subtypes have distinct distribution patterns in the normal mammary gland. The widespread distribution of ER beta suggests that it may be the dominant ER in the mammary gland where it may be acting as a natural suppressor

Cytotoxic action of alpha-linolenic and eicosapentaenoic acids on myeloma cells in vitro.

Sravan K.G.

Prostaglandins Leukot Essential Fatty Acids 1997 Apr. 1997; 56(4):285-93.

Regulation of estrogen receptor-alpha gene expression by 1, 25-dihydroxyvitamin D in MCF-7 cells.

Stoica A, Saceda M, Fakhro A, et al.

J Cell Biochem. 1999 Dec 15; 75(4):640-51.

This report describes an investigation of the role of 1, 25-dihydroxyvitamin D (VD(3)) in the regulation of estrogen receptor-alpha (ER) in the ER-positive breast cancer cell line, MCF-7. Treatment of cells with 10 nM VD(3) resulted in a 50% decline in the concentration of ER protein at 24 h. Scatchard analysis showed a corresponding decrease in the number of estradiol binding sites and no alteration in the binding affinity of estradiol for the ER (K(d) = 0.08 nM in VD(3)-treated cells compared with K(d) = 0.07 nM in control cells). Vitamin D treatment also caused a 50% decrease in the steady state amount of ER mRNA, which was maximal by 18 h. In vitro transcription run-on experiments demonstrated a decrease of approximately 60% in transcription of the estrogen receptor gene. Transient transfections using an ER promoter-CAT construct also demonstrated a 40% decrease in CAT activity after VD(3) treatment. Sequence analysis identified a potential vitamin D response element (nVDRE) within the ER promoter. When this element was mutated, the ability of VD(3) to block transcription from the ER promoter was lost. When the nVDRE was placed upstream of a heterologous promoter, nVDRE-SV40-CAT, treatment with VD(3) resulted in a 50% decrease in CAT activity. Interestingly, co-transfection of either the ER promoter-CAT or the nVDRE-SV40-CAT construct and a vitamin D receptor expression vector into COS-1 or CV-1 cells showed an approximately 4-fold increase in CAT activity after VD(3) treatment. Taken together these data suggest that VD(3) inhibition of ER gene transcription is mediated through a nVDRE in the ER promoter. Inhibition appears to be cell specific

Dietary and other methyl-group availability factors and pancreatic cancer risk in a cohort of male smokers.

Stolzenberg-Solomon RZ, Pietinen P, Barrett MJ, et al.

Am J Epidemiol. 2001 Apr 1; 153(7):680-7.

The authors examined prospectively whether dietary folate and other factors known to influence methyl-group availability were associated with the development of exocrine pancreatic cancer within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Of the 27,101 healthy male smokers aged 50--69 years who completed a self-administered dietary questionnaire at baseline, 157 developed pancreatic cancer during up to 13 years of follow-up from 1985 to 1997. Cox proportional hazards models were used to estimate the hazards ratios and 95% confidence intervals. The adjusted hazards ratio comparing the highest with the lowest quintile of dietary folate intake was 0.52 (95% confidence interval: 0.31, 0.87; p-trend = 0.05). Dietary methionine, alcohol intake, and smoking history did not modify this relation. No significant associations were observed between dietary methionine, vitamins B(6) and B(12), or alcohol intake and pancreatic cancer risk. Consistent with prior studies, this study shows that cigarette smoking was associated with an increased risk (highest compared with lowest quintile, cigarettes per day: hazards ratio = 1.82; 95% confidence interval: 1.10, 3.03; p-trend = 0.05). These results support the hypothesis that dietary folate intake is inversely associated with the risk of pancreatic cancer and confirm the risk associated with greater cigarette smoking

Modified citrus pectin slows PSA doubling time: a pilot clinical trial. Presented at the International Conference on Diet and Prevention of Cancer, Tampere, Finland, May 28-June 2, 1999.

Strum S.

1999; May 28-June 2, 1999.

Sunlight--can it prevent as well as cause cancer?

Studzinski GP, Moore DC.

Cancer Res. 1995 Sep 15; 55(18):4014-22.

Excessive exposure to sunlight is known to damage the skin. However, the emphasis of most studies has been on the consequences of sunlight exposure to fair-skinned individuals, and the situation of people with heavy skin pigmentation residing in, or migrating to, geographic locations with limited sunlight incidence has been largely neglected. Recent epidemiological studies suggested the hypothesis that sunlight deprivation, and the associated reduction in the circulating levels of vitamin D3 (vit D3) derivatives may lead to the increased incidence of the carcinomas of the breast, colon, and prostate. Two endocrine pathways may mediate these effects. The pineal function can potentially be involved, but the formation of vit D3 derivatives is gaining credibility as a mechanism for the retardation of cancer progression. Evidence is accumulating that such compounds, e.g., 1,25-dihydroxyvitamin D3 (1,25D3) induce differentiation of several neoplastic cell types, arrest or retard their proliferation, and act as chemopreventive agents in animal carcinogenesis. We also propose that the antineoplastic effects of vit D3 derivatives are exerted at several steps in tumor progression and that immunomodulating effects of 1,25D3 may contribute to these effects of sunlight. The recent findings that common cancers, e.g., carcinoma of the prostate and the breast, behave more aggressively in black Americans than in white Americans may be explained on this basis. Although more data are needed on the effects of sunlight on the circulating levels of 1,25D3, a corollary of this hypothesis is that there should be no broad condemnation of moderate sunlight exposure, as it may be available in insufficient amounts to some Americans

The potential of soybean foods as a chemoprevention approach for human urinary tract cancer.

Su SJ, Yeh TM, Lei HY, et al.

Clin Cancer Res. 2000 Jan; 6(1):230-6.

Isoflavones are excreted in human urine and can be modulated by soy-rich diets. Recently, isoflavones were suggested to have protective effects against bladder cancer cells. We sought to determine the efficacy of the antitumorigenic effects of isoflavones at concentrations found in the range of human urine excretion and compare normal urothelium and bladder cancer cells for differential cytotoxicity. A total of seven human bladder cancer cell lines and an immortalized uroepithelial cell line were used to examine the effects of genistein, daidzein, and biochanin-A, either individually or as an equal-proportion mixture regimen, on cell growth, DNA synthesis, alterations of cell cycle distribution, and induction of apoptosis. The role of cyclin B1 and cdc2 kinase in cell cycle arrest was analyzed. In addition, severe combined immunodeficient mice were used to confirm the anti-cancer effects of isoflavones in vivo. Cooperative action of isoflavones was more effective in growth inhibition and apoptosis induction than any single compound. Genistein tends to cause a dose-dependent induction of G2-M cell cycle arrest and an inhibition of cdc2 kinase activity. However, both daidzein and biochanin-A directly induced apoptosis without altering cell cycle distribution. The IC50 values in non-transformed cells were higher than those in most cancer cell lines, and the IC50 of the mixture regimen was within reach of the levels observed in urine after a soy challenge. Furthermore, both genistein and combined isoflavones exhibited a significant tumor suppressor effect in vivo (P < 0.05). The results justify the potential use of soybean foods as a practical chemoprevention approach for patients with urinary tract cancer

Resveratrol inhibits cyclooxygenase-2 transcription in human mammary epithelial cells.

Subbaramaiah K, Michaluart P, Chung WJ, et al.

Ann N Y Acad Sci. 1999; 889:214-23.

A large body of evidence suggests that inhibiting cyclooxygenase-2 (COX-2), the inducible form of COX, will be an important strategy for preventing cancer. In this study, we investigated whether resveratrol, a chemopreventive agent found in grapes, could suppress phorbol ester (PMA)-mediated induction of COX-2 in human mammary and oral epithelial cells. Treatment of cells with PMA induced COX-2 mRNA, COX-2 protein, and prostaglandin synthesis. These effects were inhibited by resveratrol. Nuclear runoffs revealed increased rates of COX-2 transcription after treatment with PMA, an effect that was inhibited by resveratrol. Resveratrol inhibited PMA-mediated activation of protein kinase C and the induction of COX-2 promoter activity by c-Jun. Phorbol ester-mediated induction of AP-1 activity was blocked by resveratrol. These data are likely to be important for understanding the anticancer and anti-inflammatory properties of resveratrol

[Pharmacological studies on ginger. IV. Effect of (6)-shogaol on the arachidonic cascade].

Suekawa M, Yuasa K, Isono M, et al.

Nippon Yakurigaku Zasshi. 1986 Oct; 88(4):263-9.

(6)-Shogaol, a pungent component of ginger, which is contained in semi-dried ginger but is rarely found in fresh ginger inhibited carrageenin-induced swelling of hind paw in rats and arachidonic acid (AA)-induced platelet aggregation in rabbits. Moreover, (6)-shogaol prevented prostaglandin I2 (PGI2) release from the aorta of rats when tested as an inhibitor of platelet aggregation. These results suggest that (6)-shogaol may have an inhibitory action on the cyclo-oxygenases in both platelets and aorta. Examination of the effects of (6)-shogaol on cyclo-oxygenases in rabbit platelets and microsome fractions of rat aorta indicated that (6)-shogaol inhibited cyclo-oxygenase activities of both tissues in a concentration-dependent manner. Furthermore, when we examined the effect of (6)-shogaol on 5-lipoxygenase from RBL-1 cells, (6)-shogaol exhibited an inhibitory action on 5-lipoxygenase activity. Therefore, it seems that the inhibitory effects of (6)-shogaol on the carrageenin-induced paw edema, AA-induced platelet aggregation and PGI2 production of aorta may be caused by the inhibition of cyclo-oxygenase activity

Enhancing effects of green tea components on the antitumor activity of adriamycin against M5076 ovarian sarcoma.

Sugiyama T, Sadzuka Y.

Cancer Lett. 1998 Nov 13; 133(1):19-26.

We have investigated the combined treatment of components of green tea with adriamycin against M5076 ovarian sarcoma, which exhibits low sensitivity to adriamycin. In M5076 tumor-bearing mice, the injection of adriamycin alone did not inhibit tumor growth, whereas the combination of theanine and adriamycin significantly reduced the tumor weight to 62% of the control level. When combined with theanine, effective antitumor activity of adriamycin was observed without an increase in the dosage. Theanine specifically increased the adriamycin concentration in the tumor by 2.7-fold. In contrast, theanine decreased the adriamycin concentrations in normal tissues. On the other hand, in vitro experiments proved that theanine inhibited the efflux of adriamycin from tumor cells, suggesting a theanine-induced increase in the adriamycin concentration in such tumors in vivo. Furthermore, the oral administration of theanine or green tea similarly enhanced the antitumor activity of adriamycin. In conclusion, the combination of theanine with adriamycin showed antitumor efficacy in spite of the non-effective dose of adriamycin on M5076 ovarian sarcoma. We have found that the modulating action of theanine is useful in clinical cancer chemotherapy

Membrane transport and antitumor activity of pirarubicin, and comparison with those of doxorubicin.

Sugiyama T, Sadzuka Y, Nagasawa K, et al.

Jpn J Cancer Res. 1999 Jul; 90(7):775-80.

We have compared the membrane transport and antitumor activity of pirarubicin with those of doxorubicin in M5076 ovarian sarcoma, which exhibits low sensitivity to doxorubicin. Pirarubicin was rapidly taken up by M5076 cells and the intracellular concentration of pirarubicin reached more than 2.5-fold that of doxorubicin. In terms of the 50% cell growth-inhibitory concentration in vitro, pirarubicin was more effective than doxorubicin. Thus, the intracellular concentration influenced the cytotoxicity of these anthracycline agents. On comparison of the nuclear uptake of pirarubicin and doxorubicin, the nucleus/cell ratio of pirarubicin was found to be about 40%, whereas that of doxorubicin reached more than 80%. As the intranuclear concentration of pirarubicin is dependent on nuclear transport, the increases in not only cell membrane transport, but also nuclear membrane transport contributed to the enhancement of the efficacy of pirarubicin. In M5076 solid tumor-bearing mice, pirarubicin reduced the tumor weight to 60% of the control level, although doxorubicin had no effect. These results were supported by the intracellular uptake of pirarubicin. Moreover, theanine, which inhibited the pirarubicin efflux from M5076 cells, increased by 1.3-fold the pirarubicin concentration in the tumor and enhanced the therapeutic efficacy of pirarubicin 1.7-fold. In conclusion, our results suggest that an increase in the concentration of an anthracycline derivative in tumor cells due to alteration of cell membrane transport results in enhancement of the antitumor activity

Inhibition of glutamate transporter by theanine enhances the therapeutic efficacy of doxorubicin.

Sugiyama T, Sadzuka Y, Tanaka K, et al.

Toxicol Lett. 2001 Apr 30; 121(2):89-96.

Theanine, a major amino acid existing in green tea, enhanced the antitumor activity of doxorubicin (DOX) due to inhibition of DOX efflux from tumor cells. In order to clarify the mechanism, we have investigated the contribution of glutamate transporters to the action of theanine, because theanine is a glutamate analogue. In M5076 ovarian sarcoma cells, glutamate transport inhibitors reduced the efflux of DOX, as well as theanine. Incidentally, theanine significantly inhibited the glutamate uptake by M5076 cells in a concentration-dependent manner similar to specific inhibitors. These results suggested that the inhibition of DOX efflux was induced by the inhibition of glutamate transport by theanine. In addition, RT-PCR and Western blot analysis revealed the expression of GLAST and GLT-1, astrocytic high-affinity glutamate transporters, in M5076 cells. Thus, theanine was shown to competitively inhibit the glutamate uptake by acting on these glutamate transporters. This action suggested the contribution of glutamate transporters to the inhibition of DOX efflux by theanine. We revealed the novel mechanism of enhancement of the antitumor efficacy of DOX via the inhibition of glutamate transporters by theanine

Chemoprevention of 1,2-dimethylhydrazine-induced colon cancer in mice by naturally occurring organosulfur compounds.

Sumiyoshi H, Wargovich MJ.

Cancer Res. 1990 Aug 15; 50(16):5084-7.

Organosulfur compounds (OSCs) present in garlic and onion oil have been shown to inhibit chemical carcinogenesis. In this study, we compared the chemopreventive efficacy of five lipid- and four water-soluble OSCs using the murine nuclear aberration assay. Administration of diallyl sulfide and S-allyl cysteine p.o. at a dose of 200 mg/kg 3 h prior to i.p. 1,2-dimethylhydrazine (DMH) injection (20 mg/kg) significantly inhibited colonic nuclear damage in female C57Bl/6J mice by 47% and 36%, respectively. The inhibitory effect of S-allyl cysteine was found to be dose dependent. The other OSCs did not affect the level of DMH-induced nuclear toxicity. Furthermore, the incidence and frequency of colonic tumors induced by DMH (20 mg/kg, 10 weekly i.p. injections) in female CF-1 mice were significantly inhibited by S-allyl cysteine pretreatment, given 3 h prior to each carcinogen injection. These data indicate that the allyl group coupled to a single sulfur atom might play an important structural role in inhibition of DMH-induced colonic nuclear toxicity and carcinogenesis. OSCs containing allyl groups stimulated glutathione S-transferase activity in both the liver and colon. However, their saturated analogues stimulated little or no hepatic and colonic glutathione S-transferase activity. Induction of hepatic and colonic glutathione S-transferase might assist in detoxification of carcinogens and could be necessary for some aspects of chemoprevention

Retinoids and their receptors in cancer development and chemoprevention.

Sun SY, Lotan R.

Crit Rev Oncol Hematol. 2002 Jan; 41(1):41-55.

