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Abstracts

Breast Cancer
Updated: 08/26/2004

ABSTRACTS

American Cancer Society's Guide to Complementary and Alternative Cancer Methods.

ACS.

2000;

Epidemiology, prevention, and early detection of breast cancer.

Alberg AJ, Helzlsouer KJ.

Curr Opin Oncol. 1997 Nov; 9(6):505-11.

Breast cancer is a leading women's health issue. Continued advances in understanding the temporal sequencing of relevant exposures promises to shed light on the continuum of breast carcinogenesis. Oral contraceptive use and the transient increase in risk following childbirth are exposures that affect the near-term risk of breast cancer. The availability of commercial testing for inherited susceptibility to breast cancer has accelerated the need for data to develop sound policy for implementing gene testing. The risks associated with BRCA1 and BRCA2 mutations may be less than previously estimated. Antiestrogens with lesser risks than tamoxifen hold promise for chemoprevention, but await testing. Not enough is known to formulate primary prevention strategies based on lifestyle interventions. Further understanding lifestyle factors that may be involved in the etiology of breast cancer and are amenable to preventive intervention thus remains a top priority, with diet and physical activity of greatest interest

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

Long-chain n-3-to-n-6 polyunsaturated fatty acid ratios in breast adipose tissue from women with and without breast cancer.

Bagga D, Anders KH, Wang HJ, et al.

Nutr Cancer. 2002; 42(2):180-5.

Animal studies suggest that dietary polyunsaturated fatty acids (PUFAs) of the n-6 class, found in corn and safflower oils, may be precursors of intermediates involved in the development of mammary tumors, whereas long-chain (LC) n-3 PUFAs, found in fish oil, can inhibit these effects. This case-control study was designed to examine the relationship between the PUFA composition of breast adipose tissue and the risk of breast cancer. Using fatty acid levels in breast adipose tissue as a biomarker of past qualitative dietary intake of fatty acids, we examined the hypothesis that breast cancer risk is negatively associated with specific LC n-3 PUFAs (eicosapentaenoic acid and docosahexaenoic acid) and positively associated with n-6 PUFAs (linoleic acid and arachidonic acid). Breast adipose tissue was collected from 73 breast cancer patients and 74 controls with macromastia. The fatty acid levels were determined by gas-liquid chromatography. A logistic regression model was used to obtain odds ratio estimates while adjusting for age. The age-adjusted n-6 PUFA (linoleic acid and arachidonic acid) content was significantly higher in cases than in controls (P = 0.02). There was a trend in the age-adjusted data suggesting that, at a given level of n-6 PUFA, LC n-3 PUFAs (eicosapentaenoic acid and docosahexaenoic acid) may have a protective effect (P = 0.06). A similar inverse relationship was observed with LC n-3-to-n-6 ratio when the data were adjusted for age (P = 0.09). We conclude that total n-6 PUFAs may be contributing to the high risk of breast cancer in the United States and that LC n-3 PUFAs, derived from fish oils, may have a protective effect

Sentinel node biopsy in breast cancer.

Barnwell JM, Arredondo MA, Kollmorgen D, et al.

Ann Surg Oncol. 1998 Mar; 5(2):126-30.

BACKGROUND: Sentinel lymph node biopsy (SNB) in breast cancer may be used in place of axillary lymph node dissection (ALND) if SNB accurately stages the axilla. This study assessed the success and accuracy of axillary SNB with isosulfan blue (ISB) and technetium-99 sulfur colloid (TSC) compared to ALND. METHODS: Forty-two women with T1 or T2 breast cancer underwent SNB and ALND. Sixty to 90 minutes before anesthetic induction, a mixture of 3 mL ISB and 1 mCi TSC was injected around the primary cancer or prior biopsy site. Intraoperatively, the SLN was identified using a gamma detector (Neoprobe 1000) or by visualization of the blue-stained lymph node and afferent lymphatics. The SLN was excised separately, and a level I/II ALND was completed. The histologic findings of the axillary contents and SLN were compared. RESULTS: An axillary SLN was found in 38 of 42 (90%) cases. SLN localization rate and predictive value were the same for women who had and those who had not undergone excisional biopsy before the date of SNB. Fifteen of 42 (36%) patients had lymph node metastases. The SLN was positive in all women with axillary metastases (negative predictive value, 100%). CONCLUSIONS: If confirmed by larger series, a negative SNB may eliminate the need for ALND for select women with breast cancer

Prospective evaluation of vitamin E for hot flashes in breast cancer survivors.

Barton DL, Loprinzi CL, Quella SK, et al.

J Clin Oncol. 1998 Feb; 16(2):495-500.

PURPOSE: Hot flashes represent a substantial clinical problem for some breast cancer survivors. Although estrogen or progesterone preparations can alleviate these symptoms in many patients, concern remains regarding the use of hormonal preparations in such women. Thus, there is a perceived need for nonhormonal treatments for hot flashes for breast cancer survivors. Based on anecdotal evidence that vitamin E was helpful, we designed a trial to investigate this matter. METHODS: We developed and conducted a placebo-controlled, randomized, crossover trial where, after a 1 week baseline period, patients received 4 weeks of vitamin E 800 IU daily, then 4 weeks of an identical-appearing placebo, or vice versa. Diaries were used to measure potential toxicities and hot flashes during the baseline week and the two subsequent 4-week treatment periods. RESULTS: The 120 patients evaluated for toxicity failed to show any. The 105 patients who finished the first treatment period showed a similar reduction in hot flash frequencies (25% v 22%; P = .90) for the two study arms. A crossover analysis, however, showed that vitamin E was associated with a minimal decrease in hot flashes (one less hot flash per day than was seen with a placebo) (P < or = ".05)." At the study end, patients did not prefer vitamin E over the placebo (32% v 29%, respectively). CONCLUSION: Although this trial was able to show a statistically significant hot flash reduction with vitamin E compared to a placebo, the clinical magnitude of this reduction was marginal

Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early-stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial efficacy and safety update analyses.

Baum M, Buzdar A, Cuzick J, et al.

Cancer. 2003 Nov 1; 98(9):1802-10.

BACKGROUND: The first analysis of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (median follow-up, 33 months) demonstrated that in adjuvant endocrine therapy for postmenopausal patients with early-stage breast cancer, anastrozole was superior to tamoxifen in terms of disease-free survival (DFS), time to recurrence (TTR), and incidence of contralateral breast cancer (CLBC). In the current article, the results of the first efficacy update, based on a median follow-up period of 47 months, are reported along with the results of an updated safety analysis, performed 7 months after the first analysis (median duration of treatment, 36.9 months). METHODS: DFS, TTR, CLBC incidence, and safety were assessed in the same patient group as in the first analysis of the ATAC trial. RESULTS: DFS estimates at 4 years remained significantly more favorable (86.9% vs. 84.5%, respectively) for patients receiving anastrozole compared with those receiving tamoxifen (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.76-0.99; P = 0.03). The benefit generated by anastrozole in terms of DFS was even greater in patients with hormone receptor-positive tumors (HR, 0.82; 95% CI, 0.70-0.96; P = 0.014). The HR for TTR also indicated a significant benefit for patients receiving anastrozole compared with those receiving tamoxifen (HR, 0.83; 95% CI, 0.71-0.96; P = 0.015), with additional benefit for patients with hormone receptor-positive tumors (HR, 0.78; 95% CI, 0.65-0.93; P = 0.007). CLBC incidence data also continued to favor anastrozole (odds ratio [OR], 0.62; 95% CI, 0.38-1.02; P = 0.062), and statistical significance was achieved in the hormone receptor-positive subgroup (OR, 0.56; 95% CI, 0.32-0.98; P = 0.042). The updated safety analysis also confirmed the findings of the first analysis, in that endometrial cancer (P = 0.007), vaginal bleeding and discharge (P < 0.001 for both), cerebrovascular events (P < 0.001), venous thromboembolic events (P < 0.001), and hot flashes (P < 0.001) all occurred less frequently in the anastrozole group, whereas musculoskeletal disorders and fractures (P < 0.001 for both) continued to occur less frequently in the tamoxifen group. These results indicated that the safety profile of anastrozole remained consistent. CONCLUSIONS: After an additional follow-up period, anastrozole continues to show superior efficacy, which is most apparent in the clinically relevant hormone receptor-positive population. Furthermore, anastrozole has numerous noteworthy advantages in terms of tolerability compared with tamoxifen. These findings suggest that the benefits of anastrozole are likely to be maintained in the long term and provide further support for the status of anastrozole as a valid treatment option for postmenopausal women with hormone-sensitive early-stage breast cancer

The dietary pigment curcumin reduces endothelial tissue factor gene expression by inhibiting binding of AP-1 to the DNA and activation of NF-kappa B.

Bierhaus A, Zhang Y, Quehenberger P, et al.

Thromb Haemost. 1997 Apr; 77(4):772-82.

The natural occurring pigment curcumin, a major component of the spice turmeric, has been described to have antioxidative, anti-tumorpromoting, anti-thrombotic and anti-inflammatory properties. It appears, that the pleiotropic effects of curcumin are at least partly due to inhibition of the transcription factors NF-kappa B and AP-1. This study investigates the effect of curcumin on the TNF alpha induced expression of endothelial Tissue Factor (TF), the central mediator of coagulation known to be controlled by AP-1 and NF-kappa B. When bovine aortic endothelial cells (BAEC) were preincubated in the presence of curcumin, TNF alpha induced TF gene transcription and expression were reduced. Transient transfection studies with TF-promoter plasmids revealed that both, NF-kappa B and AP-1 dependent TF expression, were reduced by curcumin action. The observed inhibitions were due to distinct mechanisms. Curcumin inhibited TNF alpha induced I kappa B alpha degradation and the nuclear import of NF-kappa B. In contrast, inhibition of AP-1 was due to a direct interaction of curcumin with AP-1-binding to its DNA binding motif. Thus, curcumin inhibits NF-kappa B and AP-1 by two different mechanisms and reduces expression of endothelial genes controlled by both transcription factors in vitro

Indole derivatives useful to treat estrogen-related neoplasms and disorders.

Bitonti AJ MISFWJJEWP.

1999(5,877,202)

Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy.

Blask DE, Sauer LA, Dauchy RT.

Curr Top Med Chem. 2002 Feb; 2(2):113-32.

Melatonin, as a new member of an expanding group of regulatory factors that control cell proliferation and loss, is the only known chronobiotic, hormonal regulator of neoplastic cell growth. At physiological circulating concentrations, this indoleamine is cytostatic and inhibits cancer cell proliferation in vitro via specific cell cycle effects. At pharmacological concentrations, melatonin exhibits cytotoxic activity in cancer cells. At both physiological and pharmacological concentrations, melatonin acts as a differentiating agent in some cancer cells and lowers their invasive and metastatic status through alterations in adhesion molecules and maintenance of gap junctional intercellular communication. In other cancer cell types, melatonin, either alone or in combination with other agents, induces apoptotic cell death. Biochemical and molecular mechanisms of melatonin's oncostatic action may include regulation of estrogen receptor expression and transactivation, calcium/calmodulin activity, protein kinase C activity, cytoskeletal architecture and function, intracellular redox status, melatonin receptor-mediated signal transduction cascades, and fatty acid transport and metabolism. A major mechanism mediating melatonin's circadian stage-dependent tumor growth inhibitory action is the suppression of epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) activity. This occurs via melatonin receptor-mediated blockade of tumor linoleic acid uptake and its conversion to 13-hydroxyoctadecadienoic acid (13-HODE) which normally activates EGFR/MAPK mitogenic signaling. This represents a potentially unifying model for the chronobiological inhibitory regulation of cancer growth by melatonin in the maintenance of the host/cancer balance. It also provides the first biological explanation of melatonin-induced enhancement of the efficacy and reduced toxicity of chemo- and radiotherapy in cancer patients

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.

Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence.

Block G, Patterson B, Subar A.

Nutr Cancer. 1992; 18(1):1-29.

Approximately 200 studies that examined the relationship between fruit and vegetable intake and cancers of the lung, colon, breast, cervix, esophagus, oral cavity, stomach, bladder, pancreas, and ovary are reviewed. A statistically significant protective effect of fruit and vegetable consumption was found in 128 of 156 dietary studies in which results were expressed in terms of relative risk. For most cancer sites, persons with low fruit and vegetable intake (at least the lower one-fourth of the population) experience about twice the risk of cancer compared with those with high intake, even after control for potentially confounding factors. For lung cancer, significant protection was found in 24 of 25 studies after control for smoking in most instances. Fruits, in particular, were significantly protective in cancers of the esophagus, oral cavity, and larynx, for which 28 of 29 studies were significant. Strong evidence of a protective effect of fruit and vegetable consumption was seen in cancers of the pancreas and stomach (26 of 30 studies), as well as in colorectal and bladder cancers (23 of 38 studies). For cancers of the cervix, ovary, and endometrium, a significant protective effect was shown in 11 of 13 studies, and for breast cancer a protective effect was found to be strong and consistent in a meta analysis. It would appear that major public health benefits could be achieved by substantially increasing consumption of these foods

Insulin and cancer.

Boyd DB.

Integr Cancer Ther. 2003 Dec; 2(4):315-29.

Obesity has recently been linked to mortality from the majority of cancers. The insulin/insulin-like growth factor (IGF) system may partly explain this effect. The metabolic syndrome, associated with hyperinsulinemia, may modulate this effect. Recent evidence supports the role of insulin and IGF-1 as important growth factors, acting through the tyrosine kinase growth factor cascade in enhancing tumor cell proliferation. In addition, the metabolic syndrome associated with a chronic inflammatory state and accompanying cytokine abnormalities may also contribute to tumor progression. Growing links between insulin and the etiology as well as prognosis in colon, prostate, pancreatic, and, particularly, breast cancer are reviewed. Of particular concern is the evidence that elevated IGF-1 may interfere with cancer therapy, adversely affecting prognosis. The role of insulin is of concern because of the increasing levels of obesity and the associated metabolic syndrome. Weight gain, through typical Western diet; limited levels of activity; and, more recently, stress-related changes in neuroendocrine function may lead to insulin resistance and hyperinsulinemia. The opportunity for a multidisciplinary approach involving nutrition, exercise, and stress reduction in an integrative setting may be crucial to limiting the insulin-resistant state and improving cancer outcomes

Effects of dietary indole-3-carbinol on estradiol metabolism and spontaneous mammary tumors in mice.

Bradlow HL, Michnovicz J, Telang NT, et al.

Carcinogenesis. 1991 Sep; 12(9):1571-4.

Indole-3-carbinol (I3C) is a potent inducer of cytochrome P450 enzymes in many species, including humans. We therefore studied alterations in the cytochrome P450-dependent metabolism of estradiol in different strains of mice consuming I3C in semisynthetic powdered diets at doses ranging from 250 to 5000 p.p.m. (34-700 mg/kg/day) for different periods of time. In short-term metabolic studies (3 weeks), wet liver weight increased in SW and C3H/OuJ mice in a dose-responsive manner. Dietary I3C increased the cytochrome P450 content measured in hepatic microsomes, as well as the extent of estradiol 2-hydroxylation, up to 5-fold. In a long-term feeding experiment (8 months), female C3H/OuJ mice consumed synthetic diets containing I3C at 0, 500 or 2000 p.p.m. Mammary tumor incidence and multiplicity were significantly lower at both doses of I3C, and tumor latency was prolonged in the high-dose group. We conclude that I3C is an inducer of hepatic P450-dependent estrogen metabolism in mice, and that it is chemopreventive in the C3H/OuJ mouse mammary tumor model. This protective effect may be mediated in part by the increased 2-hydroxylation and consequent inactivation of endogenous estrogens

A new indole-3-carbinol tetrameric derivative inhibits cyclin-dependent kinase 6 expression, and induces G1 cell cycle arrest in both estrogen-dependent and estrogen-independent breast cancer cell lines.

Brandi G, Paiardini M, Cervasi B, et al.

Cancer Res. 2003 Jul 15; 63(14):4028-36.

Indole-3-carbinol (I3C), autolysis product of glucosinolates present in cruciferous vegetables, has been indicated as a promising agent in preventing the development and progression of breast cancer. I3C has been shown to inhibit the growth of human cancer cells in vitro and possesses anticarcinogenic activity in vivo. Because I3C is unstable and may be converted into many polymeric products in the digestive tract, it is not yet clear whether the biological activity observed can be attributed to I3C or some of its polymeric products. In this study we synthesized a stable I3C cyclic tetrameric derivative and investigated its effects on a panel of human breast cancer cell lines. The I3C tetramer suppressed the growth of both estrogen receptor (ER) -positive (MCF-7, 734B, and BT474) and ER-negative (BT20, MDA-MB-231, and BT539) human breast cancer cell lines, and it was found to induce G(1) cell cycle arrest in a dose-dependent manner without evidence of apoptosis, suggesting a growth arrest via a cytostatic mechanism. At the molecular level, the tetramer inhibited cyclin-dependent kinase (CDK) 6 expression and activity, induced an increase in the level of p27(kip1), and reduced the level of retinoblastoma protein expression. Contrarily to CDK6, the level of CDK4, the other kinase involved in the G(1) phase of the cell cycle, remains unchanged. Interestingly, the tetramer resulted about five times more active than I3C in suppressing the growth of human breast cancer cells. On the whole, our data suggest that the I3C tetrameric derivative is a novel lead inhibitor of breast cancer cell growth that may be a considered a new, promising therapeutic agent for both ER+ and ER- breast cancer

Melatonin in humans.

Brzezinski A.

N Engl J Med. 1997 Jan 16; 336(3):186-95.

High dietary level of synthetic vitamin E on lipid peroxidation, membrane fatty acid composition and cytotoxicity in breast cancer xenograft and in mouse host tissue.

Cameron IL, Munoz J, Barnes CJ, et al.

Cancer Cell Int. 2003 Mar 12; 3(1):3.

BACKGROUND: d-alpha-tocopherol is a naturally occurring form of vitamin E not previously known to have antitumor activity. Synthetic vitamin E (sE) is a commonly used dietary supplement consisting of a mixture of d-alpha-tocopherol and 7 equimolar stereoisomers. To test for antilipid peroxidation and for antitumor activity of sE supplementation, two groups of nude mice bearing a MDA-MB 231 human breast cancer tumor were fed an AIN-76 diet, one with and one without an additional 2000 IU/kg dry food (equivalent to 900 mg of all-rac-alpha-tocopherol or sE). This provided an intake of about 200 mg/kg body weight per day. The mice were killed at either 2 or 6 weeks after the start of dietary intervention. During necropsy, tumor and host tissues were excised for histology and for biochemical analyses. RESULTS: Tumor growth was significantly reduced by 6 weeks of sE supplementation. Thiobarbituric acid reactive substances, an indicator of lipid peroxidation, were suppressed in tumor and in host tissues in sE supplemented mice. In the sE treated mice, the fatty acid composition of microsomal and mitochondrial membranes of tumor and host tissues had proportionately less linoleic acid (n-6 C 18-2), similar levels of arachidonic acid (n-6 C 20-4), but more docosahexanoic acid (n-3 C 22-6). The sE supplementation had no significant effect on blood counts or on intestinal histology but gave some evidence of cardiac toxicity as judged by myocyte vacuoles and by an indicator of oxidative stress (increased ratio of Mn SOD mRNA over GPX1 mRNA). CONCLUSIONS: At least one of the stereoisomers in sE has antitumor activity. Synthetic vitamin E appears to preferentially stabilize membrane fatty acids with more double bonds in the acyl chain. Although sE suppressed tumor growth and lipid peroxidation, it may have side-effects in the heart

Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases.

Carter CL, Allen C, Henson DE.

Cancer. 1989 Jan 1; 63(1):181-7.

Two of the most important prognostic indicators for breast cancer are tumor size and extent of axillary lymph node involvement. Data on 24,740 cases recorded in the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute were used to evaluate the breast cancer survival experience in a representative sample of women from the United States. Actuarial (life table) methods were used to investigate the 5-year relative survival rates in cases with known operative/pathologic axillary lymph node status and primary tumor diameter. Survival rates varied from 45.5% for tumor diameters equal to or greater than 5 cm with positive axillary nodes to 96.3% for tumors less than 2 cm and with no involved nodes. The relation between tumor size and lymph node status was investigated in detail. Tumor diameter and lymph node status were found to act as independent but additive prognostic indicators. As tumor size increased, survival decreased regardless of lymph node status; and as lymph node involvement increased, survival status also decreased regardless of tumor size. A linear relation was found between tumor diameter and the percent of cases with positive lymph node involvement. The results of our analyses suggest that disease progression to distant sites does not occur exclusively via the axillary lymph nodes, but rather that lymph node status serves as an indicator of the tumor's ability to spread

Conjugated linoleic acid content in breast adipose tissue of breast cancer patients and the risk of metastasis.

Chajes V, Lavillonniere F, Maillard V, et al.

Nutr Cancer. 2003; 45(1):17-23.

The association between the level of conjugated linoleic acid (CLA) in breast adipose tissue at the time of diagnosis and the subsequent development of metastasis was examined in a cohort of 209 patients presenting with an initially localized breast cancer. CLA level in breast adipose tissue was used as a qualitative biomarker of its past dietary intake. Biopsies of adipose tissue were obtained at the time of initial surgery. A CLA-enriched fraction was prepared by high performance liquid chromatography and CLA measured as a percentage of total fatty acids, using capillary gas chromatography. Mean CLA level was low (0.44% of total fatty acids) and the range between patients was narrow (0.19-0.85). With a median follow-up time of 7.5 yr, 45 patients developed metastases. A Cox proportional hazard regression model was used to identify prognostic factors. We did not find any significant association between CLA level in adipose fat and either the prognostic factor (tumor size, nodal status, histoprognostic grade, mitotic index, and estrogen or progesterone receptors) or the risk of metastasis or death. We concluded that CLA are unlikely to be involved in survivorship. However, the hypothesis that a higher intake of CLA might have a protective effect on the risk of metastasis cannot be ruled out from these data, since the level of CLA in breast cancer patients' adipose tissue is likely to be too low and the range of CLA distribution too narrow for any protection to be detectable

Indole-3-carbinol and diindolylmethane as aryl hydrocarbon (Ah) receptor agonists and antagonists in T47D human breast cancer cells.

Chen I, Safe S, Bjeldanes L.

Biochem Pharmacol. 1996 Apr 26; 51(8):1069-76.