Retinoids play an important role in regulating the growth and differentiation of normal, premalignant and malignant cell types, especially epithelial cells, mainly through interaction with two types of nuclear receptors: retinoic acid receptors (RARalpha, beta and gamma) and retinoid X receptors (RXRalpha, beta and gamma). Vitamin A deficiency in experimental animals has been associated with a higher incidence of cancer and with increased susceptibility to chemical carcinogens. This is in agreement with the epidemiological studies indicating that individuals with a lower dietary vitamin A intake are at a higher risk to develop cancer. At the molecular level, aberrant expression and function of nuclear retinoid receptors have been found in various types of cancer including premalignant lesions. Thus, aberrations in retinoid signaling are early events in carcinogenesis. Retinoids at pharmacological doses exhibit a variety of effects associated with cancer prevention. They suppress transformation of cells in vitro, inhibit carcinogenesis in various organs in animal models, reduce premalignant human epithelial lesions and prevent second primary tumors following curative therapy for epithelial malignancies such as head and neck, lung, liver, and breast cancer

Increased UDP-glucuronosyltransferase activity and decreased prostate specific antigen production by biochanin A in prostate cancer cells.

Sun XY, Plouzek CA, Henry JP, et al.

Cancer Res. 1998 Jun 1; 58(11):2379-84.

Our laboratory has characterized androgen metabolism in an androgen-responsive prostate cancer cell line (LNCaP) and showed that these cells accumulated intracellular testosterone primarily as glucuronidated metabolites. Using a cell-free assay with testosterone as substrate, we showed that LNCaP had UDP-glucuronosyltransferase (UDPGT) activity. Because dietary factors, such as flavonoids in soy products, may reduce the risk for hormone-dependent cancers, we studied the effects of flavonoids on testosterone-UDPGT activity. LNCaP cells were exposed to selected flavonoids for up to 6 days. The increase in UDPGT-specific activity was linear over this period. Of the compounds tested, biochanin A was the most potent, with increased activity at concentration range 0.5-50 microM. Activities were linear for time and protein and were unaffected by flavonoids added directly to the assay. Kinetics studies showed no change in Km for testosterone in the face of these large increases in specific activity. Cellular metabolism of testosterone reflected the increase in enzyme activity. Intact cells treated with biochanin A produced testosterone-glucuronide from testosterone at twice the rate of controls. The steroid form of the UDPGT transcript was expressed in LNCaP cells and was enhanced in biochanin A-treated LNCaP cells. Additionally, biochanin A markedly decreased prostate specific antigen (PSA) level against the effect of testosterone on PSA production. Biochanin A significantly decreased the testosterone-stimulated release of PSA, presumably because biochanin A increased UDPGT and increased the intracellular glucuronidation of testosterone. These studies suggest that the modulation of hormone metabolism by dietary factors may be important in the prevention and treatment of prostate cancer

Pharmacological activities of Genistein, an isoflavone from soy (Glycine max): part I--anti-cancer activity.

Suthar AC, Banavalikar MM, Biyani MK.

Indian J Exp Biol. 2001 Jun; 39(6):511-9.

Phytoestrogens represent a family of plant compounds such as isoflavones, flavones and lignans. A variety of these plant compounds have been identified in various human body fluids. A wide range of commonly consumed foods contains appreciable amounts of these different phytoestrogens, viz. soy products are particularly good sources of isoflavones and lignans. Accumulating evidences from molecular and cellular biology experiments, animal studies, and to a limited extent, human clinical trials suggests that phytoestrogens may potentially confer health benefits related to various cancers and diseases such as cardiovascular disorder. The evidences reviewed here represent the beneficial effects of most potential and promising isoflavone, Genistein in various types of cancers

Interaction of cimetidine with oral melphalan. A pharmacokinetic study.

Sviland L, Robinson A, Proctor SJ, et al.

Cancer Chemother Pharmacol. 1987; 20(2):173-5.

The effects of pretreatment with cimetidine (200 mg three times daily, 400 mg at night) on the pharmacokinetics of oral melphalan (10 mg) have been investigated in patients with multiple myeloma. Cimetidine pretreatment reduced the bioavailability of oral melphalan by approximately 30% (P less than 0.05). The elimination rate of melphalan from plasma was significantly increased by cimetidine (P less than 0.05), the half-life being reduced from 1.94 +/- 0.55 h to 1.57 +/- 0.53 h. Cimetidine appeared to reduce the interindividual variability in melphalan absorption, but at the cost of reduced bioavailability

Dose-dependent effect of resveratrol on proliferation and apoptosis in endothelial and tumor cell cultures.

Szende B, Tyihak E, Kiraly-Veghely Z.

Exp Mol Med. 2000 Jun 30; 32(2):88-92.

Experimental data suggest that Resveratrol, a compound found in grapes and other fruits may influence cell proliferation and apoptosis. The aim of our experiments was to study the effect of Resveratrol on tumor cell cultures and an endothelial cell culture in order to examine the effect of various doses of this compound on active cell death and cell proliferation. Human tumor (HT-29, SW-620, HT-1080) and endothelial (HUV-EC-C) cells were treated with various doses of (0.1 to 100.0 microg/ml) Resveratrol in vitro. Cell number, apoptotic and mitotic index was measured 24, 48 and 72 h after treatment. Low doses (0.1-1.0 microg/ml) of Resveratrol enhance cell proliferation, higher doses (10.0-100.0 microg/ml) induce apoptosis and decrease mitotic activity, which is reflected in changes of cell number. Resveratrol influences dose dependently the proliferative and apoptotic activity of human tumor and endothelial cells. The possible role of formaldehyde in the mechanism of action of Resveratrol is discussed

Growth inhibition and modulation of cell markers of melanoma by S-allyl cysteine.

Takeyama H, Hoon DS, Saxton RE, et al.

Oncology. 1993; 50(1):63-9.

A sulfur-containing amino acid compound, S-allyl cysteine (SAC), derived from garlic extract inhibited proliferation of nine human and murine melanoma cell line in a dose-dependent manner (1.2-10 mM) assessed by a [3H]thymidine incorporation assay. Three control human lymphoblastoid cell lines were not inhibited by SAC concentrations < 5 mM. Four human melanoma cell lines in a soft-agar assay also showed dose-dependent inhibition of colony formation by SAC. Melanin content was increased up to 95% compared to the same untreated cell lines in these four human melanoma and two B16 murine melanoma sublines. Expression of cell surface gangliosides, cellular-differentiation and transformation markers, decreased after SAC treatment. Significant morphological changes including 'flattening and/or dendritic-like elongations' were also observed. Thus SAC inhibited cellular growth and proliferation and modulated major cell differentiation markers of melanoma

Cancer protection from broccoli spouts.

Talalay P.

Health Newsfeed #597 1997. 1997

Inhibition of neuropeptide-stimulated tyrosine phosphorylation and tyrosine kinase activity stimulates apoptosis in small cell lung cancer cells.

Tallett A, Chilvers ER, Hannah S, et al.

Cancer Res. 1996 Sep 15; 56(18):4255-63.

Small cell lung cancer (SCLC) cell growth is sustained by multiple autocrine and paracrine growth loops involving neuropeptides. The bombesin family of peptides are autocrine growth factors in H345 SCLC cells and provide a paradigm for the study of growth factors and mitogenic signaling in SCLC cells. We show that bombesin (and other neuropeptides) stimulates protein tyrosine phosphorylation (particularly focal adhesion kinase) and protein tyrosine kinase (PTK) activity in intact SCLC cells. Furthermore, the broad spectrum neuropeptide receptor antagonist [D-Arg, D = Phe, D-Trp, Leu11]substance P inhibits all neuropeptide-mediated signals (including PTK activation), SCLC cell growth in vivo and in vitro, and also increases the natural rate of apoptosis seen in growing SCLC cell lines. Hence the effect of selective PTK inhibition on SCLC cell growth and apoptosis was examined. We show that selective inhibition of PTK activity, with genistein and (3,4,5-tri-hydroxyphenyl)-methylene(-propanedinitrile) tyrphostin-25 inhibits basal and neuropeptide-stimulated SCLC cell growth. Genistein and tyrphostin-25 also stimulate apoptosis in SCLC cells. Inhibition of proliferation in these cells is intimately linke to apoptosis, because these changes occurred without any effect on SCLC cell cycle kinetics, suggesting that apoptosis occurs independently of the cell cycle and that failure to progress through the cell cycle results in apoptosis. Because tyrphostin-25 fails to influence p53 or Bcl-2 expression in these cells, this mode of programmed cell death appears to be via a p53- and Bcl-2-independent mechanism. These results provide evidence that tyrosine phosphorylation is a mitogenic signal in SCLC cells and suggest that regulation of the level of protein tyrosine phosphorylation represents a critical determinant of whether SCLC cells survive and proliferate or die by apoptosis. Thus PTK inhibition may provide a novel therapeutic option in SCLC that has become resistant to conventional chemotherapeutic agents

Effect of vitamin A administration on resistance of rat heart against doxorubicin-induced cardiotoxicity and lethality.

Tesoriere L, Ciaccio M, Valenza M, et al.

J Pharmacol Exp Ther. 1994 Apr; 269(1):430-6.

The peroxyl radical-scavenging activity of vitamin A has been exploited to obtain protection against peroxidative damages induced in rat heart by administration of an acute dose of doxorubicin (10 mg/kg, in vein). Peroxidative lesions were evaluated by both biochemical and histological assays, 48 hr after the injection of doxorubicin. Heart tissue from rats receiving doxorubicin showed a marked increase of protein carbonyl levels, and of membrane conjugated dienes, as well as a decrease of membrane protein thiols. Abnormal chemistries, including a large increase of the activity of serum lactate dehydrogenase and creatine phosphokinase, an index of the myocardial damage caused by doxorubicin, were also observed. Pretreatment of rats with 25 I.U./kg b.wt. of vitamin A, once a day for 2 days, before injecting doxorubicin, substantially reduced the peroxidative damage to heart lipids and proteins, and markedly lowered the serum values of lactate dehydrogenase and creatine phosphokinase to values close to those of control rats. The significant prevention of doxorubicin-induced cardiomyopathy by vitamin A was evident from the histopathological pattern observed after light microscopy. The dosage of vitamin A useful to obtain the protective effect appears safe and does not injure the liver, as indicated by light microscopy of the tissue. A survival study, carried out by injecting rats with a single injection of 10 mg/kg of doxorubicin, showed that pretreatment with 25 I.U. of vitamin A per kg significantly increased survival rate of the animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21(CIP) expression.

Tessitore L, Davit A, Sarotto I, et al.

Carcinogenesis. 2000 Aug; 21(8):1619-22.

We investigated whether resveratrol (RV) affects azoxymethane (AOM)-induced colon carcinogenesis, by administering RV (200 microg/kg/day in drinking water) to male F344 rats for 100 days, beginning 10 days before carcinogen treatment (two weekly doses of 15 mg/kg AOM). Aberrant crypt foci (ACF) were isolated and proliferation, apoptosis and expression of the cell cycle genes bax and p21 were determined. RV significantly reduced the number of ACF/colon [25.7 +/- 3.6 (mean +/- SEM) versus 39.4 +/- 3.3 in controls; P < 0.01] and their multiplicity (2.7 +/- 0.3 versus 4.9 +/- 0.6 in controls; P < 0.01), and also abolished large ACF. In RV-treated rats, bax expression was enhanced in ACF but not in the surrounding mucosa. In both controls and RV-treated rats, proliferation was higher in ACF than in normal mucosa. p21 was expressed in ACF of controls and of RV-treated rats and in normal mucosa of controls, but was lost in normal mucosa of RV-treated animals. In conclusion, the results suggest a protective role of RV in colon carcinogenesis with a mechanism involving changes in bax and p21 expression

Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21(CIP) expression.

Tessitore L, Davit A, Sarotto I, et al.

Carcinogenesis. 2000 Aug; 21(8):1619-22.

We investigated whether resveratrol (RV) affects azoxymethane (AOM)-induced colon carcinogenesis, by administering RV (200 microg/kg/day in drinking water) to male F344 rats for 100 days, beginning 10 days before carcinogen treatment (two weekly doses of 15 mg/kg AOM). Aberrant crypt foci (ACF) were isolated and proliferation, apoptosis and expression of the cell cycle genes bax and p21 were determined. RV significantly reduced the number of ACF/colon [25.7 +/- 3.6 (mean +/- SEM) versus 39.4 +/- 3.3 in controls; P < 0.01] and their multiplicity (2.7 +/- 0.3 versus 4.9 +/- 0.6 in controls; P < 0.01), and also abolished large ACF. In RV-treated rats, bax expression was enhanced in ACF but not in the surrounding mucosa. In both controls and RV-treated rats, proliferation was higher in ACF than in normal mucosa. p21 was expressed in ACF of controls and of RV-treated rats and in normal mucosa of controls, but was lost in normal mucosa of RV-treated animals. In conclusion, the results suggest a protective role of RV in colon carcinogenesis with a mechanism involving changes in bax and p21 expression

Inhibition of human bladder cancer cell motility by genistein is dependent on epidermal growth factor receptor but not p21ras gene expression.

Theodorescu D, Laderoute KR, Calaoagan JM, et al.

Int J Cancer. 1998 Dec 9; 78(6):775-82.

A significant portion of patients who present with non-muscle invasive "superficial" bladder cancer develop the muscle "invasive" life-threatening form of the disease during subsequent follow-up. In clinical studies, overexpression of the epidermal growth factor receptor (EGFR) and the p21 ras oncogene have been strongly associated with this phenotypic tumor transition. The marked difference in incidence of invasive bladder cancer in Asia compared to the United States has made us hypothesize that, among other factors, dietary influences have an impact on such tumor progression. A significantly higher dietary consumption of soy products exists in Asia and has led to the notion that the isoflavones present in this diet may contribute to a reduction in the number of invasive transitional cell bladder cancers. In this regard, we sought to determine the effect of genistein, a naturally occurring dietary protein tyrosine kinase (PTK) inhibitor, on the growth and motility of human bladder cancer cell lines with diverse EGFR and p21ras expression phenotypes and corresponding invasive behaviors. These effects were compared with those of tyrphostin, a pure synthetic EGFR inhibitor. Our results indicate that both genistein and tyrphostin are effective inhibitors of bladder cancer motility and growth, key factors in the development of muscle invasive disease. In addition, the growth and motility inhibitory effects of genistein and tyrphostin are observed preferentially in cells that overexpress the EGFR. Cells that have a mutated p21ras but do not overexpress the EGFR are less inhibited by these 2 compounds, suggesting that their effect is primarily directed at the EGFR signal transduction pathways proximal to the p21ras gene. Our results would seem to corroborate the notion that a high dietary intake of isoflavones is a likely explanation for the decreased incidence of invasive bladder cancer

All-trans retinoic acid and interferon-alpha in the treatment of a patient with resistant metastatic osteosarcoma.

Todesco A, Carli M, Iacona I, et al.

Cancer. 2000 Dec 15; 89(12):2661-6.

BACKGROUND: A boy age 14 years who was in complete remission from Stage IIB small cell osteosarcoma, which was misdiagnosed as Ewing sarcoma and consequently was treated, developed inoperable lung metastases when he was off therapy. He received second-line treatment for recurrent Ewing sarcoma, including chemotherapy and radiotherapy, and obtained only a temporary response. A compassionate treatment with all-trans retinoic acid (ATRA) and interferon-alpha (IFNalpha) was then undertaken. METHODS: The patient initially was treated according to the national SE91 protocol for nonmetastatic Ewing sarcoma. After a bilateral pulmonary recurrence, he received second-line chemotherapy and irradiation of the largest metastasis, with a temporary partial response. The patient was then treated with a combination of oral ATRA (90 mg/m(2) for 3 days per week) and subcutaneous IFNalpha (3 x 10(6) U/m(2) 5 days per week) for 4 months. The same therapy also was administered for the control of residual disease after surgery for a total duration of 1 year of ATRA/IFN treatment. During the first 3 weeks of therapy, ATRA pharmacokinetics were studied. RESULTS: After progression of the patient's disease, despite the administration of first-line and second-line chemotherapy, combined treatment with ATRA/IFNalpha yielded a partial remission, which allowed surgical resection of the largest metastasis. The same therapy was effective in preventing tumor recurrence after incomplete removal of the remaining metastases. Treatment was well tolerated, and the patient is in stable complete remission 14 months after the end of therapy. The pharmacokinetics results confirmed the indication of an intermittent schedule for oral ATRA therapy. CONCLUSIONS: ATRA/IFNalpha treatment may be considered as an alternative approach in the treatment of patients with metastatic osteosarcoma who have disease that is resistant to conventional chemotherapy and in the treatment of patients with minimal tumor residue

Serum carotenoids and breast cancer.

Toniolo P, Van Kappel AL, Akhmedkhanov A, et al.

Am J Epidemiol. 2001 Jun 15; 153(12):1142-7.

The consumption of vegetables and fruit may protect against many types of cancer, but research evidence is not compelling for breast cancer. Carotenoids are pigments that are present in most plants and have known antioxidant properties. Blood concentrations of carotenoids have been proposed as integrated biochemical markers of vegetable, fruit, and synthetic supplements consumed. In a case-control study (270 cases, 270 controls) nested within a cohort in New York during 1985-1994, the carotenoids lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, and beta-carotene were measured in archived serum samples using liquid chromatography. There was an evident increase in the risk of breast cancer for decreasing beta-carotene, lutein, alpha-carotene, and beta-cryptoxanthin. The risk of breast cancer approximately doubled among subjects with blood levels of beta-carotene at the lowest quartile, as compared with those at the highest quartile (odds ratio = 2.21; 95% confidence interval (CI): 1.29, 3.79). The risk associated with the other carotenoids was similar, varying between 2.08 (95% CI: 1.11, 3.90) for lutein and 1.68 (95% CI: 0.99, 2.86) for beta-cryptoxanthin. The odds ratio for the lower quartile of total carotenoids was 2.31 (95% CI: 1.35, 3.96). These observations offer evidence that a low intake of carotenoids, through poor diet and/or lack of vitamin supplementation, may be associated with increased risk of breast cancer and may have public health relevance for people with markedly low intakes

Effect of cimetidine on survival after gastric cancer.

Tonnesen H, Knigge U, Bulow S, et al.

Lancet. 1988 Oct 29; 2(8618):990-2.

The effect of cimetidine on survival was investigated in 181 patients with gastric cancer. Immediately after operation or the decision not to operate, the patients were randomised in double-blind fashion to placebo or cimetidine 400 mg twice daily for two years or until death, with review every three months. Median survival in the cimetidine group was 450 days (range 1-1826) and in the placebo group 316 days (1-1653). The relative survival rates (cimetidine/placebo) were 45%/28% at 1 year, 22%/13% at 2 years, 13%/7% at 3 years, 9%/3% at 4 years, and 2%/0% at 5 years. Survival in the cimetidine group was significantly longer than in the placebo group

Resveratrol induces Fas signalling-independent apoptosis in THP-1 human monocytic leukaemia cells.

Tsan MF, White JE, Maheshwari JG, et al.

Br J Haematol. 2000 May; 109(2):405-12.

Resveratrol, a natural product present in wine, has recently been shown to inhibit the growth of a number of cancer cell lines in vitro. In the current study, we have demonstrated that resveratrol inhibits the growth of THP-1 human monocytic leukaemia cells in a dose-dependent manner with a median effective dose of 12 microM. It did not induce differentiation of THP-1 cells and had no toxic effect on THP-1 cells that had been induced to differentiate into monocytes/macrophages by phorbol myristate acetate. A significant fraction of resveratrol-treated cells underwent apoptosis as judged by flow cytometric analysis of DNA content, DNA fragmentation and caspase-specific cleavage of poly(ADP-ribosyl) polymerase. Resveratrol treatment had no effect on the expression of Fas receptor or Fas ligand (FasL) in THP-1 cells, nor did it induce clustering of Fas receptors. In addition, THP-1 cells were resistant to activating anti-Fas antibody, and neutralizing anti-Fas and/or anti-FasL antibodies had no protective effect against resveratrol-induced inhibition of THP-1 cell growth. The effect of resveratrol on THP-1 cells was reversible after its removal from the culture medium. These results suggest that (1) resveratrol inhibits the growth of THP-1 cells, at least in part, by inducing apoptosis, (2) resveratrol-induced apoptosis of THP-1 cells is independent of the Fas/FasL signalling pathway and (3) resveratrol does not induce differentation of THP-1 cells and has no toxic effect on differentiated THP-1 cells. Thus, resveratrol may be a potential chemotherapeutic agent for the control of acute monocytic leukaemia

Anti-leukemia effect of resveratrol.

Tsan MF, White JE, Maheshwari JG, et al.

Leuk Lymphoma. 2002 May; 43(5):983-7.

Resveratrol is a phytoalexin naturally present in fruits, medicinal plants and wines. It has a diversity of biological activities. While its role in the protection against coronary heart disease (CHD) in people with moderate wine consumption, remains unclear, resveratrol preferentially inhibits the growth of leukemia cells in culture. Potential mechanisms for its anti-leukemia effect include induction of leukemia cell differentiation, apoptosis, and cell cycle arrest at S-phase; and inhibition of DNA synthesis by inhibiting ribonucleotide reductase or DNA polymerase. Preliminary results suggest that resveratrol also inhibits the viability of freshly isolated leukemia cells, especially promyelocytic leukemia cells. Because of its low in vivo toxicity, resveratrol deserves further investigation as an anti-leukemia agent

Anti-leukemia effect of resveratrol.

Tsan MF, White JE, Maheshwari JG, et al.

Leuk Lymphoma. 2002 May; 43(5):983-7.

Resveratrol is a phytoalexin naturally present in fruits, medicinal plants and wines. It has a diversity of biological activities. While its role in the protection against coronary heart disease (CHD) in people with moderate wine consumption, remains unclear, resveratrol preferentially inhibits the growth of leukemia cells in culture. Potential mechanisms for its anti-leukemia effect include induction of leukemia cell differentiation, apoptosis, and cell cycle arrest at S-phase; and inhibition of DNA synthesis by inhibiting ribonucleotide reductase or DNA polymerase. Preliminary results suggest that resveratrol also inhibits the viability of freshly isolated leukemia cells, especially promyelocytic leukemia cells. Because of its low in vivo toxicity, resveratrol deserves further investigation as an anti-leukemia agent

Micronutrients and the risk of colorectal adenomas.

Tseng M, Murray SC, Kupper LL, et al.

Am J Epidemiol. 1996 Dec 1; 144(11):1005-14.

Recent studies suggest that micronutrients, especially folate, calcium, iron, and antioxidant vitamins, affect the risk of colorectal neoplasia. The objective of this case-control study was to examine the association between these micronutrients and the risk of colorectal adenomas. The study was based on 236 cases with adenomatous polyps or cancer and 409 controls, all colonoscopy patients at University of North Carolina Hospitals between July 1988 and March 1991. After colonoscopy, subjects were interviewed using a semi-quantitative food frequency questionnaire, and average daily nutrient intakes were calculated. Sex-specific odds ratios relative to the lowest quartile of intake for each micronutrient were determined using unconditional logistic regression while adjusting for a number of potential confounders. In women, folate, iron, and vitamin C were inversely related to the risk of adenomas. Folate appeared to be most protective, with women in the highest quartile only 40% as likely to develop adenomas compared with women in the lowest (odds ratio = 0.39, 95% confidence interval 0.15-1.01). In men, greater vitamin E and calcium intakes were associated with reduced risk of adenomas, with vitamin E showing the strongest inverse association. Men in the highest vitamin E quartile had a risk of 0.35 (95% confidence interval 0.14-0.92) relative to those in the lowest. These study results support previous research findings that selected micronutrients protect against colorectal neoplasia

Prevention of colon carcinogenesis and carcinoma metastasis by orally administered bovine lactoferrin in animals.

Tsuda H, Sekine K, Takasuka N, et al.

Biofactors. 2000; 12(1-4):83-8.

Bovine lactoferrin (bLF), a milk protein known to have bacteriostatic properties was examined for its preventive effects on colon and other organ carcinogenesis and experimental metastasis. (Experiment 1) The influence on colon carcinogenesis was investigated in male rats treated with azoxymethane (AOM), then received 2 or 0.2% bLF for 36 weeks. Significant reduction in the incidence (27% and 46% of the control, respectively) and number of adenocarcinomas of the large intestine was observed. (Experiment 2) In BALB/c mice bearing subcutaneous (s.c.) implants of colon carcinoma 26 (Co 26Lu). bLF demonstrated significant inhibition of spontaneous lung metastasis (approximately 43% of the control). Number of cytotoxic asialoGM1+ and CD8+ cells in white blood cells increased (171% and 122% of control, respectively) after treatment. Results of those experiments indicate that bLF remarkably prevents colon carcinogenesis and lung metastasis of colon carcinoma cells, possibly due to increasing cytotoxic cells in the peripheral blood

Milk and dairy products in cancer prevention: focus on bovine lactoferrin.

Tsuda H, Sekine K, Ushida Y, et al.

Mutat Res. 2000 Apr; 462(2-3):227-33.

Milk and dairy products constitute an important part of the western style diet. A large number of epidemiological studies have been conducted to determine effects of consumption on cancer development but the data are largely equivocal, presumably reflecting the different included components. It has been proposed that whereas fats in general could promote tumor development, individual milk fats like conjugated linoleic acid could exert inhibitory effects. There is also considerable evidence that calcium in milk products protects against colon cancer, while promoting in the prostate through suppression of circulating levels of 1,25-dihydroxyvitamin D3. Whey protein may also be beneficial, as shown by both animal and human studies, and experimental data have demonstrated that the major component bovine lactoferrin (bLF), inhibits colon carcinogenesis in the post-initiation stage in male F344 rats treated with azoxymethane (AOM) without any overt toxicity. The incidence of adenocarcinomas in the groups receiving 2% and 0.2% bLF were thus 15% and 25%, respectively, in contrast to the 57.5% control value (P<0.01 and P<0.05, respectively). Results in other animal models have provided further indications that bLF might find application as a natural ingredient of milk with potential for chemoprevention of colon and other cancers

Cancer prevention by bovine lactoferrin and underlying mechanisms--a review of experimental and clinical studies.

Tsuda H, Sekine K, Fujita K, et al.

Biochem Cell Biol. 2002; 80(1):131-6.

In experimental studies, bovine lactoferrin (bLF) has been found to significantly inhibit colon, esophagus, lung, and bladder carcinogenesis in rats when administered orally in the post-initiation stage. Furthermore, concomitant administration with carcinogens resulted in inhibition of colon carcinogenesis, possibly by suppression of phase I enzymes, such as cytochrome P450 1A2 (CYP1A2), which is preferentially induced by carcinogenic heterocyclic amines. Enhancement of the activities of their phase II counterparts, such as glutathione S-transferase might have also played a critical role in post-initiation suppression in a study of tongue carcinogenesis. Anti-metastatic effects were moreover detected when bLF was given intragastrically to mice bearing highly metastatic colon carcinoma 26 cells (Co 26Lu), with apparent enhancing influence on local and systemic immunity. Marked increase in the number of cytotoxic T and NK cells in the mucosal layer of the small intestine and peripheral blood cells was thus found, this in turn enhancing the production of Interleukin 18 (IL-18) and caspase-1 in the epithelial cells of the small intestine, with possible consequent induction of interferon (IFN)-gamma positive cells. Furthermore, bLF has been found to exert anti-hepatitis C virus (HCV) activity in a preliminary clinical trial in patients with chronic active hepatitis due to this virus, a main causative factor in hepatocellular carcinoma development in Japanese. More extensive clinical trials are now underway in the National Cancer Center Hospital and other institutes to further explore the preventive potential against colon carcinogenesis

P2Y(2) receptor-mediated proliferation of C(6) glioma cells via activation of Ras/Raf/MEK/MAPK pathway.

Tu MT, Luo SF, Wang CC, et al.

Br J Pharmacol. 2000 Apr; 129(7):1481-9.

1. Extracellular purine and pyrimidine nucleotides have been implicated in the regulation of several cellular functions including mitogenesis. In this study, experiments were conducted to characterize the P2Y receptor on C(6) glioma cells responsible for stimulating cell proliferation associated with mitogen-activated protein kinase (MAPK) activation. 2. UTP and ATP produced a similar effect on [(3)H]-thymidine incorporation in a time- and concentration-dependent manner, suggesting the involvement of P2Y(2) receptor in mediating proliferation of C(6) glioma cells. 3. In response to UTP, both p42 and p44 MAPK were activated in a time- and concentration-dependent manner using Western blot analysis with an anti-phospho-p42/p44 MAPK antibody. The phosphorylation reached maximal levels after 5 min and declining by 30 min. 4. Pretreatment with pertussis toxin (PTX) did not change these responses to UTP. Both DNA synthesis and phosphorylation of MAPK in response to UTP were attenuated by tyrosine kinase inhibitors, genistein and herbimycin A, protein kinase C (PKC) inhibitors, staurosporine and GF109203X, and removal of Ca(2+) by addition of BAPTA/AM plus EGTA. 5. UTP-induced [(3)H]-thymidine incorporation and p42/p44 MAPK phosphorylation was completely inhibited by PD98059 (an inhibitor of MEK1/2). Furthermore, we showed that overexpression of dominant negative mutants of Ras (RasN17) and Raf (Raf-301) completely suppressed MEK1/2 and p42/p44 MAPK activation induced by ATP and UTP. 6. These results conclude that the mitogenic effect of UTP mediated through a P2Y(2) receptor that involves the activation of Ras/Raf/MEK/MAPK pathway. UTP-mediated MAPK activation was modulated by Ca(2+), PKC, and tyrosine kinase associated with cell proliferation in cultured C(6) glioma cells

Soy infant formula and phytoestrogens.

Tuohy PG.

J Paediatr Child Health. 2003 Aug; 39(6):401-5.

Soy infant formula contains high levels of the isoflavones, genistein and daidzein, which are commonly referred to as phytoestrogens. These are non-steroidal chemicals with structural similarities to estrogen. Infants consuming soy formula have high levels of circulating isoflavones. These are an order of magnitude greater than the levels of isoflavones which have been shown to produce physiological effects in adult women consuming a high soy diet. There is conflicting evidence about the risks and benefits of soy phytoestrogens, with research presenting a contradictory picture. Some reviewers suggest that early exposure to soy may prevent cancer and heart disease. However, there is very little research on the effects of consumption of soy phytoestrogens by human neonates. Against this generally positive view there is an increasing number of recent reports that suggest that in experimental animals, phytoestrogens have adverse effects with respect to carcinogenesis, reproductive function, immune function, and thyroid disease. Despite the absence of adequate scientific research that quantifies the level of risk to infants, most would argue for a precautionary approach to be taken in situations where there are potential developmental effects from the consumption of pharmacologically active compounds in infancy and childhood

Helicobacter pylori infection and the development of gastric cancer.

Uemura N, Okamoto S, Yamamoto S, et al.

N Engl J Med. 2001 Sep 13; 345(11):784-9.

BACKGROUND: Although many studies have found an association between Helicobacter pylori infection and the development of gastric cancer, many aspects of this relation remain uncertain. METHODS: We prospectively studied 1526 Japanese patients who had duodenal ulcers, gastric ulcers, gastric hyperplasia, or nonulcer dyspepsia at the time of enrollment; 1246 had H. pylori infection and 280 did not. The mean follow-up was 7.8 years (range, 1.0 to 10.6). Patients underwent endoscopy with biopsy at enrollment and then between one and three years after enrollment. H. pylori infection was assessed by histologic examination, serologic testing, and rapid urease tests and was defined by a positive result on any of these tests. RESULTS: Gastric cancers developed in 36 (2.9 percent) of the infected and none of the uninfected patients. There were 23 intestinal-type and 13 diffuse-type cancers. Among the patients with H. pylori infection, those with severe gastric atrophy, corpus-predominant gastritis, and intestinal metaplasia were at significantly higher risk for gastric cancer. We detected gastric cancers in 21 (4.7 percent) of the 445 patients with nonulcer dyspepsia, 10 (3.4 percent) of the 297 with gastric ulcers, 5 (2.2 percent) of the 229 with gastric hyperplastic polyps, and none of the 275 with duodenal ulcers. CONCLUSIONS: Gastric cancer develops in persons infected with H. pylori but not in uninfected persons. Those with histologic findings of severe gastric atrophy, corpus-predominant gastritis, or intestinal metaplasia are at increased risk. Persons with H. pylori infection and nonulcer dyspepsia, gastric ulcers, or gastric hyperplastic polyps are also at risk, but those with duodenal ulcers are not

Characteristics of green tea: a review.