Indole-3-carbinol (I3C) is a major component of Brassica vegetables, and diindolylmethane (DIM) is the major acid-catalyzed condensation product derived from I3C. Both compounds competitively bind to the aryl hydrocarbon (Ah) receptor with relatively low affinity. In Ah-responsive T47D human breast cancer cells, I3C and DIM did not induce significantly CYP1A1-dependent ethoxyresorufin O-deethylase (EROD) activity or CYP1A1 mRNA levels at concentrations as high as 125 or 31 microM, respectively. A 1 nM concentration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced EROD activity in these cells, and cotreatment with TCDD plus different concentrations of I3C (1-125 microM) or DIM (1-31 microM) resulted in a > 90% decrease in the induced response at the highest concentration of I3C or DIM. I3C or DIM also partially inhibited (< 50%) induction of CYP1A1 mRNA levels by TCDD and reporter gene activity, using an Ah-responsive plasmid construct in transient transfection assays. In T47D cells cotreated with 5 nM [3H]TCDD alone or in combination with 250 microM I3C or 31 microM DIM, there was a 37 and 73% decrease, respectively, in formation of the nuclear Ah receptor. The more effective inhibition of induced EROD activity by I3C and DIM was due to in vitro inhibition of enzyme activity. Thus, both I3C and DIM are partial Ah receptor antagonists in the T47D human breast cancer cell line

Dietary flaxseed inhibits human breast cancer growth and metastasis and downregulates expression of insulin-like growth factor and epidermal growth factor receptor.

Chen J, Stavro PM, Thompson LU.

Nutr Cancer. 2002; 43(2):187-92.

Recent studies indicate that diets rich in phytoestrogens and n-3 fatty acid have anticancer potential. This study determined the effect of flaxseed (FS), the richest source of lignans and alpha-linolenic acid, on growth and metastasis of established human breast cancer in a nude mice model. Estrogen receptor-negative human breast cancer cells, MDA-MB-435, were injected into the mammary fat pad of mice (Ncr nu/nu) fed a basal diet (BD). At Week 8, mice were randomized into two diet groups, such that the groups had similar tumor size and body weight. One continued on the BD, while the other was changed to BD supplemented with 10% FS, until sacrifice at Week 15. A significant reduction (P < 0.05) in tumor growth rate and a 45% reduction (P = "0.08)" in total incidence of metastasis were observed in the FS group. Lung metastasis incidence was 55.6% in the BD group and 22.2% in the FS group, while the lymph node metastasis incidence was 88.9% in the BD group and 33.3% in the FS group (P < 0.05). Mean tumor number (tumor load) of total and lymph node metastasis was significantly lower in the FS than in the BD group (P < 0.05). Metastatic lung tumor number was reduced by 82%, and a significantly lower tumor trend (P < 0.01) was observed in the FS group. Lung weight, which also reflects metastatic tumor load, in the FS group was reduced by 20% (P < 0.05) compared with the BD group. Immunohistochemical study showed that Ki-67 labeling index and expression of insulin-like growth factor I and epithelial growth factor receptor in the primary tumor were lower in the FS (P < 0.05) than in the BD group. In conclusion, flaxseed inhibited the established human breast cancer growth and metastasis in a nude mice model, and this effect is partly due to its downregulation of insulin-like growth factor I and epidermal growth factor receptor expression

Prevention by coenzyme Q10 of the electrocardiographic changes induced by adriamycin in rats.

Choe JY, Combs AB, Folkers K.

Res Commun Chem Pathol Pharmacol. 1979 Jan; 23(1):199-202.

The administration of adriamycin (ADM) to rats has consistently caused a widening of the QRS complex of the electrocardiogram. When coenzyme Q10 was also administered, beginning two days before ADM, this widening of the QRS complex and the elongation of the Q-T interval were reduced or totally prevented, depending upon conditions. ADM alone or with coenzyme Q10 did not alter the P-R interval. Some control by coenzyme Q10 of the cardiotoxicity of adriamycin in cancer patients is promising

Effect of conjugated linoleic acid isomers on growth factor-induced proliferation of human breast cancer cells.

Chujo H, Yamasaki M, Nou S, et al.

Cancer Lett. 2003 Dec 8; 202(1):81-7.

We evaluated the effect of conjugated linoleic acid (CLA) isomers on the growth factor-induced proliferation of human breast cancer MCF-7 cells. When MCF-7 cells were cultured in RPMI 1640 medium supplemented with 1% fetal bovine serum (FBS), CLA inhibited the proliferation and notably cis9, trans11 (c9,t11)-CLA showed the strongest effect. However, cells barely grew when cultured with 1% charcoal-treated FBS (cFBS). Proliferation was promoted in cFBS cultured cells by the addition of 17beta-estradiol (E2), insulin, and epidermal growth factor (EGF). Trans10, cis12 (T10,c12)-CLA inhibited cell proliferation induced by E2 and insulin, but not by EGF. T10,c12-CLA also exhibited cell-killing activity when cells were induced with insulin. On the other hand, c9,t11-CLA was shown to have no effect on MCF-7 cell proliferation induced by and of these three growth factors. In conclusion, although both c9, t11 and t10, c12-CLA can inhibit the proliferation of MCF-7 cells, our results suggested that they have separate mechanisms and different targets of actions

Epidemiology of breast cancer. Findings from the nurses' health study.

Colditz GA.

Cancer. 1993 Feb 15; 71(4 Suppl):1480-9.

BACKGROUND. The epidemiology of breast cancer was reviewed in the context of hormonal, hereditary, histologic, and dietary risk factors. METHODS. Literature review. RESULTS. Late age at menarche and early age at first birth decrease the risk of breast cancer as does an early age at menopause. These risk factors relate to the lifetime exposure of the breast tissue to ovarian hormones. Although an early first birth is associated with a transient increase in the risk of breast cancer, perhaps as a result of the breast's exposure to high levels of hormones before terminal differentiation, in older women, parity is associated with a decreased risk of breast cancer. Among postmenopausal women, obesity is associated with higher levels of estrogens and an increased risk of breast cancer. Within the strata of breast cancer stages at diagnosis, obesity is associated with increased mortality, again supporting the influence of endogenous estrogens on this disease's incidence, recurrence, and survival rates. Consistent with these relationships, current use of estrogen therapy among postmenopausal women is associated with an increased risk of breast cancer. A family history of breast cancer is associated with approximately a two-fold increase in the risk of breast cancer, and this risk is greater if the diagnosis was made when the woman's mother was young, although even a diagnosis in an older mother is associated with an increased risk in her daughters. The follow-up of women with a history of benign breast biopsy results shows that atypical hyperplasia is associated with a fourfold increase in risk compared with a biopsy specimen without proliferative changes. Atypia doubles the risk. These data support the concept of atypia as a precursor lesion for breast cancer and may warrant its use as a marker in further studies. Consistent data from retrospective and prospective studies show a positive association between moderate alcohol intake and the risk of breast cancer. This may reflect the increase in estrogen levels observed among women who consume alcohol. Data from prospective studies do not support a relationship between dietary fat intake and the risk of breast cancer either in premenopausal or postmenopausal women. CONCLUSIONS. Few of these associations offer the potential for intervention to reduce the breast cancer risk

Reduction by coenzyme Q10 of the acute toxicity of adriamycin in mice.

Combs AB, Choe JY, Truong DH, et al.

Res Commun Chem Pathol Pharmacol. 1977 Nov; 18(3):565-8.

Pretreatment for four days with coenzyme Q10 (COQ10) reduced the acute toxicity in mice treated with adriamycin. In two sequential protocols, adriamycin allowed only 36 and 42% survival, respectively. Pretreatment with COQ10 allowed 80 and 86% survival, respectively. The differences are significant, p less than 0.05. The mechanism for this reduction in the acute toxicity may be based upon the prevention by the supplementary COQ10 of the inhibition caused by adriamycin to COQ10-dependent enzymes in cardiac and and other tissues. The prospect of diminishing the toxicity of adriamycin in cancer patients remains promising and important

Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells.

Cos S, Fernandez R, Guezmes A, et al.

Cancer Res. 1998 Oct 1; 58(19):4383-90.

Melatonin, the principal pineal gland hormone, exerts a direct antiproliferative effect on estrogen-responsive MCF-7 cells in culture. The purpose of the current study was to investigate the effects of melatonin on the invasion capacity of MCF-7 cells. In vitro, melatonin at physiological doses (1 nM) reduced (P < 0.001) the invasiveness of tumoral cells measured in Falcon invasion chambers. Subphysiological (0.1 pM) and pharmacological concentrations (10 microM) of melatonin failed to inhibit cell invasion. Melatonin was also able to block 17beta-estradiol-induced invasion (P < 0.001). Pretreatment of MCF-7 cells with 1 nM melatonin increased the response of tumoral cells to the anti-invasive effects of this indolamine. To explore possible mechanisms by which melatonin reduces invasiveness, we measured the attachment of MCF-7 cells to a basement membrane, the chemotactic response of the cells, and their type IV collagenolytic activity. The presence of melatonin (1 nM) in the culture medium significantly reduced the ability of MCF-7 cells to attach to the basement membrane; this effect was enhanced by pretreating the cells with the same indolamine (P < 0.001). Melatonin also counteracts the stimulatory effects of 17beta-estradiol on cell adhesion (P < 0.001). The chemotactic response of MCF-7 cells also decreased in the presence of 1 nM melatonin, and this melatonin-induced reduction of cell migration was more effective on cells that were previously incubated for 5 days with melatonin than it was on nonpretreated cells (P < 0.001). The simultaneous addition of 17beta-estradiol and melatonin resulted in a significantly lower chemotactic response than that of 17beta-estradiol-treated cells (P < 0.001). However, type IV collagenolytic activity was not influenced by melatonin. Our results demonstrate that melatonin reduces the invasiveness of MCF-7 cells, causing a decrease in cell attachment and cell motility, probably by interacting with the estrogen-mediated mechanisms of MCF-7 cell invasiveness. In addition, we also studied the influence of melatonin on the expression of two cell surface adhesion molecules (E-cadherin and beta1 integrin) and an intermediate filament protein (vimentin), the expression of which has been correlated with the relative invasive capacity of human breast cancer cells. The culture of tumor cells in the presence of melatonin (1 nM) increased the membrane staining for E-cadherin and beta1 integrin as well as the number of E-cadherin and beta1 integrin immunoreactive cells (P < 0.01). Neither control MCF-7 cells nor those treated with melatonin stained for vimentin. Preliminary in vivo experiments carried out on ovariectomized athymic nude mice implanted with 17beta-estradiol pellets and inoculated with 5 x 10(6) MCF-7 cells in the inguinal mammary fat pad suggest that melatonin could decrease the tumorigenicity of these tumor cells. However, these results need further confirmation. Taken together, our results suggest that melatonin shifts MCF-7 human breast cancer cells to a lower invasive status by increasing the beta1 integrin subunit and E-cadherin expression and promoting the differentiation of tumor cells. Finally, our study points out the existence of the anti-invasive actions of melatonin as a part of the oncostatic action of melatonin

Influence of serum from healthy or breast tumor-bearing women on the growth of MCF-7 human breast cancer cells.

Cos S, Alvarez A, Mediavilla MD, et al.

Int J Mol Med. 2000 Jun; 5(6):651-6.

Sera from women healthy (HW) or with breast (BCW), ovarian or endometrial cancer, were added (10%) to the culture media of MCF-7 cells and cell proliferation assessed 4 days later to verify: a) whether sera from BCW, obtained before or 8 days after tumor ablaction, influence the proliferation of these cells, b) whether the effects of serum from BCW are specific for mammary tumor cells. Sera from BCW, but not sera from women with ovarian or endometrial cancer, increased MCF-7 cell proliferation in comparison with sera from HW. After surgical ablation of the breast tumors, serum's ability to increase MCF-7 cell proliferation decreased significantly. These effects cannot be explained by differences on serum levels of estradiol or melatonin. These results suggest the presence of growth-promoting substances of possible tumoral origin in serum of BCW, a fact that should be considered as support for the surgical treatment of tumor masses

Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signaling.