Uhlenbruck GGR.

Z Onkol. 1998; 30(3):57-63.

The effect of conjugated linoleic acid on arachidonic acid metabolism and eicosanoid production in human saphenous vein endothelial cells.

Urquhart P, Parkin SM, Rogers JS, et al.

Biochim Biophys Acta. 2002 Feb 28; 1580(2-3):150-60.

The effects of a conjugated linoleic acid (CLA) mixture of single isomers (50:50, w/w, cis9,trans11:trans10,cis12) and the individual isomers on (a) the production of resting and calcium ionophore stimulated (14)C-eicosanoids and (b) the incorporation of (14)C-arachidonic acid (AA) into membrane phospholipids of human saphenous vein endothelial cells were investigated. The CLA mixture and the individual isomers were found to inhibit resting production of (14)C-prostaglandin F(2a) by 50, 43 and 40%, respectively. A dose dependent inhibition of stimulated (14)C-prostaglandins was observed with the CLA mixture (IC(50) 100 microM). The cis9,trans11 and trans10,cis12 (50 microM) isomers individually inhibited the overall production of stimulated (14)C-prostaglandins (between 35 and 55% and 23 and 42%, respectively). When tested at a high concentration (100 microM), cis9,trans11 was found to inhibit eicosanoid production in contrast to trans10,cis12 that caused stimulation. The overall degree of (14)C-AA incorporation into membrane phospholipids of the CLA (mixture and individual isomers) treated cells was found to be lower than that of control cells and the cis9,trans11 isomer was found to increase the incorporation of (14)C-AA into phosphatidylcholine. Docosahexaenoic acid, eicosapentaenoic acid and linoleic acid did not alter the overall degree of incorporation of (14)C-AA. The results of this study suggest that both isomers inhibit eicosanoid production, and although trans10,cis12 exhibits pro-inflammatory activity at high concentrations, the CLA mixture maintains its beneficial anti-inflammatory action that contributes to its anti-carcinogenic and anti-atherogenic properties

Possible chemopreventive effects of bovine lactoferrin on esophagus and lung carcinogenesis in the rat.

Ushida Y, Sekine K, Kuhara T, et al.

Jpn J Cancer Res. 1999 Mar; 90(3):262-7.

A milk component, bovine lactoferrin (bLF), previously shown by us to be a strong chemopreventive of colon carcinoma development, was examined for its influence on other organs using a rat multi-organ carcinogenesis model. Male F344 rats, aged 6 weeks, were treated sequentially with diethylnitrosamine (DEN, i.p.), dihydroxy-di-N-propylnitrosamine (DHPN, in drinking water) and N-nitrosomethylbenzylamine (NMBA, s.c.) during the first 8 weeks (DDN treatment), and then bLF was administered in the basal diet, at a dose of 2, 0.2, 0.02 or 0.002%. Other groups were given DDN treatment or bLF alone as controls. All surviving animals were killed at week 41, and major organs were examined histopathologically for neoplastic lesions. In the esophagus, a tendency for reduction in development of papillomas was evident in the bLF-treated animals, along with a significant suppression of relatively large-sized papillomas (more than 50 mm3 volume) at the 0.2% dose (P<0.05, 11% of the control). The multiplicity of tumors (adenomas and carcinomas) in the lung was also decreased in animals fed 0.02% bLF (1.98+/-0.41 per cm2 lung tissue section, P<0.05) compared to the control group (3.48+/-0.33). No enhancing or inhibitory effects of bLF on tumor development in other organs were noted. The present results indicate that bLF exerts chemopreventive effects in the esophagus and lung in addition to the colon

Effect of selenium in combination with Adriamycin or Taxol on several different cancer cells.

Vadgama JV, Wu Y, Shen D, et al.

Anticancer Res. 2000 May; 20(3A):1391-414.

The anti-neoplastic properties of an Selenium compound were studied in vitro on several tumor cell lines: Breast (MCF-7, MCF-10, SKBR-3, BCAP37), Lung (RH2), Prostate (LNCap and PC-3), Colon (T84, Caco-2), Small Intestine (HCF8), and Liver (HepG2). We also examined additive or synergistic effect of Selenium in combination with standard anti-cancer drugs, Adriamycin (Doxorubicin) and Taxol. The effect of Selenium was assessed by apoptosis; DNA synthesis; growth rate by MTT assay; uptake of amino acid MeAIB by System A; and morphological changes. Our results demonstrate that MCF-7 and SKBR-3 showed increase in apoptosis as measured by DNA fragmentation and increase in "rounded" cells and membrane "blebbing", decrease in MeAIB uptake, and decrease in DNA synthesis. These changes were Selenium dose dependent with optimal inhibition at Selenium concentration between 4 and 40 ng/ml after 72 hrs of treatment. Similar observations were made with RH2, HCF8, Caco-2, and HepG2 cells. In contrast, LNCap, PC-3, and T-84 were not significantly affected by Selenium. However, addition of Adriamycin or Taxol in combination with Selenium caused small but significant inhibition of prostate cancer cells LNCap and PC-3. Addition of chemotherapeutic agents either Taxol or Doxorubicin with Selenium caused further inhibition of MCF-7, SKBR-3, RH2, HCF8, and HepG2 cells. In conclusion, Selenium has a significant anti-neoplastic effect on breast, lung, liver, and small intestinal tumor cells. Supplementation of Selenium enhanced chemotherapeutic effect of Taxol and Doxorubicin in these cells beyond that seen with the chemotherapeutic drugs used alone. These in vitro studies on several cancer cell lines suggest a potential benefit of Selenium-enhancement of anticancer effects other systems, and therefore offer further relevance to clinical trials efforts

Vitamin D and vitamin D analogs in cancer treatment.

van den Bemd GJ, Chang GT.

Curr Drug Targets. 2002 Feb; 3(1):85-94.

The secosteroid hormone 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) is a key player in the regulation of bone mineralization and calcium homeostasis. In addition, 1,25-(OH)2D3 has antiproliferative and prodifferentiation effects on various cells in vitro and in vivo. The growth-inhibitory properties of 1,25-(OH)2D3 could be harnessed in the treatment of cancer. However, its use as an anti-cancer drug is limited because of the calcemic effects of pharmacological doses. In an attempt to dissociate the antiproliferative and calcemic effects, numerous vitamin D3 analogs were developed. The mechanisms by which 1,25-(OH)2D3 and 1,25-(OH)2D3 analogs exert their growth-inhibitory effects are not clear but include effects on cell differentiation, apoptosis, cell cycle regulation, metastases, and angiogenesis. In the current review aspects involved in the tumor suppressive activity of 1,25-(OH)2D3 and 1,25-(OH)2D3 analogs will be addressed. The use of vitamin D3 compounds, alone or in combination with other drugs, in cancer treatment and the potential drawbacks will also be discussed

N-acetylcysteine (NAC) and glutathione (GSH): antioxidant and chemopreventive properties, with special reference to lung cancer.

van Zandwijk N.

J Cell Biochem Suppl. 1995; 22:24-32.

Lung cancer arises as a focal transformation of chronically injured epithelium with cigarette smoke as one of its well-recognized causes. Apart from oxidants (free radicals), cigarette smoke contains such a multitude of (pre)carcinogens that it is astonishing that not every heavy smoker becomes a victim of malignancy. This points to the interindividual variability in susceptibility to carcinogens; several lines of evidence suggest that metabolic factors are involved in such variability. Metabolism of carcinogens as well as the subsequent (multi)steps of carcinogenesis are affected by host factors and governed by the balance between opposing forces, such as metabolic activation and detoxification, formation and scavenging of radicals, and DNA damage and repair, which seem to imply that carcinogenic compounds can initiate tumor growth only in amounts saturating detoxification mechanisms. In this context it is well known that glutathione (GSH) plays a crucial role in the detoxification of xenobiotics. N-Acetylcysteine (NAC), an aminothiol and synthetic precursor of intracellular cysteine and GSH, has been used for many years in Europe as a mucolytic drug. Clinically, it is a safe agent without major side effects and has been considered to have a place in cancer prevention, too. The antimutagenic and anticarcinogenic properties of NAC could be ascribed to multiple protective mechanisms, such as NAC nucleophilicity, antioxidant activity, its ability to act as a precursor of intracellular reduced GSH, modulation of detoxification, and DNA repair processes. On these grounds, NAC has emerged as a most promising cancer chemopreventive agent.(ABSTRACT TRUNCATED AT 250 WORDS)

N-acetylcysteine (NAC) and glutathione (GSH): antioxidant and chemopreventive properties, with special reference to lung cancer.

van Zandwijk N.

J Cell Biochem Suppl. 1995; 22:24-32.

Lung cancer arises as a focal transformation of chronically injured epithelium with cigarette smoke as one of its well-recognized causes. Apart from oxidants (free radicals), cigarette smoke contains such a multitude of (pre)carcinogens that it is astonishing that not every heavy smoker becomes a victim of malignancy. This points to the interindividual variability in susceptibility to carcinogens; several lines of evidence suggest that metabolic factors are involved in such variability. Metabolism of carcinogens as well as the subsequent (multi)steps of carcinogenesis are affected by host factors and governed by the balance between opposing forces, such as metabolic activation and detoxification, formation and scavenging of radicals, and DNA damage and repair, which seem to imply that carcinogenic compounds can initiate tumor growth only in amounts saturating detoxification mechanisms. In this context it is well known that glutathione (GSH) plays a crucial role in the detoxification of xenobiotics. N-Acetylcysteine (NAC), an aminothiol and synthetic precursor of intracellular cysteine and GSH, has been used for many years in Europe as a mucolytic drug. Clinically, it is a safe agent without major side effects and has been considered to have a place in cancer prevention, too. The antimutagenic and anticarcinogenic properties of NAC could be ascribed to multiple protective mechanisms, such as NAC nucleophilicity, antioxidant activity, its ability to act as a precursor of intracellular reduced GSH, modulation of detoxification, and DNA repair processes. On these grounds, NAC has emerged as a most promising cancer chemopreventive agent.(ABSTRACT TRUNCATED AT 250 WORDS)

The inhibition of the estrogenic effects of pesticides and environmental chemicals by curcumin and isoflavonoids.

Verma SP, Goldin BR, Lin PS.

Environ Health Perspect. 1998 Dec; 106(12):807-12.

Many environmental chemicals and pesticides have been found to be estrogenic and have been shown to stimulate the growth of estrogen receptor-positive (ER-positive) human breast cancer cells. Since it is difficult to avoid human exposure to environmental estrogens, a potentially important area of research is the development of dietary strategies to prevent the stimulated growth of breast tumors by environmental estrogens. In this context, the inhibitory action of curcumin and a combination of curcumin and isoflavonoids were studied in ER-positive human breast cancer cells (MCF-7 and T47D) and ER-negative MDA-MB-231 cells induced by the pesticide o,p'-DDT and the environmental pollutants 4-nonylphenol and 4-octylphenol. The median inhibitory concentration (IC50) for curcumin in T47D cells was 10 microM when measured at either a 48-hr or a 6-day incubation time. The IC50 value for curcumin was within the 8-10 microM range for inhibiting the growth of T47D cells induced by a 10- microM concentration each of 4-nonylphenol, 4-octylphenol, and o, p'-DDT. The IC50 for curcumin in MCF-7 cells induced by 10 microM of either o,p'-DDT, 4-octylphenol, or 4-nonylphenol were 9, 39, and >50 microM, respectively. A combination of curcumin and isoflavonoids was able to inhibit the induced growth of ER-positive cells up to 95%. For MDA-MB-231 cells, the IC50 for curcumin was 17 microM, which was reduced to 11 microM in the presence of 25 microM genistein. Curcumin and genistein induce drastic changes in the morphological shape of both ER-positive and ER-negative cells. Data presented here indicate that a mixture of curcumin and isoflavonoids is the most potent inhibitor against the growth of human breast tumor cells. These data suggest that combinations of natural plant compounds may have preventive and therapeutic applications against the growth of breast tumors induced by environmental estrogens

Competitive inhibition by genistein and ATP dependence of daunorubicin transport in intact MRP overexpressing human small cell lung cancer cells.

Versantvoort CH, Broxterman HJ, Lankelma J, et al.

Biochem Pharmacol. 1994 Sep 15; 48(6):1129-36.

In several multidrug resistant tumor cell lines without overexpression of P-glycoprotein (non-Pgp MDR), a decreased accumulation of drugs has been shown to contribute to resistance. We have recently reported that daunorubicin (DNR) accumulation was decreased in the multidrug resistance-associated protein overexpressing GLC4/ADR non-Pgp MDR small cell lung cancer cell line due to an enhanced energy-dependent efflux which could be inhibited by the isoflavonoid genistein. The purpose of this work was 2-fold: (i) to investigate the mechanism by which genistein inhibits the DNR efflux in the GLC4/ADR cells; and (ii) to characterize the dependence of DNR transport on ATP concentration in intact GLC4/ADR cells. The active transport of DNR in GLC4/ADR cells appeared to be a saturable process with an apparent Km of DNR of 1.4 +/- 0.4 microM. Genistein increased the apparent Km value of DNR, suggesting that this agent is a competitive inhibitor of DNR transport. These data provide additional evidence that energy-dependent DNR transport in GLC4/ADR cells is a protein-mediated process. In addition, genistein decreased cellular ATP concentration in a dose-dependent manner in sensitive as well as in resistant cells. Marked inhibition of DNR transport activity in intact GLC4/ADR cells was found when cellular ATP concentration was decreased below 2 mM by sodium azide or 2-deoxy-D-glucose. Thus, since DNR transport in intact GLC4/ADR is already inhibited at modest cellular ATP depletion, a limitation in ATP supply might open ways to make MDR cells more susceptible to drug toxicity

Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety.

Vieth R.

Am J Clin Nutr. 1999 May; 69(5):842-56.

For adults, the 5-microg (200 IU) vitamin D recommended dietary allowance may prevent osteomalacia in the absence of sunlight, but more is needed to help prevent osteoporosis and secondary hyperparathyroidism. Other benefits of vitamin D supplementation are implicated epidemiologically: prevention of some cancers, osteoarthritis progression, multiple sclerosis, and hypertension. Total-body sun exposure easily provides the equivalent of 250 microg (10000 IU) vitamin D/d, suggesting that this is a physiologic limit. Sailors in US submarines are deprived of environmentally acquired vitamin D equivalent to 20-50 microg (800-2000 IU)/d. The assembled data from many vitamin D supplementation studies reveal a curve for vitamin D dose versus serum 25-hydroxyvitamin D [25(OH)D] response that is surprisingly flat up to 250 microg (10000 IU) vitamin D/d. To ensure that serum 25(OH)D concentrations exceed 100 nmol/L, a total vitamin D supply of 100 microg (4000 IU)/d is required. Except in those with conditions causing hypersensitivity, there is no evidence of adverse effects with serum 25(OH)D concentrations or = 1000 microg (40000 IU)/d. Because vitamin D is potentially toxic, intake of >25 microg (1000 IU)/d has been avoided even though the weight of evidence shows that the currently accepted, no observed adverse effect limit of 50 microg (2000 IU)/d is too low by at least 5-fold

Conjugated linoleic acid suppresses the growth of human breast adenocarcinoma cells in SCID mice.

Visonneau S, Cesano A, Tepper SA, et al.

Anticancer Res. 1997 Mar; 17(2A):969-73.