Cover CM, Hsieh SJ, Tran SH, et al.

J Biol Chem. 1998 Feb 13; 273(7):3838-47.

Indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables such as cabbage, broccoli, and Brussels sprouts, has been shown to reduce the incidence of spontaneous and carcinogen-induced mammary tumors. Treatment of cultured human MCF7 breast cancer cells with I3C reversibly suppresses the incorporation of [3H]thymidine without affecting cell viability or estrogen receptor (ER) responsiveness. Flow cytometry of propidium iodide-stained cells revealed that I3C induces a G1 cell cycle arrest. Concurrent with the I3C-induced growth inhibition, Northern blot and Western blot analyses demonstrated that I3C selectively abolished the expression of cyclin-dependent kinase 6 (CDK6) in a dose- and time-dependent manner. Furthermore, I3C inhibited the endogenous retinoblastoma protein phosphorylation and CDK6 phosphorylation of retinoblastoma in vitro to the same extent. After the MCF7 cells reached their maximal growth arrest, the levels of the p21 and p27 CDK inhibitors increased by 50%. The antiestrogen tamoxifen also suppressed MCF7 cell DNA synthesis but had no effect on CDK6 expression, while a combination of I3C and tamoxifen inhibited MCF7 cell growth more stringently than either agent alone. The I3C-mediated cell cycle arrest and repression of CDK6 production were also observed in estrogen receptor-deficient MDA-MB-231 human breast cancer cells, which demonstrates that this indole can suppress the growth of mammary tumor cells independent of estrogen receptor signaling. Thus, our observations have uncovered a previously undefined antiproliferative pathway for I3C that implicates CDK6 as a target for cell cycle control in human breast cancer cells. Moreover, our results establish for the first time that CDK6 gene expression can be inhibited in response to an extracellular antiproliferative signal

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

Bisphosphonates in the Management of Breast Cancer.

Cristofanilli M, Hortobagyi GN.

Cancer Control. 1999 May; 6(3):241-6.

BACKGROUND: Bone is the most frequent site of metastasis in patients with breast cancer. Bone metastasis, particularly osteolytic bone destruction, is usually associated with significant morbidity and deterioration of quality of life. Bisphosphonates are specific inhibitors of osteoclast activity used in the treatment of hypercalcemia of malignancy and osteolytic bone disease. METHODS: We reviewed pertinent literature on the use of bisphosphonates therapy to treat metastatic breast cancer. RESULTS: The use of bisphosphonates in the management of osteolytic bone metastases results in improved palliation of symptoms. Use of these agents in the adjuvant setting may help to prevent bone metastases. CONCLUSIONS: Bisphosphonates represent an effective palliative treatment when combined with chemotherapy and hormonal therapy for the management of osteolytic bone metastases. Identifying the exact mechanism of action requires further investigation to better define the possibility of a direct antitumor effect. The role of bisphosphonates in the adjuvant setting is still controversial, pending the results of large randomized trials

In Disease of the Breast.

Davidson NE, Kennedy MJADKDc.

2000; Second Edition

Protein kinase C and breast cancer.

Davidson NE, Kennedy MJ.

Cancer Treat Res. 1996; 83:91-105.

Bisphosphonates in the treatment of bone diseases.

Delmas PD.

N Engl J Med. 1996 Dec 12; 335(24):1836-7.

Effects of indole-3-carbinol (I3C) and phenethyl isothiocyanate (PEITC) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced DNA adducts in rat mammary glands and liver (meeting abstract).

Devanaboyina U.

Proc Annu Meet Am Assoc Cancer Res. 1997;(38):2427.

Sensitive detection of 8-hydroxy-2'deoxyguanosine in DNA by 32P-postlabeling assay and the basal levels in rat tissues.

Devanaboyina U, Gupta RC.

Carcinogenesis. 1996 May; 17(5):917-24.

Oxidative damage from reactive oxygen species including free radicals has been considered to play a vital role in many degenerative diseases and measurement of 8-hydroxy-2'-deoxyguanosine (Oh8dG) in tissue DNA has been used as a benchmark for oxidative DNA damage. We report here an ultrasensitive 32P-postlabeling method to detect and quantitate Oh8dG in DNA and have determined basal levels of Oh8dG in rat tissues. The method is comprised of DNA digestion to 3'-monophosphates, 5'-32P-labeling, conversion to 5'-monophosphates and separation by a 2-directional PEI-cellulose TLC (D1 = 1.5 M formic acid; and D2 = 0.6 M ammonium formate, pH 6.0). Under these conditions, all radioactive contaminants were either removed from the chromatogram (normal nucleotides and 32Pi) or remained at the origin (ATP and other contaminants), while Oh8dG migrated in the middle of the chromatogram. Calf thymus DNA incubated with ascorbic acid and H202 produced predominantly one spot under the chromatography conditions used; a chromatographically identical spot was also detected in untreated DNA, but at a much lower level (125 +/- 40 Oh8dG/10(6) nucleotides). A chromatographically identical spot was also found in dGp incubated with ascorbic acid and H202, but not with dAp, dCp or dTp. When applied to rat tissue DNA, the assay readily permitted detection of Oh8dG in the liver, lung, kidney, heart, brain, spleen, intestines and mammary epithelial cells of 3-month old female Sprague-Dawley rats. The tissue Oh8dG levels were found in the range of 87 +/- 29 to 133 +/- 49 per 10(6) nucleotides, with liver and heart being the highest and kidney and brain the lowest. These values are in the vicinity to those found by gas chromatography/mass spectrometry but 10-50 times higher than those reported by HPLC-electrochemical detection. Because of its high sensitivity (<1 Oh8dG per 10(5-6) nucleotides) to detect Oh8dG using nanogram quantity of DNA digest, the 32P-postlabeling method is likely to be valuable in quantitating Oh8dG in human tissue biopsies

Conjugated linoleic acid and oxidative behaviour in cancer cells.

Devery R, Miller A, Stanton C.

Biochem Soc Trans. 2001 May; 29(Pt 2):341-4.

Convincing evidence from rodent models of carcinogenesis indicates that cis-9,trans-11 (c9t11) conjugated linoleic acid (CLA) is a potent naturally occurring anti-carcinogen in the human diet. CLA has been reported to alter the fatty acid composition of biological tissues in a manner that increases their oxidative stability. However, recent information suggests that an antioxidant role for CLA does not seem plausible. Given the knowledge that c9t11 CLA is present in a wide range of meat and dairy food products, our studies have begun to investigate mechanisms by which CLA-enriched milk fat exerts its anti-carcinogenic effects. An oxidative mechanism appears to be involved in its growth-suppressive effects, since supplementation of growth culture medium with CLA (17-71.5 microM) made breast cancer cells more susceptible to lipid peroxidation. Studies have indicated that cancer cells may become enriched in CLA during growth in culture. This may make intracellular lipids more susceptible to ordinary levels of oxidative stress, to the point of producing a cytotoxic effect

Some aspects of vitamin E related to humans and breast cancer prevention.

Dimitrov NV, Pan RQ, Bauer J, et al.

Adv Exp Med Biol. 1994; 364:119-27.

The biological activities of vitamin E are related to the cellular functions and presence of sufficient tissue concentrations of this micronutrient. Most of the stored vitamin E is in the adipose tissue where it appears to be distributed equally. The breast adipose tissue has similar vitamin E concentrations as other parts of the body. The ductal systems also store vitamin E in sufficient concentrations to maintain cellular functions. The milk secreted from the ducts of the breast contains a high concentration of tocopherol. Whereas the normal breast tissue presumably utilizes vitamin E as an antioxidant, tumor tissue appears to handle vitamin E differently. Breast tumors possessing estrogen negative receptors and having poor histological differentiation have lower concentrations of vitamin E than tumors with positive estrogen receptors and well differentiated histology. Since vitamin E is considered the principal, if not sole, chain-breaking lipophilic antioxidant in plasma and tissue, its role as a potential chemopreventive agent in breast cancer should be further investigated. The combination of vitamin E with other cancer chemopreventive agents appears to be a reasonable procedure

Estrogen receptor expression profile of disseminated epithelial tumor cells in bone marrow of breast cancer patients.

Ditsch N, Mayer B, Rolle M, et al.

Recent Results Cancer Res. 2003; 162:141-7.

The estrogen receptor (ER) status in primary breast cancer represents an important prognostic factor and has a profound impact on therapeutic decisions. However, ER expression profile on disseminated breast cancer cells is largely unknown, although these cells are one of the main target structures in adjuvant therapy after local curative resection (R0) achieved in most breast cancer patients. Thus, the present pilot study was designed to evaluate the ER expression profile on disseminated epithelial cells in bone marrow, one of the preferential organs for manifestation of distant metastases in breast cancer. Using the alkaline phosphatase anti-alkaline phosphatase-immunogold double staining procedure, in a panel of 17 breast cancer patients, epithelial cells (mab CK2) detected in bone marrow were analyzed for ER expression (mab 1D5) and compared with ER expression in the corresponding primary tumors. Whereas eleven of the 17 patients (64.7%) were ER-positive in primary carcinomas, only two patients (11.8%) revealed ER-positive epithelial cells in bone marrow. In addition, one of these two patients demonstrated a heterogeneous ER expression pattern, with both ER-positive and ER-negative epithelial cells in bone marrow. Although in both of these cases the ER-positive epithelial cells in bone marrow derived from ER-positive primary tumors, in this small patient cohort none of the prognostic relevant clinical and pathological factors tested, i.e., TNM-classification, grading, and ER status in primary breast cancer, correlated with the ER status in bone marrow. The striking discrepancy between ER expression in primary breast cancers and the corresponding disseminated epithelial cells in bone marrow suggests either the selective dissemination of ER-negative tumor cells into the bone marrow or a negative impact of the bone marrow microenvironment on epithelial ER expression. This phenomenon might influence therapeutic effects of antihormonal treatment

Traditional and alternative therapies for breast cancer.

Dog TL, Riley D, Carter T.

Altern Ther Health Med. 2001 May; 7(3):36-7.

Common benign conditions of the breast. In Cancer of the Breast, Fourth Edition 1995.

Donegan WL.

1995;

Characterization of the biological activity of gamma-glutamyl-Se-methylselenocysteine: a novel, naturally occurring anticancer agent from garlic.

Dong Y, Lisk D, Block E, et al.

Cancer Res. 2001 Apr 1; 61(7):2923-8.