Conjugated linoleic acid (CLA), which is mainly derived from dairy products, has been shown both in vitro and in animal models to have strong anti-tumor activity. Particular effects were observed on the growth and metastatic spread of transplantable mammary tumors. In this study, we examined the effect of dietary CLA on the growth of human breast adenocarcinoma cells in severe combined immunodeficient (SCID) mice. Mice were fed 1% CLA for two weeks prior to subcutaneous inoculation of 10(7) MDA-MB468 cells and throughout the study. Dietary CLA inhibited local tumor growth by 73% and 30% at 9 and 14 weeks post-inoculation, respectively. Moreover, CLA completely abrogated the spread of breast cancer cells to lungs, peripheral blood, and bone marrow. These results indicate the ability of dietary CLA to block both the local growth and systemic spread of human breast cancer via mechanisms independent of the host immune system

Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation.

Vlahopoulos S, Boldogh I, Casola A, et al.

Blood. 1999 Sep 15; 94(6):1878-89.

Tumor necrosis factor alpha (TNFalpha) is a pluripotent activator of inflammation by inducing a proinflammatory cytokine cascade. This phenomenon is mediated, in part, through inducible expression of the CXC chemokine, interleukin-8 (IL-8). In this study, we investigate the role of TNFalpha-inducible reactive oxygen species (ROS) in IL-8 expression by "monocyte-like" U937 histiocytic lymphoma cells. TNFalpha is a rapid activator of IL-8 gene expression by U937, producing a 50-fold induction of mRNA within 1 hour of treatment. In gene transfection assays, the effect of TNFalpha requires the presence of an inducible nuclear factor-kappaB (NF-kappaB) (Rel A) binding site in the IL-8 promoter. TNFalpha treatment induces a rapid translocation of the 65 kD transcriptional activator NF-kappaB subunit, Rel A, whose binding in the nucleus occurs before changes in intracellular ROS. Pretreatment (or up to 15 minutes posttreatment) relative to TNFalpha with the antioxidant dimethyl sulfoxide (DMSO) (2% [vol/vol]) blocks 80% of NF-kappaB-dependent transcription. Surprisingly, however, DMSO has no effect on inducible Rel A binding. Similar selective effects on NF-kappaB transcription are seen with the unrelated antioxidants, N-acetylcysteine (NAC) and vitamin C. These data indicate that TNFalpha induces a delayed ROS-dependent signalling pathway that is required for NF-kappaB transcriptional activation and is separable from that required for its nuclear translocation. Further definition of this pathway will yield new insights into inflammation initiated by TNFalpha signalling

Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation.

Vlahopoulos S, Boldogh I, Casola A, et al.

Blood. 1999 Sep 15; 94(6):1878-89.

Tumor necrosis factor alpha (TNFalpha) is a pluripotent activator of inflammation by inducing a proinflammatory cytokine cascade. This phenomenon is mediated, in part, through inducible expression of the CXC chemokine, interleukin-8 (IL-8). In this study, we investigate the role of TNFalpha-inducible reactive oxygen species (ROS) in IL-8 expression by "monocyte-like" U937 histiocytic lymphoma cells. TNFalpha is a rapid activator of IL-8 gene expression by U937, producing a 50-fold induction of mRNA within 1 hour of treatment. In gene transfection assays, the effect of TNFalpha requires the presence of an inducible nuclear factor-kappaB (NF-kappaB) (Rel A) binding site in the IL-8 promoter. TNFalpha treatment induces a rapid translocation of the 65 kD transcriptional activator NF-kappaB subunit, Rel A, whose binding in the nucleus occurs before changes in intracellular ROS. Pretreatment (or up to 15 minutes posttreatment) relative to TNFalpha with the antioxidant dimethyl sulfoxide (DMSO) (2% [vol/vol]) blocks 80% of NF-kappaB-dependent transcription. Surprisingly, however, DMSO has no effect on inducible Rel A binding. Similar selective effects on NF-kappaB transcription are seen with the unrelated antioxidants, N-acetylcysteine (NAC) and vitamin C. These data indicate that TNFalpha induces a delayed ROS-dependent signalling pathway that is required for NF-kappaB transcriptional activation and is separable from that required for its nuclear translocation. Further definition of this pathway will yield new insights into inflammation initiated by TNFalpha signalling

Risk modification in lung cancer by a dietary intake of preserved foods and soyfoods: findings from a case-control study in Okinawa, Japan.

Wakai K, Ohno Y, Genka K, et al.

Lung Cancer. 1999 Sep; 25(3):147-59.

To disclose the association of dietary intake of preserved foods and soyfoods with lung cancer risk, we analyzed the data from a case-control study conducted in Okinawa, Japan, from 1988 to 1991. The analysis, based on 333 cases and 666 age-, sex- and residence-matched population controls, provided the following major findings. (1) The more the miso soup intake, the higher the risk (test for trend: P = 0.001 for males; P = 0.043 for females). (2) Frequent intake of pickles (excluding salted fish) tended to be linked with an elevated risk in males. The adjusted odds ratio (OR) for once or twice per week or more, relative to less than once a month was 1.88 (95% confidence interval (CI): 1.26-2.81). (3) Frequent intake of soybeans was associated with a decreased risk in men (OR: 0.63, 95% CI: 0.40-0.98 for once or twice per week or more, relative to less than once a month). (4) Daily consumers of tofu were at a decreased risk, particularly for squamous cell carcinoma; the OR (95% CI) being 0.55 (0.34-0.89) in males and 0.14 (0.02-0.89) in females. These findings suggested deleterious effects of preserved foods and protective ones of soyfoods rich in isoflavones

Phytoestrogen concentration determines effects on DNA synthesis in human breast cancer cells.

Wang C, Kurzer MS.

Nutr Cancer. 1997; 28(3):236-47.

Thirteen isoflavonoids, flavonoids, and lignans, including some known phytoestrogens, were evaluated for their effects on DNA synthesis in estrogen-dependent (MCF-7) and -independent (MDA-MB-231) human breast cancer cells. Treatment for 24 hours with most of the compounds at 20-80 microM sharply inhibited DNA synthesis in MDA-MB-231 cells. In MCF-7 cells, on the other hand, biphasic effects were seen. At 0.1-10 microM, coumestrol, genistein, biochanin A, apigenin, luteolin, kaempferol, and enterolactone induced DNA synthesis 150-235% and, at 20-90 microM, inhibited DNA synthesis by 50%. Treatment of MCF-7 cells for 10 days with genistein or coumestrol showed continuous stimulation of DNA synthesis at low concentrations. Time-course experiments with genistein in MCF-7 cells showed effects to be reversed by 48-hour withdrawal of genistein at most concentrations. Induction of DNA synthesis in MCF-7 cells, but not in MDA-MB-231 cells, is consistent with an estrogenic effect of these compounds. Inhibition of estrogen-dependent and -independent breast cancer cells at high concentrations suggests additional mechanisms independent of the estrogen receptor. The current focus on the role of phytoestrogens in cancer prevention must take into account the biphasic effects observed in this study, showing inhibition of DNA synthesis at high concentrations but induction at concentrations close to probable levels in humans

Suppression of invasion and MMP-9 expression in NIH 3T3 and v-H-Ras 3T3 fibroblasts by lovastatin through inhibition of ras isoprenylation.

Wang IK, Lin-Shiau SY, Lin JK.

Oncology. 2000 Sep; 59(3):245-54.

Lovastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, was found to block the synthesis of cholesterol and to affect posttranslational modification or isoprenylation, which is essential for membrane localization and biological activity of several proteins including Ras in the signal transduction pathway. Ras activates a multitude of downstream activities with roles in cellular processing, including invasion and metastasis. We investigated the anti-invasive activity of lovastatin in NIH 3T3 and v-H-Ras-transformed NIH 3T3 (v-H-Ras 3T3) cells. Lovastatin suppressed cell invasion in vitro in a dose-dependent manner. By zymographic assay, a decrease in matrix metalloproteinase-9 (MMP-9) activity but not matrix metalloproteinase-2 (MMP-2) activity by lovastatin was detected. RT-PCR demonstrated a reduction in gene expression of MMP-9 after treatment with lovastastin. To confirm the lovastatin-induced down-regulation of MMP-9 expression, we transfected an MMP-9/luciferase reporter vector, under MMP-9 promoter control, into both NIH 3T3 and v-H-Ras 3T3. A reduction in luciferase activity was observed with lovastatin treatment. In addition, lovastatin also reduced AP-1 and NFkappaB binding activities. These anti-invasive features were attenuated by the presence of mevalonate. These results suggest that down-regulation of MMP-9 contributes to the anti-invasive activity of lovastatin. Furthermore, we added exogenous mevalonate, which enhances the potency of cell invasion, and Ras farnesyltransferase inhibitor (manumycin A), which inhibits the potency of cell invasion. In accordance, Western blot analysis showed that lovastatin decreased membrane localization of Ras proteins. These data indicate that the anti-invasion activity of lovastatin happens through a decrease in Ras isoprenylation and functions

Long-term exposure of HL60 cells to 1,25-dihydroxyvitamin D3 reduces their tumorigenicity: a model for cancer chemoprevention.

Wang X, Ponzio NM, Studzinski GP.

Proc Soc Exp Biol Med. 1997 Sep; 215(4):399-404.

Several lines of evidence suggest that 1,25-dihydroxyvitamin D3 (1,25D3) may be important in chemoprevention of human cancer. Here, we show that human promyelocytic leukemia cells HL60 cultured in the presence of 30 nM 1,25D3 (30A cells) for 3 years exhibited a reduced rate of tumor growth when injected into nu/nu mice, while cells grown in 40 nM 1,25D3 (40AF cells) failed to form detectable tumors in 11 out of the 12 inoculated mice, interestingly, both 30A and 40AF cells grew approximately twice as fast as the parental HL60-G cells under tissue culture conditions, even in the presence of 1,25D3, to which they developed resistance. Tests of the susceptibility of these cells to natural killer (NK) cell cytotoxicity showed that 40AF, but not HL60-G or 30A cells, were targets for the murine spleen NK cells. However, lysis of 30A cells was also detected when human NK cells were used in this assay, though the effector-to-target cell ratio necessary to obtain significant lysis above background levels was higher for 30A (80:1) than for 40AF (10:1) cells. These results suggest a mechanism for the reported chemopreventive effects of sunlight-generated 1,25D3 or dietary vitamin D3

Initiation and post-initiation chemopreventive effects of diallyl sulfide in esophageal carcinogenesis.

Wargovich MJ, Imada O, Stephens LC.

Cancer Lett. 1992 May 30; 64(1):39-42.

Diallyl sulfide (DAS), one of a number of organosulfur compounds accounting for the flavor and smell associated with garlic, has been shown to inhibit a number of chemically induced forms of cancer. In this study, DAS was examined for its chemopreventive effects in both the initiation and post-initiation phases of nitrosomethylbenzylamine-induced esophageal carcinogenesis in the Sprague-Dawley rat. Although highly inhibitory during initiation, DAS is ineffective when given after the carcinogen. DAS, though not effective as a preventive in post-initiation, was not found to promote esophageal carcinogenesis

Pretreatment of young pigs with vitamin E attenuates the elevation in plasma interleukin-6 and cortisol caused by a challenge dose of lipopolysaccharide.

Webel DM, Mahan DC, Johnson RW, et al.

J Nutr. 1998 Oct; 128(10):1657-60.

The effect of a short-term, high-dose intramuscular injection of d-alpha-tocopherol was studied in pigs given a challenge dose of lipopolysaccharide (LPS). Twenty-four pigs surgically fitted with jugular catheters were used in a 2 x 2 factorial design. Pigs received either 0 or 600 mg d-alpha-tocopherol by intramuscular injection for 3 d before receiving an intraperitoneal injection of saline containing either 0 or 5 microgram/kg body weight Escherichia coli LPS. Blood was collected from indwelling jugular catheters at 0, 1, 2, 4, 6, 8, 12 and 24 h after injection of LPS. Plasma alpha-tocopherol levels were 13-fold greater (P < 0.01) at time 0 in pigs pretreated with 600 mg d-alpha-tocopherol (9.9 +/- 1.3 mg/L) than in those not treated with d-alpha-tocopherol (0.74 +/- 0.09 mg/L). Injection of LPS increased (P < 0.05) plasma levels of interleukin-6 (IL-6) and cortisol at 2-h postinjection, regardless of vitamin E treatment. However, pigs that received alpha-tocopherol before the LPS challenge had substantially lower (P < 0.05) peak levels of IL-6 and cortisol than pigs not receiving alpha-tocopherol. These results suggest that supplementation with a surfeit level of vitamin E reduces the response of pigs to endotoxin

Human lactoferrin: a novel therapeutic with broad spectrum potential.

Weinberg ED.

J Pharm Pharmacol. 2001 Oct; 53(10):1303-10.

Lactoferrin (Lf), a natural defence iron-binding protein, has been found to possess antibacterial, antimycotic, antiviral, antineoplastic and anti-inflammatory activity. The protein is present in exocrine secretions that are commonly exposed to normal flora: milk, tears, nasal exudate, saliva, bronchial mucus, gastrointestinal fluids, cervico-vaginal mucus and seminal fluid. Additionally, Lf is a major constituent of the secondary specific granules of circulating polymorphonuclear neutrophils (PMNs). The apoprotein is released on degranulation of the PMNs in septic areas. A principal function of Lf is that of scavenging free iron in fluids and inflamed areas so as to suppress free radical-mediated damage and decrease the availability of the metal to invading microbial and neoplastic cells. Mechanisms of action of Lf in addition to iron deprivation are also described. Administration of exogenous human or bovine Lf to hosts with various infected or inflamed sites has resulted in some prophylactic or therapeutic effects. However, an adverse response to the protein might occur if it were to stimulate antibody production or if it were to provide iron to the invading pathogen. The recombinant form of human Lf has become available and development of the product for use in a wide range of medical conditions can now be anticipated

Antiproliferative effect of the garlic compound S-allyl cysteine on human neuroblastoma cells in vitro.

Welch C, Wuarin L, Sidell N.

Cancer Lett. 1992 Apr 30; 63(3):211-9.

A variety of compounds derived from garlic bulbs have been shown in animal systems to possess anticancer properties. However, little information is available regarding the effectiveness of garlic in the prevention or treatment of human cancers. In the current study, we have assessed the ability of S-allyl cysteine (SAC), a derivative of aged garlic extract, to affect the proliferation and differentiation of LA-N-5 human neuroblastoma cells in vitro. Time-and dose-dependent inhibition of cell grow was observed in cultures treated with SAC for at least 2 days, with a half-maximal response at approximately 600 micrograms/ml. SAC treatment was unable to induce differentiation in neuroblastoma cells as assessed by morphological, biochemical and molecular markers. In addition, SAC was unable to potentiate the effects of retinoic acid and 8-bromo-cyclic AMP, agents known to promote differentiation of LA-N-5 cells. Our results indicate that SAC can inhibit human neuroblastoma cell growth in vitro. However, the apparent inability of this compound to induce differentiation may limit its therapeutic potential

Total cholesterol and risk of mortality in the oldest old.

Weverling-Rijnsburger AW, Blauw GJ, Lagaay AM, et al.

Lancet. 1997 Oct 18; 350(9085):1119-23.

BACKGROUND: The impact of total serum cholesterol as a risk factor for cardiovascular disease decreases with age, which casts doubt on the necessity for cholesterol-lowering therapy in the elderly. We assessed the influence of total cholesterol concentrations on specific and all-cause mortality in people aged 85 years and over. METHODS: In 724 participants (median age 89 years), total cholesterol concentrations were measured and mortality risks calculated over 10 years of follow-up. Three categories of total cholesterol concentrations were defined: or = 6.5 mmol/L. In a subgroup of 137 participants, total cholesterol was measured again after 5 years of follow-up. Mortality risks for the three categories of total cholesterol concentrations were estimated with a Cox proportional-hazards model, adjusted for age, sex, and cardiovascular risk factors. The primary causes of death were coded according to the International Classification of Diseases (ICD-9). FINDINGS: During 10 years of follow-up from Dec 1, 1986, to Oct 1, 1996, a total of 642 participants died. Each 1 mmol/L increase in total cholesterol corresponded to a 15% decrease in mortality (risk ratio 0.85 [95% CI 0.79-0.91]). This risk estimate was similar in the subgroup of participants who had stable cholesterol concentrations over a 5-year period. The main cause of death was cardiovascular disease with a similar mortality risk in the three total cholesterol categories. Mortality from cancer and infection was significantly lower among the participants in the highest total cholesterol category than in the other categories, which largely explained the lower all-cause mortality in this category. INTERPRETATION: In people older than 85 years, high total cholesterol concentrations are associated with longevity owing to lower mortality from cancer and infection. The effects of cholesterol-lowering therapy have yet to be assessed

Selenium and Cancer: New Views.