Gamma-glutamyl-Se-methylselenocysteine (GGMSC) has recently been identified as the major Se compound in natural garlic and selenized garlic. Our working hypothesis is that GGMSC serves primarily as a carrier of Se-methylselenocysteine (MSC), which has been demonstrated in past research to be a potent cancer chemopreventive agent in animal carcinogenesis bioassays. The present study was designed to examine the in vivo responses to GGMSC or MSC using a variety of biochemical and biological end points, including (a) urinary Se excretion as a function of bolus dose; (b) tissue Se accumulation profile; (c) anticancer efficacy; and (d) gene expression changes as determined by cDNA array analysis. Our results showed that like MSC, GGMSC was well absorbed p.o., with urinary excretion as the major route for eliminating excess Se. When fed chronically, the profile of Se accumulation in various tissues was very comparable after treatment with either GGMSC or MSC. In rats that had been challenged with a carcinogen, supplementation with either GGMSC or MSC resulted in a lower prevalence of premalignant lesions in the mammary gland, and fewer mammary carcinomas when these early lesions were allowed to progress. More importantly, we found that a short term GGMSC/MSC treatment schedule of 4 weeks immediately after carcinogen dosing was sufficient to provide significant cancer protection, even in the absence of a sustained exposure past the initial 4-week period. With the use of the Clontech Atlas Rat cDNA Array, we further discovered that the gene expression changes induced in mammary epithelial cells of rats that were given either GGMSC or MSC showed a high degree of concordance. On the basis of the collective biology, biochemistry, and molecular biology data, we conclude that GGMSC is an effective anticancer agent with a mechanism of action very similar to that of MSC

Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status.

Ellis MJ, Coop A, Singh B, et al.

Cancer Res. 2003 Oct 1; 63(19):6523-31.

BACKGROUND: The biological basis for the superior efficacy of neoadjuvant letrozole versus tamoxifen for postmenopausal women with estrogen receptor (ER)-positive locally advanced breast cancer was investigated by analyzing tumor proliferation and expression of estrogen-regulated genes before and after the initiation of therapy. METHODS: Tumor samples were obtained at baseline and at the end of treatment from 185 patients participating in a double blind randomized Phase III study of neoadjuvant endocrine therapy. These paired specimens were simultaneously analyzed for Ki67, ER, progesterone receptor (PgR), trefoil factor 1 (PS2), HER1 (epidermal growth factor receptor), and HER2 (ErbB2 or neu) by semiquantitative immunohistochemistry. RESULTS: The treatment-induced reduction in geometric mean Ki67 was significantly greater with letrozole (87%) than tamoxifen (75%; analysis of covariance P = 0.0009). Differences in the average Ki67 reduction were particularly marked for ER-positive tumors that overexpressed HER1 and/or HER2 (88 versus 45%, respectively; P = 0.0018). Twenty-three of 92 tumors (25%) on tamoxifen and 14 of 93 on letrozole (15%) showed a paradoxical increase in Ki67 with treatment, and the majority of these cases was HER1/2 negative. Letrozole, but not tamoxifen, significantly reduced expression of the estrogen-regulated proteins PgR and trefoil factor 1, regardless of HER1/2 status (P < 0.0001). ER down-regulation occurred with both agents, although levels decreased more with tamoxifen (P < 0.0001). CONCLUSION: Letrozole inhibited tumor proliferation to a greater extent than tamoxifen. The molecular basis for this advantage appears complex but includes possible tamoxifen agonist effects on the cell cycle in both HER1/2+ and HER1/2- tumors. A pattern of continued proliferation despite appropriate down-regulation of PgR expression with estrogen deprivation or tamoxifen was also documented. This observation suggests the estrogenic regulation of proliferation and PgR expression may be dissociated in endocrine therapy resistant cells

Screening mammograms by community radiologists: variability in false-positive rates.

Elmore JG, Miglioretti DL, Reisch LM, et al.

J Natl Cancer Inst. 2002 Sep 18; 94(18):1373-80.

BACKGROUND: Previous studies have shown that the agreement among radiologists interpreting a test set of mammograms is relatively low. However, data available from real-world settings are sparse. We studied mammographic examination interpretations by radiologists practicing in a community setting and evaluated whether the variability in false-positive rates could be explained by patient, radiologist, and/or testing characteristics. METHODS: We used medical records on randomly selected women aged 40-69 years who had had at least one screening mammographic examination in a community setting between January 1, 1985, and June 30, 1993. Twenty-four radiologists interpreted 8734 screening mammograms from 2169 women. Hierarchical logistic regression models were used to examine the impact of patient, radiologist, and testing characteristics. All statistical tests were two-sided. RESULTS: Radiologists varied widely in mammographic examination interpretations, with a mass noted in 0%-7.9%, calcification in 0%-21.3%, and fibrocystic changes in 1.6%-27.8% of mammograms read. False-positive rates ranged from 2.6% to 15.9%. Younger and more recently trained radiologists had higher false-positive rates. Adjustment for patient, radiologist, and testing characteristics narrowed the range of false-positive rates to 3.5%-7.9%. If a woman went to two randomly selected radiologists, her odds, after adjustment, of having a false-positive reading would be 1.5 times greater for the radiologist at higher risk of a false-positive reading, compared with the radiologist at lowest risk (95% highest posterior density interval [similar to a confidence interval] = 1.17 to 2.08). CONCLUSION: Community radiologists varied widely in their false-positive rates in screening mammograms; this variability range was reduced by half, but not eliminated, after statistical adjustment for patient, radiologist, and testing characteristics. These characteristics need to be considered when evaluating false-positive rates in community mammographic examination screening

The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables.

Elson CE, Yu SG.

J Nutr. 1994 May; 124(5):607-14.

Anutritive isoprenoid constituents of fruits, vegetables, cereal grains and essential oils exhibit a spectrum of anticarcinogenic activities. The induction of hepatic Phase II detoxifying activities by dietary isoprenoids appears to underlie their blocking action. The second anticarcinogenic action of the dietary isoprenoids, suppression of the growth of chemically initiated and transplanted tumors is, we suggest, secondary to the inhibition of mevalonate pathway activities. Mevinolin, a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase activity, depletes cells of the intermediate products of the pathway that are required for the posttranslational modification of proteins, a process giving the proteins lipophilic anchors that bind to membranes. As a consequence, nuclear lamins and ras oncoproteins remain in nascent states, and cells do not proliferate. gamma-Tocotrienol, perillyl alcohol, geraniol and d-limonene suppress hepatic HMG-CoA reductase activity, a rate-limiting step in cholesterol synthesis, and modestly lower serum-cholesterol levels of animals. These isoprenoids also suppress tumor growth. The HMG-CoA reductase of neoplastic tissues differs from that of sterologenic tissues in being markedly resistant to sterol feedback inhibition. Our review suggests that the mevalonate pathway of tumor tissues is uniquely sensitive to the inhibitory actions of the dietary isoprenoids

Reduced cancer incidence among the blind.

Feychting M, Osterlund B, Ahlbom A.

Epidemiology. 1998 Sep; 9(5):490-4.

Melatonin is a hormone primarily produced by the pineal gland at night and is suppressed by exposure to light. Experimental studies have indicated that melatonin may protect against cancer development. In the majority of totally blind people, melatonin is never suppressed by light exposure. The aim of this study was to test the hypothesis that blind people have a decreased cancer incidence, and that this effect is more pronounced in the totally blind than in the severely visually impaired. We identified a cohort of 1,567 totally blind and 13,292 severely visually impaired subjects and obtained information about cancer incidence from the Swedish Cancer Registry. We calculated standardized incidence ratios (SIRs) based on the number of person-years and incidence rates specific for national age, sex, and calendar year. Totally blind people had a lower incidence of all cancers combined [SIR = 0.69; 95% confidence interval (CI) = 0.59-0.82]. The risk reduction was observed in both men and women and was equally pronounced in hormone-dependent tumors as in other types of cancer. In the severely visually impaired, SIR was 0.95 (95% CI = 0.91-1.00). The findings support the hypothesis that blind people have a lower cancer incidence, although other explanations than the higher melatonin exposure must also be considered

Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study.

Fisher B, Costantino JP, Wickerham DL, et al.

J Natl Cancer Inst. 1998 Sep 16; 90(18):1371-88.

BACKGROUND: The finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992. METHODS: Women (N=13388) at increased risk for breast cancer because they 1) were 60 years of age or older, 2) were 35-59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or 3) had a history of lobular carcinoma in situ were randomly assigned to receive placebo (n=6707) or 20 mg/day tamoxifen (n=6681) for 5 years. Gail's algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the probability (risk) of occurrence of breast cancer over time. RESULTS: Tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50-59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen. Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles'), and spine fractures was observed. The rate of endometrial cancer was increased in the tamoxifen group (risk ratio = "2.53;" 95% confidence interval = "1.35-4.97);" this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women aged 50 years or older. CONCLUSIONS: Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease

Relevance of the biosynthesis of coenzyme Q10 and of the four bases of DNA as a rationale for the molecular causes of cancer and a therapy.

Folkers K.

Biochem Biophys Res Commun. 1996 Jul 16; 224(2):358-61.

In the human, coenzyme Q10 (vitamin Q10) is biosynthesized from tyrosine through a cascade of eight aromatic precursors. These precursors indispensably require eight vitamins, which are tetrahydrobiopterin, vitamins B6, C, B2, B12, folic acid, niacin, and pantothenic acid as their coenzymes. Three of these eight vitamins (the coenzyme B6, and the coenzymes niacin and folic acid) are indispensable in the biosynthesis of the four bases (thymidine, guanine, adenine, and cytosine) of DNA. One or more of the three vitamins required for DNA are known to cause abnormal pairing of the four bases, which can then result in mutations and the diversity of cancer. The coenzyme B6, required for the conversion of tyrosine to p-hydroxybenzoic acid, is the first coenzyme required in the cascade of precursors. A deficiency of the coenzyme B6 can cause dysfunctions, prior to the formation of vitamin Q10, to DNA. Former data on blood levels of Q10 and new data herein on blood levels of B6, measured as EDTA, in cancer patients established deficiencies of Q10 and B6 in cancer. This complete biochemistry relating to biosyntheses of Q10 and the DNA bases is a rationale for the therapy of cancer with Q10 and other entities in this biochemistry

Mutagenicity of low-filtered 30 kVp X-rays, mammography X-rays and conventional X-rays in cultured mammalian cells.

Frankenberg-Schwager M, Garg I, Fran-Kenberg D, et al.

Int J Radiat Biol. 2002 Sep; 78(9):781-9.

PURPOSE: To measure the mutagenic effectiveness of low-filtered 30 kVp X-rays, mammography X-rays and conventional (200 kVp) X-rays in mammalian cells. MATERIALS AND METHODS: Two different cell lines and mutation assays were used. Exponentially growing SV40-transformed human fibroblasts were exposed to graded doses of mammography (29 kVp, tungsten anode, 50 microm Rh filter) or conventional X-rays and the frequency of 6-thioguanine-resistent HPRT-deficient mutants was determined. Exponentially growing hamster A(L) cells, which contain a single human chromosome 11 conferring the expression of the human surface protein CD59, were subjected to magnetic cell separation (MACS) in order to remove spontaneous mutants before irradiation with low-filtered 30 kVp (tungsten anode, 0.5 mm Al filter) or conventional X-rays. Fractions of radiation-induced

Opposing effects of dietary n-3 and n-6 fatty acids on mammary carcinogenesis: The Singapore Chinese Health Study.

Gago-Dominguez M, Yuan JM, Sun CL, et al.

Br J Cancer. 2003 Nov 3; 89(9):1686-92.