Whanger PD.

New Views 1998. 2004

My experience with DMSO and cancer.

Whitaker J.

Health & Healing: Tomorrow's Medicine Today. 1995; 5(8):3.

The antitumor effect of postoperative treatment with genistein alone or combined with cyclophosphamide in mice bearing transplantable tumors.

Wietrzyk J, Opolski A, Madej J, et al.

Acta Pol Pharm. 2000 Nov; 57 Suppl:5-8.

Genistein has been shown to be an inhibitor of tumor growth as well in vitro as in vivo. In addition to its antitumor effect, genistein reveals the antimetastatic and antiangiogenic properties. In this paper we described the results of our studies on the antimetastatic activity of genistein alone or combined with cyclophosphamide (CY) in mice which before this treatment were exposed to surgical excision of the primary tumor. Three transplantable subcutaneously growing mouse tumors were applied: Lewis lung cancer (LL2), B16F-10 melanoma and 16/C mammary cancer. The antitumor and antimetastatic effect was evaluated by the estimation of a number of lung colonies and a number of primary tumor recurrence as compared to the control mice exposed to the s.c. tumor extirpation only. Twenty days after the surgery, an average of 52 lung tumor colonies per mouse were detected in control mice bearing LL2 cancer. The treatment with genistein resulted in the reduction of the lung colonies to 24 per mouse. The treatment with CY reduced the number of lung colonies to 12 (p < 0.05) and combined treatment with both agents to 4 (p < 0.05). The percentage of primary tumor recurrence was 25, 86, 67 and 80% in the control, genistein treated, CY treated, and genistein + CY treated mice, respectively. Twenty days after the surgery, no lung metastases in the control mice bearing B16F-10 melanoma were observed. The percentage of primary tumor recurrence in the control, genistein treated, CY treated and genistein + CY treated mice was: 86, 29, 57 and 67% respectively. Two different protocols of the treatment with genistein were applied in 16/C mammary cancer model. In the first one genistein was injected before and in the other after surgical excision of tumor. The histological examination revealed the presence of lung metastases in all, untreated and treated, according to both protocols groups of mice. The percentage of primary tumor recurrence in the control mice, genistein treated according to the protocol I, and II was: 100, 40, and 40%, respectively

Antiangiogenic and antitumour effects in vivo of genistein applied alone or combined with cyclophosphamide.

Wietrzyk J, Boratynski J, Grynkiewicz G, et al.

Anticancer Res. 2001 Nov; 21(6A):3893-6.

The antitumour and antiangiogenic effects in vivo of genistein, applied alone or in combined therapy with cyclophosphamide, in the Lewis lung carcinoma (LL2) and B16 melanoma mouse tumour models, were analysed. Our own new method, allowing quantification of the volume of blood present in tumour tissue, enabled estimation of the degree of vascularization. Tumour cells entrapped in alginate beads were injected subcutaneously into mice. The quantification of alginate implant vascularization was performed with 125I-labeled mouse albumin injected intravenously. In mice bearing transplantable Lewis lung cancer the additive antiangiogenic, but not cytostatic, effect of genistein combined with cyclophosphamide (CY) was observed, since the treatment with genistein alone reduced tumour blood supply in 35% (tumour weight in 36%), with CY in 38% (tumour weight in 70%) and with both compounds in 61% (tumour weight in 75%). In the B16 melanoma model the respective values were: 60 and 44% for genistein, 83 and 79% for CY and 76 and 74% for combined treatment. These results indicate a higher antiangiogenic rather than cytostatic effect of genistein in both mouse tumour models applied

Serum alpha-tocopherol and subsequent risk of lung cancer among male smokers.

Woodson K, Tangrea JA, Barrett MJ, et al.

J Natl Cancer Inst. 1999 Oct 20; 91(20):1738-43.

BACKGROUND: Higher blood levels of alpha-tocopherol, the predominant form of vitamin E, have been associated in some studies with a reduced risk of lung cancer, but other studies have yielded conflicting results. To clarify this association, we examined the relationship between prospectively collected serum alpha-tocopherol and lung cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort. METHODS: The ATBC Study was a randomized, clinical trial of 29 133 white male smokers from Finland who were 50-69 years old and who had received alpha-tocopherol (50 mg), beta-carotene (20 mg), both, or neither daily for 5-8 years. Data regarding medical histories, smoking, and dietary factors were obtained at study entry, as was a serum specimen for baseline alpha-tocopherol determination. alpha-Tocopherol measurements were available for 29 102 of the men, among whom 1144 incident cases of lung cancer were diagnosed during a median observation period of 7.7 years. The association between alpha-tocopherol and lung cancer was evaluated with the use of multivariate proportional hazards regression. RESULTS: A 19% reduction in lung cancer incidence was observed in the highest versus lowest quintile of serum alpha-tocopherol (relative risk = 0.81; 95% confidence interval = 0. 67-0.97). There was a stronger inverse association among younger men (<60 years), among men with less cumulative tobacco exposure (<40 years of smoking), and possibly among men receiving alpha-tocopherol supplementation. CONCLUSIONS: In the ATBC Study cohort, higher serum alpha-tocopherol status is associated with lower lung cancer risk; this relationship appears stronger among younger persons and among those with less cumulative smoke exposure. These findings suggest that high levels of alpha-tocopherol, if present during the early critical stages of tumorigenesis, may inhibit lung cancer development

Tofu and risk of breast cancer in Asian-Americans.

Wu AH, Ziegler RG, Horn-Ross PL, et al.

Cancer Epidemiol Biomarkers Prev. 1996 Nov; 5(11):901-6.

Breast cancer rates among Asian-Americans are lower than those of US whites but considerably higher than rates prevailing in Asia. It is suspected that migration to the US brings about a change in endocrine function among Asian women, although reasons for this change remain obscure. The high intake of soy in Asia and its reduced intake among Asian-Americans has been suggested to partly explain the increase of breast cancer rates in Asian-Americans. We conducted a population-based case-control study of breast cancer among Chinese-, Japanese-, and Filipino-American women in Los Angeles County MSA, San Francisco Oakland MSA, and Oahu, Hawaii. Using a common questionnaire which assessed frequency of intake of some 90 food items, 597 Asian-American women (70% of those eligible) diagnosed with incident, primary breast cancer during 1983-1987 and 966 population-based controls (75% of those eligible) were interviewed. Controls were matched to cases on age, ethnicity, and area of residence. This analysis compares usual adult intake of soy (estimated primarily from tofu intake) among breast cancer cases and control women. After adjustment for age, ethnicity and study area, intake of tofu was more than twice as high among Asian-American women born in Asia (62 times per year) compared to those born in the US (30 times per year). Among migrants, intake of tofu decreased with years of residence in the US. Risk of breast cancer decreased with increasing frequency of intake of tofu after adjustment for age, study area, ethnicity, and migration history; the adjusted OR associated with each additional serving per week was 0.85 (95% CI = 0.74-0.99). The protective effect of high tofu intake was observed in pre- and postmenopausal women. This association remained after adjustment for selected dietary factors and menstrual and reproductive factors. However, this study was not designed specifically to investigate the role of soy intake and our assessment of soy intake may be incomplete. We cannot discount the possibility that soy intake is a marker of other protective aspects of Asian diet and/or Asian lifestyle

Curcumin inhibits IL1 alpha and TNF-alpha induction of AP-1 and NF-kB DNA-binding activity in bone marrow stromal cells.

Xu YX, Pindolia KR, Janakiraman N, et al.

Hematopathol Mol Hematol. 1997; 11(1):49-62.

We have previously demonstrated that anti-inflammatory and antioxidant compound curcumin (diferuloyl-methane) inhibits the expression of monocyte chemoattractant protein-1 (MCP-1/JE) in bone marrow stromal cells by suppressing the transcriptional activity of the MCP-1/JE gene. Since both AP-1 (TRE) and NF-kB (kB) binding motifs are present in the promoter of MCP-1/JE gene, we examined the effect of curcumin on IL1 alpha- and TNF-alpha-induced activation of ubiquitous transcription factors AP-1 and NF-kB by electrophoretic mobility shift assay and Western blotting. IL1 alpha and TNF-alpha rapidly induced both AP-1 and NF-kB DNA binding activities in +/+(-)1.LDA11 stromal cells. However, treatment of these cells with curcumin blocked the activation of AP-1 and NF-kB by both cytokines. These data suggest that inhibition of MCP-1/JE transcription by curcumin involves blocking of AP-1 and NF-kB activation by IL1 alpha or TNF-alpha

Chewing-gum flavor affects measures of global complexity of multichannel EEG.

Yagyu T, Wackermann J, Kinoshita T, et al.

Neuropsychobiology. 1997; 35(1):46-50.

Global complexity of spontaneous brain electric activity was studied before and after chewing gum without flavor and with 2 different flavors. One-minute, 19-channel, eyes-closed electroencephalograms (EEG) were recorded from 20 healthy males before and after using 3 types of chewing gum: regular gum containing sugar and aromatic additives, gum containing 200 mg theanine (a constituent of Japanese green tea), and gum base (no sugar, no aromatic additives); each was chewed for 5 min in randomized sequence. Brain electric activity was assessed through Global Omega (Omega)-Complexity and Global Dimensional Complexity (GDC), quantitative measures of complexity of the trajectory of EEG map series in state space; their differences from pre-chewing data were compared across gum-chewing conditions. Friedman Anova (p < 0.043) showed that effects on Omega-Complexity differed significantly between conditions and differences were maximal between gum base and theanine gum. No differences were found using GDC. Global Omega-Complexity appears to be a sensitive measure for subtle, central effects of chewing gum with and without flavor

Antiproliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract.

Yanagihara K, Ito A, Toge T, et al.

Cancer Res. 1993 Dec 1; 53(23):5815-21.

Seven isoflavones, biochanin A, daidzein, genistein, genistin, prunectin, puerarin, and pseudobaptigenin were tested for cytostatic and cytotoxic effects on 10 newly established cancer cell lines of the human gastrointestinal origin. Proliferation of HSC-41E6, HSC-45M2, and SH101-P4 stomach cancer cell lines was strongly inhibited by biochanin A and genistein, whereas other stomach, esophageal, and colon cancer lines were moderately suppressed by both compounds. Biochanin A and genistein were cytostatic at low concentrations (< 20 micrograms/ml for biochanin A, 40 micrograms/ml for biochanin A, > 20 micrograms/ml for genistein). DNA fragmentation was observed at cytotoxic doses of both compounds, indicating the apoptotic mode of cell death by the compounds. Chromatin condensation and nuclear fragmentation of each cell line were also observed. The advent of apoptosis was dose dependent for both isoflavones. Biochanin A suppressed tumor growth of HSC-45M2 and HSC-41E6 lines in athymic nude mice. Our results suggest that two of isoflavone derivatives, biochanin A and genistein, inhibit the cell growth of stomach cancer cell lines in vitro through activation of a signal transduction pathway for apoptosis. Moreover, in vivo experiments demonstrate that biochanin A can be used as an anticancer agent

Population-based, case-control study of blood C-peptide level and breast cancer risk.

Yang G, Lu G, Jin F, et al.

Cancer Epidemiol Biomarkers Prev. 2001 Nov; 10(11):1207-11.

Insulin resistance has been suggested to be associated with an increased risk of breast cancer. Insulin sensitivity can be measured using blood C-peptide, a marker of insulin secretion. It is thus conceivable that blood C-peptide levels may be associated with breast cancer risk. To evaluate this hypothesis, we analyzed data from a subset (143 case-control pairs matched by age and status of menopause) of women who participated in the Shanghai Breast Cancer Study, a population-based, case-control study conducted in Shanghai during 1996-1998. Fasting blood samples were collected from study subjects to measure C-peptide levels. For cancer patients, the samples were collected before any cancer therapy. Conditional logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals related to C-peptide levels. Breast cancer risk was increased with increasing levels of C-peptide (trend test, P = 0.01), with an odds ratio of 2.7 (95% confidence interval = 1.2-5.9) observed for the highest compared with the lowest tertile of C-peptide concentration after adjusting for body mass index and age at the first live birth. The risk was not altered after fully adjusting for other traditional risk factors for breast cancer. This positive association was observed in both pre and postmenopausal women and regardless of the levels of waist-to-hip ratio or body mass index. The results from this study were consistent with the insulin-resistance hypothesis for breast cancer and suggest that increased levels of C-peptide may contribute to the development of breast cancer

Bovine lactoferrin and lactoferricin, a peptide derived from bovine lactoferrin, inhibit tumor metastasis in mice.

Yoo YC, Watanabe S, Watanabe R, et al.

Jpn J Cancer Res. 1997 Feb; 88(2):184-90.

We investigated the effect of a bovine milk protein, lactoferrin (LF-B), and a pepsin-generated peptide of LF-B, lactoferricin (Lfcin-B), on inhibition of tumor metastasis produced by highly metastatic murine tumor cells, B16-BL6 melanoma and L5178Y-ML25 lymphoma cells, using experimental and spontaneous metastasis models in syngeneic mice. The subcutaneous (s.c.) administration of bovine apo-lactoferrin (apo-LF-B, 1 mg/mouse) and Lfcin-B (0.5 mg/mouse) 1 day after tumor inoculation significantly inhibited liver and lung metastasis of L5178Y-ML25 cells. However, human apolactoferrin (apo-LF-H) and bovine holo-lactoferrin (holo-LF-B) at the dose of 1 mg/mouse failed to inhibit tumor metastasis of L5178Y-ML25 cells. Similarly, the s.c. administration of apo-LF-B as well as Lfcin-B, but not apo-LF-H and holo-LF-B, 1 day after tumor inoculation resulted in significant inhibition of lung metastasis of B16-BL6 cells in an experimental metastasis model. Furthermore, in in vivo analysis for tumor-induced angiogenesis, both apo-LF-B and Lfcin-B inhibited the number of tumor-induced blood vessels and suppressed tumor growth on day 8 after tumor inoculation. However, in a long-term analysis of tumor growth for up to 21 days after tumor inoculation, single administration of apo-LF-B significantly suppressed the growth of B16-BL6 cells throughout the examination period, whereas Lfcin-B showed inhibitory activity only during the early period (8 days). In spontaneous metastasis of B16-BL6 melanoma cells, multiple administration of both apo-LF-B and Lfcin-B into tumor-bearing mice significantly inhibited lung metastasis produced by B16-BL6 cells, though only apo-LF-B exhibited an inhibitory effect on tumor growth at the time of primary tumor amputation (on day 21) after tumor inoculation. These results suggest that apo-LF-B and Lfcin-B inhibit tumor metastasis through different mechanisms, and that the inhibitory activity of LF-B on tumor metastasis may be related to iron (Fe3+)-saturation

Effects of glutamine supplements and radiochemotherapy on systemic immune and gut barrier function in patients with advanced esophageal cancer.

Yoshida S, Matsui M, Shirouzu Y, et al.

Ann Surg. 1998 Apr; 227(4):485-91.