We investigated the effects of individual fatty acids on breast cancer in a prospective study of 35,298 Singapore Chinese women aged 45-74 years, who were enrolled during April 1993 to December 1998 (The Singapore Chinese Health Study). At recruitment, each study subject was administered, in-person, a validated, semiquantitative food frequency questionnaire consisting of 165 food and beverage items. As of December 31, 2000, 314 incident cases of breast cancer had occurred. We used the Cox regression methods to examine individual fatty acids in relation to breast cancer risk, with adjustment for age at baseline interview, year of interview, dialect group, level of education, daily alcohol drinking, number of live births, age when menstrual periods became regular, and family history of breast cancer. Consumption of saturated, monounsaturated or polyunsaturated fat overall was unrelated to risk. On the other hand, high levels of dietary n-3 fatty acids from fish/shellfish (marine n-3 fatty acids) were significantly associated with reduced risk. Relative to the lowest quartile of intake, individuals in the higher three quartiles exhibited a 26% reduction in risk (relative risk (RR)=0.74, 95% confidence interval (CI)=0.58, 0.94)); RRs were similar across the top three quartiles of intake (0.75, 0.75, 0.72, respectively). Overall, there was no association between n-6 fatty acids and breast cancer risk. However, among subjects who consumed low levels of marine n-3 fatty acids (lowest quartile of intake), a statistically significant increase in risk was observed in individuals belonging to the highest vs the lowest quartile of n-6 fatty acid consumption (RR=1.87, 95% CI=1.06-3.27); the corresponding RR for advanced breast cancer was 2.45 (95% CI=1.20-4.97, P for trend=0.01). To our knowledge, these are the first prospective findings linking the intake of marine n-3 fatty acids to breast cancer protection

Endocrine disruption by indole-3-carbinol and tamoxifen: blockage of ovulation.

Gao X, Petroff BK, Oluola O, et al.

Toxicol Appl Pharmacol. 2002 Sep 15; 183(3):179-88.

Immature Sprague-Dawley rats received daily doses of indole-3-carbinol (I3C, 0-1.5 g/kg/day), 3,3'-diindolymethane (DIM, 0-400 mg/kg/day), tamoxifen (TAM, 0-0.5 mg/kg/day), or vehicle to determine if their antiestrogenic effects occur by the same mechanism and whether I3C's action is mediated by DIM. Follicular development was induced on day 24 of age by equine chorionic gonadotropin (eCG, 5 IU) 1 day after the initial dose. In a hormone replacement study, human chorionic gonadotropin (hCG, 10 IU sc, 48 h post-eCG) was used to mimic a normal preovulatoy luteinizing hormone (LH) surge following treatment with either I3C or TAM. Blood and ovaries were collected throughout follicular development and the number of ova shed was measured on the morning following expected ovulation (72 h post-eCG). I3C but not TAM reduced body weight gain at higher doses after 4 days of dosing. Ovarian weight gain and ovulation were inhibited by both I3C and TAM in a dose-dependent fashion. During the preovulatory period, both I3C and TAM blocked normal LH and follicle-stimulating hormone (FSH) surges and suppressed serum progesterone (P(4)) profoundly without changing circulating levels of estrogen (E(2)). At the time of expected ovulation, serum E(2) was increased in rats receiving I3C or tamoxifen, whereas serum P(4) was dose-dependently decreased. DIM exerted no significant effects on any of the endpoints studied, even at the highest dose, indicating that the antiestrogenic effects of I3C are not mediated by this metabolite of I3C. hCG successfully restored ovarian weight gain and ovulation in TAM-treated rats. However, hCG only partially reversed the blockage of ovulation by I3C, although ovarian weight gain was restored to normal. In summary, both I3C and TAM block ovulation by altering preovulatory concentrations of LH and FSH, but I3C appears to exert its effect(s) by (a) different mechanism(s) of action. I3C seems to act at both the ovarian and hypothalamic levels by mechanisms similar to those seen in TCDD-treated rats, whereas TAM appears to act only on the hypothalamic-pituitary axis as an anti-estrogen

Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer.

Goldhirsch A, Wood WC, Gelber RD, et al.

J Clin Oncol. 2003 Sep 1; 21(17):3357-65.

This account of the highlights of the eighth St Gallen (Switzerland) meeting in 2003 emphasizes new information that has emerged during the 2 years since the seventh meeting in 2001. This article should be read in conjunction with the report of that earlier meeting. Recommendations for patient care are so critically dependent on assessment of endocrine responsiveness that the importance of high-quality steroid hormone receptor determination and standardized quantitative reporting cannot be overemphasized. The International Consensus Panel modified the risk categories so that only endocrine receptor-absent status was sufficient to reclassify an otherwise low-risk, node-negative disease into the category of average risk. Absence of steroid hormone receptors also was recognized as indicating endocrine nonresponsiveness. Some important areas highlighted at the recent meeting include: (1) recognition of the separate nature of endocrine-nonresponsive breast cancer-both invasive cancers and ductal carcinoma-in-situ; (2) improved understanding of the mechanisms of acquired endocrine resistance, which offer exciting prospects for extending the impact of successful sequential endocrine therapies; (3) presentation of high-quality evidence indicating that chemotherapy and tamoxifen should be used sequentially rather than concurrently; (4) availability of a potential alternative to tamoxifen for treatment of postmenopausal women with endocrine-responsive disease; and (5) the promise of newly defined prognostic and predictive markers

Dietary (n-3)/(n-6) fatty acid ratio: possible relationship to premenopausal but not postmenopausal breast cancer risk in U.S. women.

Goodstine SL, Zheng T, Holford TR, et al.

J Nutr. 2003 May; 133(5):1409-14.

Recent research has suggested that an increased (n-3) fatty acid intake and/or increased (n-3)/(n-6) polyunsaturated fatty acid (PUFA) ratio in the diet is associated with a lower breast cancer risk. This case-control study investigated the association between intake of (n-3) and other fatty acids and the (n-3)/(n-6) PUFA ratio and breast cancer risk. After combining data from two related case-control studies in Connecticut, we had information available on a total of 1119 women (565 cases and 554 controls). Cases were all histologically confirmed, incident breast carcinoma patients. Controls were hospital-based (Yale-New Haven Hospital study site) and population-based (Tolland County study site). Information on dietary intake was obtained through a validated food-frequency questionnaire. Standard multivariate methods were used to address the independent effects of specific fatty acids, fat classes and macronutrients on breast cancer risk. In the full study population, there were no significant trends for any macronutrient/fatty acid when comparing the highest to the lowest quartile of intake. When the analysis was restricted to premenopausal women, consumption of the highest compared with the lowest quartile of the (n-3)/(n-6) PUFA ratio was associated with a nonsignificant 41% lower risk of breast cancer [odds ratio (OR) = 0.59, 95% confidence interval (CI) 0.29, 1.19, P for trend = 0.09]. A higher (n-3)/(n-6) PUFA ratio was significantly associated with a lower risk of breast cancer when the data were restricted to the Tolland County (population-based) study site; OR = 0.50, 95% CI 0.27, 0.95, P for trend = 0.02. These results are consistent with the hypothesis that a higher (n-3)/(n-6) PUFA ratio may reduce the risk of breast cancer, especially in premenopausal women

A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer.

Goss PE, Ingle JN, Martino S, et al.

N Engl J Med. 2003 Nov 6; 349(19):1793-802.

BACKGROUND: In hormone-dependent breast cancer, five years of postoperative tamoxifen therapy--but not tamoxifen therapy of longer duration--prolongs disease-free and overall survival. The aromatase inhibitor letrozole, by suppressing estrogen production, might improve the outcome after the discontinuation of tamoxifen therapy. METHODS: We conducted a double-blind, placebo-controlled trial to test the effectiveness of five years of letrozole therapy in postmenopausal women with breast cancer who have completed five years of tamoxifen therapy. The primary end point was disease-free survival. RESULTS: A total of 5187 women were enrolled (median follow-up, 2.4 years). At the first interim analysis, there were 207 local or metastatic recurrences of breast cancer or new primary cancers in the contralateral breast--75 in the letrozole group and 132 in the placebo group--with estimated four-year disease-free survival rates of 93 percent and 87 percent, respectively, in the two groups (P< or ="0.001" for the comparison of disease-free survival). A total of 42 women in the placebo group and 31 women in the letrozole group died (P="0.25" for the comparison of overall survival). Low-grade hot flashes, arthritis, arthralgia, and myalgia were more frequent in the letrozole group, but vaginal bleeding was less frequent. There were new diagnoses of osteoporosis in 5.8 percent of the women in the letrozole group and 4.5 percent of the women in the placebo group (P="0.07);" the rates of fracture were similar. After the first interim analysis, the independent data and safety monitoring committee recommended termination of the trial and prompt communication of the results to the participants. CONCLUSIONS: As compared with placebo, letrozole therapy after the completion of standard tamoxifen treatment significantly improves disease-free survival

Chemoprevention of chemically-induced mammary carcinogenesis by indole-3-carbinol.

Grubbs CJ, Steele VE, Casebolt T, et al.

Anticancer Res. 1995 May; 15(3):709-16.

Indole-3-carbinol, a component of cruciferous vegetables, was evaluated for it efficacy in the prevention of chemically-induced mammary tumors using three different protocols. Because this compound was unstable, it was administered by gavage rather than in the diet. A preliminary dose range study revealed that dose levels of 100 and 50 mg/day, 5x/week, were not toxic to female Sprague-Dawley rats. Initial studies in the DMBA model showed that administering indole-3-carbinol during the initiation and promotion phases were highly effective chemopreventive methods (91-96% reduction in cancer multiplicity). Subsequent studies showed that the administration of indole-3-carbinol only during the initiation phase (7 days prior to until 7 days post DMBA) was also highly effective as a chemopreventive agent. Determination of enzyme levels in the livers of animals treated long-term with indole-3-carbinol showed high levels of induction of various phase I and phase II drug metabolizing enzymes. Finally, indole-3-carbinol when administered both prior to and after MNU (a direct acting carcinogen) caused a significant decrease (65%) in mammary tumor multiplicity. These results support previous studies that indole-3-carbinol can prevent mammary carcinogenesis by direct and indirect acting carcinogens. Therefore, indole-3-carbinol might be a good candidate for chemoprevention of breast cancer in women

Effect of Caffeine, a xanthine derivative, in the inhibition of experimental lung metastasis induced by B16F10 melanoma cells.

Gude RP, Menon LG, Rao SG.

J Exp Clin Cancer Res. 2001 Jun; 20(2):287-92.

Caffeine, a methyl xanthine derivative, was studied to assess the effect on B16F10 melanoma induced experimental metastasis. Caffeine was administered at a dose of 100 and 50 mg/kg body weight by both routes, to tumour bearing animals. Solid tumour reduction studies with Caffeine showed a significant reduction in tumour volume for 100 mg/kg dose by both oral and i.p. routes. The Caffeine treated metastatic tumour bearing animals significantly (p<0.001) inhibited lung tumour nodules. Serum sialic acid levels and lung hydroxyproline contents in the treated groups were significantly (p<0.001) low, when compared with the untreated control animals. In the present study, our results suggest that Caffeine inhibits solid tumour development and pulmonary experimental metastasis induced by B16F10 melanoma cells, in murine model

Alteration of p53 damage response by tamoxifen treatment.

Guillot C, Falette N, Courtois S, et al.

Clin Cancer Res. 1996 Sep; 2(9):1439-44.

Hormone therapy is often used in association with chemotherapy in the treatment of estrogen-responsive breast cancers. By using breast adenocarcinoma cell lines, we show that antiestrogen treatment leads to a dramatic decrease of p53 protein levels. This effect leads to a loss of wild-type p53 response to genotoxic treatment. This inhibition is assessed by the lack of p53 protein accumulation and the loss of the p53-dependent induction of p21(WAF1/CIP1) expression. Given that the effects of several anticancer agents are mediated through DNA damage, these observations suggest that antiestrogen treatment could modulate cellular response to chemotherapeutic agents

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

A critical evaluation of sentinel lymph node dissection in malignancy.