OBJECTIVE: The objective of this study was to determine whether oral glutamine supplements can protect lymphocyte and gut barrier function in patients with advanced esophageal cancer undergoing radiochemotherapy. SUMMARY BACKGROUND DATA: Glutamine supplements improved protein metabolism in tumor bearing rats who underwent chemotherapy and reduced the toxicity of chemotherapy through an enhancement of glutathione production in rats. METHODS: Thirteen patients with esophageal cancer were randomly placed in either a control or a glutamine group. Glutamine was administered orally (30 g/day) at the start of radiochemotherapy and for the subsequent 28 days. All patients underwent mediastinal irradiation and chemotherapy consisting of 5-fluorouracil and cisplatin. The lymphocyte count was determined, and blast formation was assessed after stimulation with phytohemagglutinin and concanavalin A. Gut barrier function was assessed by measuring the total amount of phenolsulfonphthalein excreted in the urine after the oral administration of phenolsulfonphthalein. RESULTS: Glutamine supplements prevented a reduction in the lymphocyte count (control: 567 +/- 96/mm3 vs. glutamine: 1007 +/- 151, p < 0.05), and blast formation of lymphocyte (phytohemagglutinin, control: 19478 +/- 2121 dpm vs. glutamine: 33860 +/- 1433, p < 0.01, concanavalin A, control: 19177 +/- 1897 dpm vs. glutamine: 29473 +/- 2302, p < 0.01), and amount of phenolsulfonphthalein excretion in the urine was greater with control than with glutamine group (control: 15.4 +/- 2.4% vs. glutamine: 7.4 +/- 1.2, p < 0.05) 7 days after the initiation of radiochemotherapy. CONCLUSIONS: Oral glutamine supplementation protects lymphocytes and attenuates gut permeability in patients with esophageal cancer during radiochemotherapy

[Effect of cimetidine with chemotherapy on stage IV colorectal cancer].

Yoshimatsu K, Ishibashi K, Hashimoto M, et al.

Gan To Kagaku Ryoho. 2003 Oct; 30(11):1794-7.

We herein report the result of a prospective study to investigate the efficacy of cimetidine administration in conjunction with chemotherapy for stage IV colorectal cancer. Sixty-two patients treated with Leucovorin/5-fluorouracil therapy were enrolled from 1996 to 2000. Both groups were well matched for pre-treatment characteristics. There was no difference in survival in cur B patients. However, the cimetidine group had significantly prolonged survival in the patients with cur C or non-resectable carcinoma. This study suggests that cimetidine treatment may improve the survival of patients with non-curative surgery for stage IV colorectal cancer

Flavonoids can block PSA production by breast and prostate cancer cell lines.

Zand RSR.

Clin Chim Acta. 2002;(317):17-26.

Curcumin inhibits cyclooxygenase-2 transcription in bile acid- and phorbol ester-treated human gastrointestinal epithelial cells.

Zhang F.

Carcinogenesis 1999 Mar. 1999; 20(3):445-51.

Vitamin C inhibits the growth of a bacterial risk factor for gastric carcinoma: Helicobacter pylori.

Zhang HM, Wakisaka N, Maeda O, et al.

Cancer. 1997 Nov 15; 80(10):1897-903.

BACKGROUND: Helicobacter pylori infection is a risk factor for gastric carcinogenesis. High dietary vitamin C intake appears to protect against gastric carcinoma. It has been suggested that vitamin C exerts the protective effect by scavenging free radicals that may be enhanced by H. pylori. However, vitamin C has not been investigated in relation to the direct action on H. pylori. In this study, the authors attempted to clarify this possibility both in vitro and in vivo. METHODS: Susceptibility testing of H. pylori (64 strains) was performed by the agar dilution method. Bactericidal actions were determined by a broth cultivation technique. The effect of vitamin C on in vivo H. pylori colonization was evaluated by using the Mongolian gerbil model. RESULTS: At concentrations of 2048, 512, and 128 microg/mL (minimum inhibitory concentrations [MICs]), vitamin C could inhibit the growth of 90% of the bacterial stains incubated at pH values of 7.4, 6.0, and 5.5, respectively. The broth cultures exposed to the MICs of vitamin C displayed a 1.57 approximately 2.5-log decrease in the number of viable bacteria, and the loss of viability was observed in 24 hours at concentrations 8-fold higher than the MICs. In an in vivo experiment, H. pylori colonies decreased significantly in animals treated with vitamin C after oral administration of vitamin C (10 mg/head/day) for 7 days. CONCLUSIONS: High doses of vitamin C inhibit the growth of H. pylori in vitro as well as in vivo

Laboratory studies of berberine used alone and in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea to treat malignant brain tumors.

Zhang RX, Dougherty DV, Rosenblum ML.

Chin Med J (Engl ). 1990 Aug; 103(8):658-65.

Berberine was evaluated for antitumor activity against malignant brain tumors. In addition, studies on combination of berberine with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) were done. Several experimental approaches were used. In vitro studies were performed on a series of 6 human malignant brain tumor cell lines and rat 9L brain tumor cells (gliosarcoma) by using a colony forming efficiency (CFE) assay. 9L was also evaluated by a sister chromatid exchange (SCE) assay. In addition, in vivo treatment of intracerebral 9L solid brain tumors was analyzed by CFE assay. Berberine used alone at a dose of 150 micrograms/ml showed an average of 91% cell kill (1.08 log kill) for the 6 malignant brain tumor cell lines. On the average, BCNU alone at a dose of 23 microM gave a 43% cell kill (0.24 log kill). Treatment with a combination of berberine and BCNU at 23 microM showed additive effects with an average of 97% cell kill (1.55 log kill). The relative number of SCEs for 9L cells was increased 2.7 times over background following in vitro treatment with 150 micrograms/ml berberine. Following in vivo treatment of animals harboring solid 9L brain tumors with 10 mg/kg of berberine, an 80.9% cell kill (0.69 log kill) was noted. This activity is equivalent to treatment with 1/3 LD10 dose of BCNU (4.44 mg/kg). In vivo combination treatment with berberine and BCNU showed additive cytotoxicity. Using a BCNU-resistant 9L subline (9L-2), treatment with berberine in combination with BCNU also demonstrated additive cytotoxicity. In conclusion, our results indicate that berberine has potent antitumor activity against human and rat malignant brain tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells.

Zhang WJ, Frei B.

FASEB J. 2001 Nov; 15(13):2423-32.

Endothelial activation and monocyte adhesion are initiating steps in atherogenesis thought to be caused in part by oxidative stress. The metabolic thiol antioxidant alpha-lipoic acid has been suggested to be of therapeutic value in pathologies associated with redox imbalances. We investigated the role of (R)-alpha-lipoic acid (LA) vs. glutathione and ascorbic acid in tumor necrosis factor alpha (TNF-alpha) -induced adhesion molecule expression and nuclear factor kappaB (NF-kappaB) signaling in human aortic endothelial cells (HAEC). Preincubation of HAEC for 48 h with LA (0.05-1 mmol/l) dose-dependently inhibited TNF-alpha (10 U/ml) -induced adhesion of human monocytic THP-1 cells, as well as mRNA and protein expression of E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. LA also strongly inhibited TNF-alpha-induced mRNA expression of monocyte chemoattractant protein-1 but did not affect expression of TNF-alpha receptor 1. Furthermore, LA dose-dependently inhibited TNF-alpha-induced IkappaB kinase activation, subsequent degradation of IkappaB, the cytoplasmic NF-kappaB inhibitor, and nuclear translocation of NF-kappaB. In contrast, TNF-alpha-induced NF-kappaB activation and adhesion molecule expression were not affected by ascorbic acid or by manipulating cellular glutathione status with l-2-oxo-4-thiazolidinecarboxylic acid, N-acetyl-l-cysteine, or d,l-buthionine-S,R-sulfoximine. Our data show that clinically relevant concentrations of LA, but neither vitamin C nor glutathione, inhibit adhesion molecule expression in HAEC and monocyte adhesion by inhibiting the IkappaB/NF-kappaB signaling pathway at the level, or upstream, of IkappaB kinase

Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells.

Zhang WJ, Frei B.

FASEB J. 2001 Nov; 15(13):2423-32.

Endothelial activation and monocyte adhesion are initiating steps in atherogenesis thought to be caused in part by oxidative stress. The metabolic thiol antioxidant alpha-lipoic acid has been suggested to be of therapeutic value in pathologies associated with redox imbalances. We investigated the role of (R)-alpha-lipoic acid (LA) vs. glutathione and ascorbic acid in tumor necrosis factor alpha (TNF-alpha) -induced adhesion molecule expression and nuclear factor kappaB (NF-kappaB) signaling in human aortic endothelial cells (HAEC). Preincubation of HAEC for 48 h with LA (0.05-1 mmol/l) dose-dependently inhibited TNF-alpha (10 U/ml) -induced adhesion of human monocytic THP-1 cells, as well as mRNA and protein expression of E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. LA also strongly inhibited TNF-alpha-induced mRNA expression of monocyte chemoattractant protein-1 but did not affect expression of TNF-alpha receptor 1. Furthermore, LA dose-dependently inhibited TNF-alpha-induced IkappaB kinase activation, subsequent degradation of IkappaB, the cytoplasmic NF-kappaB inhibitor, and nuclear translocation of NF-kappaB. In contrast, TNF-alpha-induced NF-kappaB activation and adhesion molecule expression were not affected by ascorbic acid or by manipulating cellular glutathione status with l-2-oxo-4-thiazolidinecarboxylic acid, N-acetyl-l-cysteine, or d,l-buthionine-S,R-sulfoximine. Our data show that clinically relevant concentrations of LA, but neither vitamin C nor glutathione, inhibit adhesion molecule expression in HAEC and monocyte adhesion by inhibiting the IkappaB/NF-kappaB signaling pathway at the level, or upstream, of IkappaB kinase

Significant inhibition by the flavonoid antioxidant silymarin against 12-O-tetradecanoylphorbol 13-acetate-caused modulation of antioxidant and inflammatory enzymes, and cyclooxygenase 2 and interleukin-1alpha expression in SENCAR mouse epidermis: implications in the prevention of stage I tumor promotion.

Zhao J, Sharma Y, Agarwal R.

Mol Carcinog. 1999 Dec; 26(4):321-33.

The flavonoid antioxidant silymarin is used clinically in Europe and Asia for the treatment of liver diseases and is sold in the United States and Europe as a dietary supplement. Recently we showed that silymarin possesses exceptionally high cancer-preventive effects in different mouse skin carcinogenesis models and affords strong anticancer effects in human skin, cervical, prostate, and breast carcinoma cells. More recently, we showed that the anti-tumor-promoting effect of silymarin is primarily targeted against stage I tumor promotion in mouse skin (Cancer Res 1999;59:622-632). Based on this recent study, in this report, further investigations were made to identify and define the biochemical and molecular mechanisms of silymarin's effect during stage I tumor promotion in mouse skin. A single topical application of silymarin at 3-, 6-, and 9-mg doses onto SENCAR mouse skin followed 30 min later with 12-O-tetradecanoylphorbol 13-acetate (TPA) at a 3-microg dose resulted in a 76-95% inhibition (P < 0.001) of TPA-caused skin edema. Similarly, these doses of silymarin also showed 39-90%, 29-85%, and 15-67% protection (P < 0.05 or 0.001), against TPA-caused depletion of epidermal superoxide dismutase, catalase, and glutathione peroxidase activity, respectively. Pretreatment of mice with silymarin also produced highly significant inhibition of TPA-caused induction of epidermal lipid peroxidation (47-66% inhibition, P < 0.001) and myeloperoxidase activity (56-100% inhibition, P < 0.001). In additional studies assessing the effect of silymarin on arachidonic acid metabolism pathways involving lipoxygenase and cyclooxygenase (COX), similar doses of silymarin showed highly significant inhibition of TPA-caused induction of epidermal lipoxygenase (49-77% inhibition, P < 0.001) and COX (35-64% inhibition, P < 0.01 or 0.001) activity. Western immunoblot analysis showed that the observed effect of silymarin on COX activity was due to inhibition of TPA-inducible COX-2 with no change in constitutive COX-1 protein levels. In other studies, silymarin also showed dose-dependent inhibition of TPA-caused induction of epidermal interleukin 1alpha (IL-1alpha) protein (39-72% inhibition, P < 0.005 or 0.001) and mRNA expression. Taken together, the results from these biochemical and molecular studies further substantiate our recent observation of silymarin's anti-tumor-promoting effects primarily at stage I tumor promotion. Furthermore, the observed inhibitory effects of silymarin on COX-2 and IL-1alpha should be further explored to develop preventive strategies against those cancers in which these molecular targets play one of the causative roles, such as non-melanoma skin, colon, and breast cancers in humans

Well-done meat intake and the risk of breast cancer.

Zheng W, Gustafson DR, Sinha R, et al.

J Natl Cancer Inst. 1998 Nov 18; 90(22):1724-9.

BACKGROUND: Heterocyclic amines, mutagens formed in meats cooked at high temperatures, have been demonstrated as mammary carcinogens in animals. We conducted a nested, case-control study among 41836 cohort members of the Iowa Women's Health Study to evaluate the potential role of heterocyclic amines and intake of well-done meat in the risk for human breast cancer. METHODS: A questionnaire was mailed to individuals in the cohort who had breast cancer diagnosed during the period from 1992 through 1994 and a random sample of cancer-free cohort members to obtain information on usual intake of meats and on meat preparation practices. Color photographs showing various doneness levels of hamburger, beefsteak, and bacon were included. Multivariate analysis was performed on data from 273 case subjects and 657 control subjects who completed the survey. RESULTS: A dose-response relationship was found between doneness levels of meat consumed and breast cancer risk. The adjusted odds ratios (ORs) for very well-done meat versus rare or medium-done meat were 1.54 (95% confidence interval [CI]=0.96-2.47) for hamburger, 2.21 (95% CI=1.30-3.77) for beef steak, and 1.64 (95% CI=0.92-2.93) for bacon. Women who consumed these three meats consistently very well done had a 4.62 times higher risk (95% CI=1.36-15.70) than that of women who consumed the meats rare or medium done. Risk of breast cancer was also elevated with increasing intake of well-done to very well-done meat. CONCLUSIONS: Consumption of well-done meats and, thus, exposures to heterocyclic amines (or other compounds) formed during high-temperature cooking may play an important role in the risk of breast cancer

Well-done meat intake and the risk of breast cancer.

Zheng W, Gustafson DR, Sinha R, et al.

J Natl Cancer Inst. 1998 Nov 18; 90(22):1724-9.

BACKGROUND: Heterocyclic amines, mutagens formed in meats cooked at high temperatures, have been demonstrated as mammary carcinogens in animals. We conducted a nested, case-control study among 41836 cohort members of the Iowa Women's Health Study to evaluate the potential role of heterocyclic amines and intake of well-done meat in the risk for human breast cancer. METHODS: A questionnaire was mailed to individuals in the cohort who had breast cancer diagnosed during the period from 1992 through 1994 and a random sample of cancer-free cohort members to obtain information on usual intake of meats and on meat preparation practices. Color photographs showing various doneness levels of hamburger, beefsteak, and bacon were included. Multivariate analysis was performed on data from 273 case subjects and 657 control subjects who completed the survey. RESULTS: A dose-response relationship was found between doneness levels of meat consumed and breast cancer risk. The adjusted odds ratios (ORs) for very well-done meat versus rare or medium-done meat were 1.54 (95% confidence interval [CI]=0.96-2.47) for hamburger, 2.21 (95% CI=1.30-3.77) for beef steak, and 1.64 (95% CI=0.92-2.93) for bacon. Women who consumed these three meats consistently very well done had a 4.62 times higher risk (95% CI=1.36-15.70) than that of women who consumed the meats rare or medium done. Risk of breast cancer was also elevated with increasing intake of well-done to very well-done meat. CONCLUSIONS: Consumption of well-done meats and, thus, exposures to heterocyclic amines (or other compounds) formed during high-temperature cooking may play an important role in the risk of breast cancer

Inhibition of murine bladder tumorigenesis by soy isoflavones via alterations in the cell cycle, apoptosis, and angiogenesis.

Zhou JR, Mukherjee P, Gugger ET, et al.

Cancer Res. 1998 Nov 15; 58(22):5231-8.