Haigh PIGAE.

2000; Updates(14):1-11.

Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice.

Hanahan D, Bergers G, Bergsland E.

J Clin Invest. 2000 Apr; 105(8):1045-7.

Breast cancer after treatment of Hodgkin's disease.

Hancock SL, Tucker MA, Hoppe RT.

J Natl Cancer Inst. 1993 Jan 6; 85(1):25-31.

BACKGROUND: Most studies of survivors of Hodgkin's disease have shown a low risk for subsequent breast cancer, even though much lower doses of radiation than those used for Hodgkin's disease have been shown to induce breast cancer in other settings. PURPOSE: This study quantifies the risk of breast cancer following Hodgkin's disease treatment according to age at treatment and type of treatment. METHODS: To evaluate the risk of breast cancer from irradiation, we reviewed records of 885 women treated for Hodgkin's disease between 1961 and 1990 (mean follow-up, 10 years). Risks for breast cancer incidence and mortality were calculated by comparison with expected rates for a general female population matched by age and race. RESULTS: Twenty-five patients have developed invasive breast cancer, yielding a relative risk (RR) of 4.1 (95% confidence interval [CI] = 2.5-5.7). An additional patient developed multifocal carcinoma in situ. Age at irradiation strongly influenced risk: RR was 136 for women treated before 15 years of age (95% CI = 34-371). RR declined with age at irradiation (P for trend < .0001), but the elevation remained statistically significant for subjects less than 30 years old at the time of irradiation (for those 15-24, RR = "19" [95% CI = "10.3-32];" for those 24-29, RR = "7" [95% CI = "3.2-14.4])." In women above 30 years of age, the risk was not elevated (RR = "0.7;" 95% CI = "0.2-1.8)." Risk of breast cancer increased significantly with time since treatment (P for trend < .0001). The RR was 2.0 (95% CI = "1.0-3.5)" with follow-up under 15 years and 13.6 (95% CI = "7.9-18.2)" with follow-up equal to or exceeding 15 years. The addition of mechlorethamine, vincristine, procarbazine, and prednisone chemotherapy to irradiation increased the risk within the first 15 years. Most breast cancers (22 of 26) arose within or at the margin of the radiation field and were infiltrating ductal carcinomas. Stage distribution and outcome suggest that the increased incidence was not solely attributable to vigilant screening. RR of death from breast cancer was 5.1 (95% CI = "2.2-10.0)." CONCLUSIONS: Women treated for Hodgkin's disease with radiation before 30 years of age are at markedly increased risk for breast cancer, with risk increasing dramatically more than 15 years after therapy. IMPLICATIONS: The high RR for development of breast cancer in women exposed to therapeutic radiation under 30 years of age raises important issues about optimal treatment strategies for patients with Hodgkin's disease, breast cancer, and other cancers

Malignant tumors of the breast.

Harris JRMMNL.

1997;( Section 2)

Bone mass, bone loss, and osteoporosis prophylaxis.

Heaney RP.

Ann Intern Med. 1998 Feb 15; 128(4):313-4.

The macrophage activating potential of ubiquinones. In Biomedical and Clinical Aspects of Coenzyme 1981, pp. 325-34.

Hogenauer GMPDJ.

1981;325-34.

Seasonal variation in the secretion of mammotrophic hormones in normal women and women with previous breast cancer.

Holdaway IM, Mason BH, Gibbs EE, et al.

Breast Cancer Res Treat. 1997 Jan; 42(1):15-22.

Hormones such as melatonin whose serum concentrations vary seasonally have been previously implicated in the growth of breast cancer. The present study was undertaken to identify possible seasonal variation in a range of mammotrophic hormones which could exert a chronobiologic influence in women with breast tumours. Fifteen premenopausal women with a history of previous breast cancer (BC subjects) and 10 control women underwent 2-hourly serum sampling for 24 h at both summer and winter solstice for measurement of melatonin, growth hormone (GH), insulin-like growth factor-I (IGF-I), cortisol, prolactin and thyrotrophin (TSH). Hormone secretion at the different seasons was compared by measuring the area under the 24 h serum hormone concentration x time curves and by time series analysis of summer-to-winter differences in hormone concentration. Control women had significantly higher GH and IGF-I levels in summer compared to winter and significantly higher cortisol secretion in winter than summer. In contrast, BC women had no significant seasonal difference in IGF-I concentrations and had a reversal of the normal seasonal pattern of melatonin secretion, although seasonal changes in GH production were similar to controls. Prolactin and TSH showed no significant summer/winter variation in either group. Thus, seasonal variations in hormone secretion seen in normal women were, with exception of GH, absent or reversed in women with a previous history of breast cancer. As a result these individuals may be exposed to an asynchronous hormonal stimulus which could influence tumour growth. These changes could reflect a constitutional abnormality in BC women or may have been induced by the previous breast tumour

Holland-Frei Cancer Medicine.

Holland JFKDWPRBRCJrFE.

2000;

Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group.

Hortobagyi GN, Theriault RL, Porter L, et al.

N Engl J Med. 1996 Dec 12; 335(24):1785-91.

BACKGROUND: Bisphosphonates such as pamidronate disodium inhibit osteoclast-induced bone resorption associated with cancer that has metastasized to bone. METHODS: Women with stage IV breast cancer who were receiving cytotoxic chemotherapy and had at least one lytic bone lesion were given either placebo or pamidronate (90 mg) as a two-hour intravenous infusion monthly for 12 cycles. Skeletal complications, including pathologic fractures, the need for radiation to bone or bone surgery, spinal cord compression, and hypercalcemia (a serum calcium concentration above 12 mg per deciliter [3.0 mmol per liter] or elevated to any degree and requiring treatment), were assessed monthly. Bone pain, use of analgesic drugs, performance status, and quality of life were assessed throughout the trial. RESULTS: The efficacy of treatment was evaluated in 380 of 382 randomized patients, 185 receiving pamidronate and 195 receiving placebo. The median time to the occurrence of the first skeletal complication was greater in the pamidronate group than in the placebo group (13.1 vs. 7.0 months, P=0.005), and the proportion of patients in whom any skeletal complication occurred was lower (43 percent vs. 56 percent, P = 0.008). There was significantly less increase in bone pain (P=0.046) and deterioration of performance status (P=0.027) in the pamidronate group than in the placebo group. Pamidronate was well tolerated. CONCLUSIONS: Monthly infusions of pamidronate as a supplement to chemotherapy can protect against skeletal complications in women with stage IV breast cancer who have osteolytic bone metastases

Suppression of c-Jun/AP-1 activation by an inhibitor of tumor promotion in mouse fibroblast cells.

Huang TS, Lee SC, Lin JK.

Proc Natl Acad Sci U S A. 1991 Jun 15; 88(12):5292-6.

Curcumin, a dietary pigment responsible for the yellow color of curry, is a potent inhibitor of tumor promotion by phorbol esters. Functional activation of transcriptional factor c-Jun/AP-1 is believed to play an important role in signal transduction of phorbol 12-myristate 13-acetate-induced tumor promotion. Suppression of the c-Jun/AP-1 activation by curcumin is observed in mouse fibroblast cells. In vitro experiments indicate that inhibition of c-Jun/AP-1 binding to its cognate motif by curcumin may be responsible for the inhibition of c-Jun/AP-1-mediated gene expression. These findings show that the effect of curcumin on phorbol 12-myristate 13-acetate-induced inflammation/tumor promotion could be studied at the molecular level

A Review of the Department of Defense's Program for Breast Cancer Research 1997.

IOM.Institute of Medicine/Committee to Review the Department of Defense's Breast Cancer Research Program.

1997

Comparison of selenium and sulfur analogs in cancer prevention.

Ip C, Ganther HE.

Carcinogenesis. 1992 Jul; 13(7):1167-70.

Several organoselenium compounds have been shown to have powerful anticarcinogenic activity. In view of certain similarities between selenium and sulfur biochemistry, we have evaluated the chemopreventive efficacy of three pairs of analogs using the 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor model in rats. The compounds tested were selenocystamine/cysteamine, Semethylselenocysteine/S-methylcysteine, selenobetaine/sulfobetaine. In the first study, each agent was added to the basal AIN-76A diet and was given before and continued after DMBA treatment until the end. All three selenium compounds were active; a 50% inhibition was achieved at approximately 25 x 10(-6) mol/kg with Se-methylselenocysteine and selenobetaine and at approximately 40 x 10(-6) mol/kg with selenocystamine. In the sulfur series, only cysteamine and S-methylcysteine produced anticancer activity, and the levels required for comparable responses were 500- to 750-fold higher compared to the corresponding selenium analogs. Sulfobetaine was inactive even when present at near maximally tolerated levels. In the second study, Se-methylselenocysteine and S-methylcysteine were chosen for further examination during the initiation and post-initiation phases of mammary carcinogenesis. Se-Methylselenocysteine was effective when it was given either before or after DMBA administration. In contrast, S-methylcysteine was effective only after DMBA treatment. Thus, compared to the sulfur structural analogs, selenium compounds are much more active in cancer protection and may have a multi-modal mechanism in preventing cellular transformation as well as in delaying or inhibiting the expression of malignancy after carcinogen exposure

Conjugated linoleic acid-enriched butter fat alters mammary gland morphogenesis and reduces cancer risk in rats.

Ip C, Banni S, Angioni E, et al.

J Nutr. 1999 Dec; 129(12):2135-42.

Conjugated linoleic acid (CLA) is a potent cancer preventive agent in animal models. To date, all of the in vivo work with CLA has been done with a commercial free fatty acid preparation containing a mixture of c9,t11-, t10,c12- and c11,t13-isomers, although CLA in food is predominantly (80-90%) the c9,t11-isomer present in triacylglycerols. The objective of this study was to determine whether a high CLA butter fat has biological activities similar to those of the mixture of free fatty acid CLA isomers. The following four different endpoints were evaluated in rat mammary gland: 1) digitized image analysis of epithelial mass in mammary whole mount; 2) terminal end bud (TEB) density; 3) proliferative activity of TEB cells as determined by proliferating cell nuclear antigen immunohistochemistry; and 4) mammary cancer prevention bioassay in the methylnitrosourea model. It should be noted that TEB cells are the target cells for mammary chemical carcinogenesis. Feeding butter fat CLA to rats during the time of pubescent mammary gland development reduced mammary epithelial mass by 22%, decreased the size of the TEB population by 30%, suppressed the proliferation of TEB cells by 30% and inhibited mammary tumor yield by 53% (P < 0.05). Furthermore, all of the above variables responded with the same magnitude of change to both butter fat CLA and the mixture of CLA isomers at the level of CLA (0.8%) present in the diet. Interestingly, there appeared to be some selectivity in the uptake or incorporation of c9,t11-CLA over t10,c12-CLA in the tissues of rats given the mixture of CLA isomers. Rats consuming the CLA-enriched butter fat also consistently accumulated more total CLA in the mammary gland and other tissues (four- to sixfold increases) compared with those consuming free fatty acid CLA (threefold increases) at the same dietary level of intake. We hypothesize that the availability of vaccenic acid (t11-18:1) in butter fat may serve as the precursor for the endogenous synthesis of CLA via the Delta9-desaturase reaction. Further studies will be conducted to investigate other attributes of this novel dairy product

Methylselenocysteine modulates proliferation and apoptosis biomarkers in premalignant lesions of the rat mammary gland.