Soy isoflavones exhibit a number of biological effects, suggesting that they may have a role in cancer prevention. Our objectives are to determine whether components of soy products or purified soy isoflavones can inhibit the progression of bladder cancer. We compared the in vitro effects of pure soy isoflavones and soy phytochemical concentrate on growth curves, cell cycle progression, and apoptosis in murine and human bladder cancer cell lines. Pure soy isoflavones (genistein, genistin, daidzein, and biochanin A) and soy phytochemical concentrate exhibit dose-dependent growth inhibition of murine (MB49 and MBT-2) and human (HT-1376, UM-UC-3, RT-4, J82, and TCCSUP) bladder cancer cell lines, although the degree of inhibition varies among lines. Soy isoflavones induce a G2-M cell cycle arrest in all human and murine lines evaluated by flow cytometry. In addition, some bladder cancer lines show DNA fragmentation consistent with apoptosis. We next evaluated the ability of genistein, soy phytochemical concentrate, and soy protein isolate, respectively, to inhibit the growth of transplantable murine bladder cancer in vivo. C57BL/6 mice were randomly assigned to treatment groups (n = 12/group): (a) AIN-76A diet; (b) AIN-76A diet plus genistein, i.p., 50 mg/kg body weight/day; (c) AIN-76 diet with soy phytochemical concentrate at 0.2% of the diet; (d) AIN-76 diet with soy phytochemical concentrate at 1.0% of the diet; and (e) AIN-76A diet with soy protein isolate, 20% by weight. Mice were inoculated s.c. with 5 x 10(4) syngeneic MB49 bladder carcinoma cells, and tumor growth was quantitated. Neither genistein nor soy products reduced body weight gain. Tumor volumes from mice treated with genistein, dietary soy phytochemical concentrate at 1%, or dietary soy protein isolate were reduced by 40% (P < 0.007), 48% (P < 0.001), or 37% (P < 0.01), respectively, compared with controls. We characterized the effects of treatment on several biomarkers in tumor tissue: proliferation index by proliferating cell nuclear antigen staining, apoptotic index by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling staining, and angiogenesis by microvessel quantitation. Soy products reduced angiogenesis, increased apoptosis, and slightly reduced proliferation while showing no histopathological effects on the normal bladder mucosa. Our data suggest that soy isoflavones can inhibit bladder tumor growth through a combination of direct effects on tumor cells and indirect effects on the tumor neovasculature. Soy products warrant further investigation in bladder cancer prevention and treatment programs or as antiangiogenic agents

Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice.

Zhou JR, Gugger ET, Tanaka T, et al.

J Nutr. 1999 Sep; 129(9):1628-35.

The objectives of our studies are to characterize the ability of dietary soybean components to inhibit the growth of prostate cancer in mice and alter tumor biomarkers associated with angiogenesis. Soy isoflavones (genistein or daidzein) or soy phytochemical concentrate inhibit the growth of prostate cancer cells LNCaP, DU 145 and PC-3 in vitro, but only at supraphysiologic concentrations, i.e., 50% inhibitory concentration (IC(50)) > 50 micromol/L. G2-M arrest and DNA fragmentation consistent with apoptosis of prostate cancer cells are also observed at concentrations causing growth inhibition. In contrast, the in vitro proliferation of vascular endothelial cells was inhibited by soy phytochemcials at much lower concentrations. We evaluated the ability of dietary soy phytochemical concentrate and soy protein isolate to inhibit the growth of the LNCaP human prostate cancer in severe combined immune-deficient mice. Mice inoculated subcutaneously with LNCaP cells (2 x 10(6)) were randomly assigned to one of the six dietary groups based on the AIN-76A formulation for 3 wk. A 2 x 3 factorial design was employed with two protein sources (20%, casein vs. soy protein) and three levels of soy phytochemical concentrate (0, 0.2 and 1.0% of the diet). Soy components did not alter body weight gain or food intake. Compared with casein-fed controls, the tumor volumes after 3 wk were reduced by 11% (P = 0.45) by soy protein, 19% (P = 0.17) by 0.2% soy phytochemical concentrate, 28% by soy protein with 0.2% soy phytochemical concentrate (P < 0.05), 30% by 1.0% soy phytochemical concentrate (P < 0.05) and 40% by soy protein with 1.0% soy phytochemical concentrate (P < 0.005). Histologic examination of tumor tissue showed that consumption of soy products significantly reduced tumor cell proliferation, increased apoptosis and reduced microvessel density. The angiogenic protein insulin-like growth factor-I was reduced in the circulation of mice fed soy protein and phytochemical concentrate. Our data suggest that dietary soy products may inhibit experimental prostate tumor growth through a combination of direct effects on tumor cells and indirect effects on tumor neovasculature

Inhibition of orthotopic growth and metastasis of androgen-sensitive human prostate tumors in mice by bioactive soybean components.

Zhou JR, Yu L, Zhong Y, et al.

Prostate. 2002 Oct 1; 53(2):143-53.

BACKGROUND: Systematic analysis of the influence of diet on the initiation and progression of prostate cancer is often difficult in human populations, for which dietary variables overlap a diversity of genetic backgrounds and social behaviors. Animal models that emulate human prostate cancer allow experimental analysis of the mechanisms of action of nutritional agents that show anti-prostate cancer activity. METHODS: We have used an orthotopic implant model to characterize the in vivo response of androgen-sensitive LNCaP prostate tumors to three well-characterized soy dietary supplements: isoflavone depleted soy protein, soy phytochemical concentrate (SPC), and genistin. RESULTS: In male SCID mice orthotopically implanted with the androgen-sensitive human prostate cell line LNCaP, dietary supplements of soy protein, genistin, and SPC reduced primary tumor weight by 42% (P = 0.07), 57% (P < 0.05) and 70% (P < 0.005), respectively. All three soy supplements significantly increased tumor apoptosis and decrease microvessel density, with no significant change in tumor proliferation. Each supplement produced a distinct serum androgen response, with genistin producing the greatest decrease in total serum testosterone and dihydrotestosterone (DHT) (P < 0.05) and the greatest increase in testosterone to DHT ratio (P < 0.05) and soy protein the greatest decrease in bioactive androgen (P < 0.05). Only SPC significantly inhibited metastases to lymph nodes and lungs, and only SPC produced a significant increase in tumor p53 expression. CONCLUSION: Taken together, these data suggest that the anti-prostate cancer activity of dietary soy protein, soy phytochemicals, and genistin use different molecular pathways. In addition, we have demonstrated that this animal model can be used in the design of dietary strategies for prostate cancer prevention and therapy

Combined inhibition of estrogen-dependent human breast carcinoma by soy and tea bioactive components in mice.

Zhou JR, Yu L, Mai Z, et al.

Int J Cancer. 2004 Jan 1; 108(1):8-14.

Breast cancer is significantly less prevalent among Asian women, whose diets contain high intake of soy products and tea. The objective of our present study was to identify the combined effects of dietary soy phytochemicals and tea components on breast tumor progression in a clinically relevant in vivo model of MCF-7 androgen-dependent human breast tumor in female SCID mice. MCF-7 tumor growth, tumor cell proliferation and apoptosis, microvessel density, and expressions of tumor estrogen receptors were compared in mice treated with genistin-rich soy isoflavones (GSI), soy phytochemical concentrate (SPC), black tea (BT), green tea (GT), SPC/BT combination and SPC/GT combination. GSI and SPC led to dose-dependent inhibition of MCF-7 tumor growth via inhibition of cancer cell proliferation in vivo. GT showed more potent anti-breast tumor activity than BT. GT infusion at 1.5 g tealeaf/100 mL water produced significant (p < 0.05) reductions of 56% in final tumor weight. GT plus SPC at 0.1% of the diet further reduced final tumor weight by 72% (p < 0.005). Analysis of serum and tumor biomarkers showed that the combined effects of SPC and GT inhibited tumor angiogenesis, and reduced estrogen receptor (ER)-alpha and serum levels of insulin-like growth factor (IGF)-I. Our study suggests that dietary SPC plus GT may be used as a potential effective dietary regimen for inhibiting progression of estrogen-dependent breast cancer

Combined inhibition of estrogen-dependent human breast carcinoma by soy and tea bioactive components in mice.

Zhou JR, Yu L, Mai Z, et al.

Int J Cancer. 2004 Jan 1; 108(1):8-14.

Breast cancer is significantly less prevalent among Asian women, whose diets contain high intake of soy products and tea. The objective of our present study was to identify the combined effects of dietary soy phytochemicals and tea components on breast tumor progression in a clinically relevant in vivo model of MCF-7 androgen-dependent human breast tumor in female SCID mice. MCF-7 tumor growth, tumor cell proliferation and apoptosis, microvessel density, and expressions of tumor estrogen receptors were compared in mice treated with genistin-rich soy isoflavones (GSI), soy phytochemical concentrate (SPC), black tea (BT), green tea (GT), SPC/BT combination and SPC/GT combination. GSI and SPC led to dose-dependent inhibition of MCF-7 tumor growth via inhibition of cancer cell proliferation in vivo. GT showed more potent anti-breast tumor activity than BT. GT infusion at 1.5 g tealeaf/100 mL water produced significant (p < 0.05) reductions of 56% in final tumor weight. GT plus SPC at 0.1% of the diet further reduced final tumor weight by 72% (p < 0.005). Analysis of serum and tumor biomarkers showed that the combined effects of SPC and GT inhibited tumor angiogenesis, and reduced estrogen receptor (ER)-alpha and serum levels of insulin-like growth factor (IGF)-I. Our study suggests that dietary SPC plus GT may be used as a potential effective dietary regimen for inhibiting progression of estrogen-dependent breast cancer

Effects of soybean extract on morphology and survival of Caco-2, SW620, and HT-29 cells.

Zhu Q, Meisinger J, Van Thiel DH, et al.

Nutr Cancer. 2002; 42(1):131-40.

Soybean consumption may be beneficial to prevention of certain human cancers. Low incidence of colon cancer in Asian countries is associated with consumption of soybean products. A limited number of human and animal studies suggested that soybean consumption might prevent colon cancer; other studies did not support this conclusion. Therefore, it is important to understand the biological effects of soybeans on colon cells. In the present study, cultures of Caco-2, SW620, and HT-29 cells were treated with soybean extract, the soluble fraction of a soybean product. The crude extract contains proteins and many soluble components of soybeans. After incubation with soybean extract (1-6%, vol/vol) for 24 h, most Caco-2 cells were found to contain numerous vacuoles within the cytoplasm and to become very flat. Exposure to > 6% soybean extract resulted in cell death and giant vacuoles. Soybean extract (0.25-2%) induced small vacuoles within the cytoplasm of SW620 cells. SW620 cells detached from culture dishes at > 2% soybean extract. Exposure to 0.5-2% soybean extract produced vacuoles within HT-29 cells similar to those observed in SW620 cells. Soybean extract significantly reduced density of Caco-2, SW620, and HT-29 cells. Reducing protein content of soybean extract reduced but did not abolish its effects on colon cells. Purified genistein (12.5 micrograms/ml) was capable of producing morphological changes similar to those observed after treatment of colon cells with soybean extract. Assays using annexin V-propidium iodide demonstrated that treatment of Caco-2 and SW620 cells with soybean extract increased cell death. Membranes of vacuoles in soybean-treated Caco-2 and SW620 cells were labeled with Texas red-conjugated wheat germ agglutinin, a cytological marker for the Golgi apparatus. Exposure to soybean extract enhanced protein levels of Rab6, a small GTP-binding protein that is involved in regulation of membrane traffic of the Golgi apparatus. Data from this study suggest that exposure to soybean extract or isoflavones affects morphology and survival of colon cancer cells and that the response to soybean extract varies depending on the cell lines examined

Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention.

Zi X, Agarwal R.

Proc Natl Acad Sci U S A. 1999 Jun 22; 96(13):7490-5.

Reduction in serum prostate-specific antigen (PSA) levels has been proposed as an endpoint biomarker for hormone-refractory human prostate cancer intervention. We examined whether a flavonoid antioxidant silibinin (an active constituent of milk thistle) decreases PSA levels in hormone-refractory human prostate carcinoma LNCaP cells and whether this effect has biological relevance. Silibinin treatment of cells grown in serum resulted in a significant decrease in both intracellular and secreted forms of PSA concomitant with a highly significant to complete inhibition of cell growth via a G1 arrest in cell cycle progression. Treatment of cells grown in charcoal-stripped serum and 5alpha-dihydrotestosterone showed that the observed effects of silibinin are those involving androgen-stimulated PSA expression and cell growth. Silibinin-induced G1 arrest was associated with a marked decrease in the kinase activity of cyclin-dependent kinases (CDKs) and associated cyclins because of a highly significant decrease in cyclin D1, CDK4, and CDK6 levels and an induction of Cip1/p21 and Kip1/p27 followed by their increased binding with CDK2. Silibinin treatment of cells did not result in apoptosis and changes in p53 and bcl2, suggesting that the observed increase in Cip1/p21 is a p53-independent effect that does not lead to an apoptotic cell death pathway. Conversely, silibinin treatment resulted in a significant neuroendocrine differentiation of LNCaP cells as an alternative pathway after Cip1/p21 induction and G1 arrest. Together, these results suggest that silibinin could be a useful agent for the intervention of hormone-refractory human prostate cancer

Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention.

Zi X, Agarwal R.

Proc Natl Acad Sci U S A. 1999 Jun 22; 96(13):7490-5.

Reduction in serum prostate-specific antigen (PSA) levels has been proposed as an endpoint biomarker for hormone-refractory human prostate cancer intervention. We examined whether a flavonoid antioxidant silibinin (an active constituent of milk thistle) decreases PSA levels in hormone-refractory human prostate carcinoma LNCaP cells and whether this effect has biological relevance. Silibinin treatment of cells grown in serum resulted in a significant decrease in both intracellular and secreted forms of PSA concomitant with a highly significant to complete inhibition of cell growth via a G1 arrest in cell cycle progression. Treatment of cells grown in charcoal-stripped serum and 5alpha-dihydrotestosterone showed that the observed effects of silibinin are those involving androgen-stimulated PSA expression and cell growth. Silibinin-induced G1 arrest was associated with a marked decrease in the kinase activity of cyclin-dependent kinases (CDKs) and associated cyclins because of a highly significant decrease in cyclin D1, CDK4, and CDK6 levels and an induction of Cip1/p21 and Kip1/p27 followed by their increased binding with CDK2. Silibinin treatment of cells did not result in apoptosis and changes in p53 and bcl2, suggesting that the observed increase in Cip1/p21 is a p53-independent effect that does not lead to an apoptotic cell death pathway. Conversely, silibinin treatment resulted in a significant neuroendocrine differentiation of LNCaP cells as an alternative pathway after Cip1/p21 induction and G1 arrest. Together, these results suggest that silibinin could be a useful agent for the intervention of hormone-refractory human prostate cancer

The relation between hypocholesterolemia and degree of maturation in acute myeloid leukemia.

Zyada LE, Hassan HT, Rees JK, et al.

Hematol Oncol. 1990 Jan; 8(1):65-9.

Plasma cholesterol concentrations were determined in 83 acute myeloid leukemia patients. Mean plasma cholesterol concentration (+/- S.D.) at the time of diagnosis was 2.91 mmol/L (+/- 1.13). The percentage of AML patients having hypocholesterolemia was 90.4 per cent. The lowest cholesterol levels were observed in the poorly differentiated FAB subtypes of acute myeloid leukaemia: AMyL(M1) and AMoL(M5a). The results showed that the initial hypocholesterolemia in acute myeloid leukemia is significantly related to the degree of both cytological and cytochemical maturation of leukemic blast cells at diagnosis. The degree of maturation at diagnosis has been shown to be related to prognosis in favour of more differentiated subtypes of acute myeloid leukemia. Also, hypocholesterolemia has been shown in several epidemiological studies to be related to an increased mortality from human cancer. Therefore, the degree of maturation may serve as a link between hypocholesterolemia and the increased mortality from human cancer