Ip C, Dong Y.

Anticancer Res. 2001 Mar; 21(2A):863-7.

In the rat mammary carcinogenesis model, premalignant lesions known as intraductal proliferations (IDPs) are detectable within a few weeks after carcinogen treatment. These early transformed colonies are the precursors for the eventual formation of carcinomas. Our past research indicated that methylselenocysteine added to the diet of rats reduced the development of IDPs of all sizes (the size of each IDP was estimated operationally by the number of 5-micron serial sections showing the same pathology). The appearance of an IDP lesion represents a balance between cell proliferation and cell death. The modulation of these two cellular events by methylselenocysteine was investigated. The abdominal-inguinal mammary gland was excised 6 weeks after MNU administration. Proliferation and apoptosis were evaluated by BrdU labeling and the TUNEL assay, respectively. The expression levels of several cell cycle and apoptosis regulatory proteins, including cyclin D1, cyclin A, p27, p16, bcl-2, box and bak, were also assessed. All of the above endpoints were quantified by immunohistochemistry in paraffin-embedded sections. The results showed that the magnitude of the response to methylselenocysteine intervention seemed to depend on the size of the IDP lesion. For the purpose of this study, the small and large lesions were classified as those containing 30 serial sections, respectively. With the small lesions, methylselenocysteine significantly inhibited BrdU labeling and the expression of cyclin D1 and cyclin A, but increased the expression of p27. Interesting, only p27 was upregulated in the larger IDP lesions, while BrdU labeling and the cyclins were not affected. It is possible that the transformed phenotype becomes less sensitive to selenium-mediated arrest of proliferation once it progresses to a more advanced pathological stage. In contrast, methylselenocysteine stimulated apoptosis (TUNEL assay) by 3 to 4 fold, and this increase was evident in both the small and large IDP lesions. Consistent with the induction of apoptosis, a reduced expression of bcl-2 was also observed in the methylselenocysteine group. In summary, our data suggest that exposure to methylselenocysteine blocks clonal expansion of premalignant lesions at an early stage. This is achieved by simultaneously modulating certain molecular pathways that are responsible for inhibiting cell proliferation and enhancing apoptosis

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

Prevention of mammary cancer with conjugated linoleic acid: role of the stroma and the epithelium.

Ip MM, Masso-Welch PA, Ip C.

J Mammary Gland Biol Neoplasia. 2003 Jan; 8(1):103-18.

Conjugated linoleic acid (CLA), found naturally in dairy products and ruminant meats, refers to isomers of octadecadienoic acid with conjugated double bonds. CLA inhibits both

[Vitamin A augmentation of the effects of chemotherapy in metastatic breast cancers after menopause. Randomized trial in 100 patients].

Israel L, Hajji O, Grefft-Alami A, et al.

Ann Med Interne (Paris). 1985; 136(7):551-4.

Vitamin A was administered to randomly allocated patients in a group of 100 patients with metastatic breast carcinoma treated by chemotherapy. The daily doses (given indefinitely) ranged from 350,000 to 500,000 IU according to body weight. A significant increase in the complete response rate was observed. When subgroups determined by menopausal status were considered, it was observed that serum retinol levels were only significantly increased in the post-menopausal group on high dose Vitamin A. Response rates, duration of response and projected survival were only significantly increased in this subgroup. The therapeutic and biological implications of these findings are discussed

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

Structure-activity relationships for G2 checkpoint inhibition by caffeine analogs.

Jiang X, Lim LY, Daly JW, et al.

Int J Oncol. 2000 May; 16(5):971-8.

Caffeine inhibits the G2 checkpoint activated by DNA damage and enhances the toxicity of DNA-damaging agents towards p53-defective cancer cells. The relationship between structure and G2 checkpoint inhibition was determined for 56 caffeine analogs. Replacement of the methyl group at position 3 or 7 resulted in loss of activity, while replacement at position 1 by ethyl or propyl increased activity slightly. 8-Substituted caffeines retained activity, but were relatively insoluble. The structure-activity profile did not resemble those for other known pharmacological activities of caffeine. The active analogs also potentiated the killing of p53-defective cells by ionizing radiation, but none was as effective as caffeine

Is there a real risk of radiation-induced breast cancer for postmenopausal women?

Jung H.

Radiat Environ Biophys. 2001 Jun; 40(2):169-74.

The risk of radiation-induced breast cancer decreases with increasing age at exposure. Thus, for calculating the individual risk for a patient undergoing mammography, age-related risk coefficients need to be used. In this report, the results of epidemiological studies on risks of radiation-induced breast cancer are reviewed indicating that the available data do not show the risk to be enhanced for women exposed at the age of 55 years or older. This lack of evidence is reflected by the fact that the risk coefficients recommended by national and international advisory bodies differ by a factor of 10 or more for age at exposure of 50-60 years or older. A hypothesis is proposed indicating that the risk of radiation-induced breast cancer might decrease considerably at the time of menopause. The hypothesis is based on the following line of arguments: (1) evidence has accumulated from molecular genetic studies indicating that the development of colorectal cancer requires a cascade of subsequent mutations consisting of at least seven genetic events. (2) For colorectal cancer, the annual rates of incidence and mortality increase with age to the power of 5-6. Thus, the number of mutation steps (minus 1) is approximately reflected by the power of age dependence. (3) For western populations, the incidence and mortality of breast cancer up to the age of about 50 years increase with age to the power of about 6, indicating that a similar number of genetic events might be involved in development of breast cancer as has been identified for colorectal cancer. (4) For women aged 50 years or older, breast cancer occurs at an annual rate that is about proportional to age or age squared. This may mean that after menopause, the processes in the multistep mutation cascade leading to breast cancer are slowed down by a factor of about 4 or more. (5) The constant relative risk model of radiation carcinogenesis implies for solid cancers that radiation acts by inducing additional mutations in the earlier steps of the multistep cascade. It is suggested that the break-point in the age-specific annual rate of breast cancer incidence at menopause is associated with a corresponding drop in radiation sensitivity with respect to induction of breast cancer

Se-methylselenocysteine induces apoptosis mediated by reactive oxygen species in HL-60 cells.

Jung U, Zheng X, Yoon SO, et al.

Free Radic Biol Med. 2001 Aug 15; 31(4):479-89.

Recent studies have implicated apoptosis as one of the most plausible mechanisms of the chemopreventive effects of selenium compounds, and reactive oxygen species (ROS) as important mediators in apoptosis induced by various stimuli. In the present study, we demonstrate that Se-methylselenocysteine (MSC), one of the most effective selenium compounds at chemoprevention, induced apoptosis in HL-60 cells and that ROS plays a crucial role in MSC-induced apoptosis. The uptake of MSC by HL-60 cells occurred quite early, reaching the maximum within 1 h. The dose-dependent decrease in cell viability was observed by MSC treatment and was coincident with increased DNA fragmentation and sub-G(1) population. 50 microM of MSC was able to induce apoptosis in 48% of cell population at a 24 h time point. Moreover, the release of cytochrome c from mitochondria and the activation of caspase-3 and caspase-9 were also observed. The measurement of ROS by dichlorofluorescein fluorescence revealed that dose- and time-dependent increase in ROS was induced by MSC. N-acetylcysteine, glutathione, and deferoxamine blocked cell death, DNA fragmentation, and ROS generation induced by MSC. Moreover, N-acetylcysteine effectively blocked caspase-3 activation and the increase of the sub-G(1) population induced by MSC. These results imply that ROS is a critical mediator of the MSC-induced apoptosis in HL-60 cells

EGCG, a major component of green tea, inhibits tumour growth by inhibiting VEGF induction in human colon carcinoma cells.

Jung YD, Kim MS, Shin BA, et al.

Br J Cancer. 2001 Mar 23; 84(6):844-50.

Catechins are key components of teas that have antiproliferative properties. We investigated the effects of green tea catechins on intracellular signalling and VEGF induction in vitro in serum-deprived HT29 human colon cancer cells and in vivo on the growth of HT29 cells in nude mice. In the in vitro studies, (-)-epigallocatechin gallate (EGCG), the most abundant catechin in green tea extract, inhibited Erk-1 and Erk-2 activation in a dose-dependent manner. However, other tea catechins such as (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epicatechin (EC) did not affect Erk-1 or 2 activation at a concentration of 30 microM. EGCG also inhibited the increase of VEGF expression and promoter activity induced by serum starvation. In the in vivo studies, athymic BALB/c nude mice were inoculated subcutaneously with HT29 cells and treated with daily intraperitoneal injections of EC (negative control) or EGCG at 1.5 mg day(-1)mouse(-1)starting 2 days after tumour cell inoculation. Treatment with EGCG inhibited tumour growth (58%), microvessel density (30%), and tumour cell proliferation (27%) and increased tumour cell apoptosis (1.9-fold) and endothelial cell apoptosis (3-fold) relative to the control condition (P< 0.05 for all comparisons). EGCG may exert at least part of its anticancer effect by inhibiting angiogenesis through blocking the induction of VEGF

Conjugated linoleic acid inhibits cell proliferation through a p53-dependent mechanism: effects on the expression of G1-restriction points in breast and colon cancer cells.

Kemp MQ, Jeffy BD, Romagnolo DF.

J Nutr. 2003 Nov; 133(11):3670-7.

Previous reports have documented the antiproliferative properties of a mixture of conjugated isomers (CLA) of linoleic acid [LA (18:2)]. In this study, we investigated the mechanisms of CLA action on cell cycle progression in breast and colon cancer cells. Treatment with CLA inhibited cell proliferation in breast cancer MCF-7 cells containing wild-type p53 (p53(+/+)). At cytostatic concentrations, CLA elicited cell cycle arrest in G1 and induced the accumulation of the tumor suppressors p53, p27 and p21 protein. Conversely, CLA reduced the expression of factors required for G1 to S-phase transition including cyclins D1 and E, and hyperphoshorylated retinoblastoma Rb protein. In contrast, the overexpression of mutant p53 (175Arg to His) in MFC-7 cells prevented the CLA-dependent accumulation of p21 and the reduction of cyclin E levels suggesting that the expression of wild-type p53 is required for CLA-mediated activation of the G1 restriction point. To further elucidate the role of p53, the effects of CLA in colon cancer HCT116 cells (p53(+/+)) and p53-deficient (p53(-/-)) HCT116 cells (HCTKO) were examined. The treatment of HCT116 cells with CLA increased the levels of p53, p21, p27 and hypophosphorylated (pRb) protein and reduced the expression of cyclin E, whereas these effects were not seen in p53-deficient HCTKO cells. The t10,c12-CLA isomer was more effective than c9,t11-CLA in inhibiting cell proliferation of MCF-7 breast cancer cells and enhancing the accumulation of p53 and pRb. We conclude that the antiproliferative properties of CLA appear to be a function, at least in part, of the relative content of specific isomers and their ability to elicit a p53 response that leads to the accumulation of pRb and cell growth arrest

Caffeine diminishes cytotoxic effects of paclitaxel on a human lung adenocarcinoma cell line.

Kitamoto Y, Sakurai H, Mitsuhashi N, et al.

Cancer Lett. 2003 Feb 28; 191(1):101-7.

This study was performed to investigate how caffeine modifies the cytotoxic effects of paclitaxel on a human lung carcinoma cell line. Caffeine doses up to 5mM had less effect on clonogenic survival. The cell killing effect, due to paclitaxel, increased in a dose-dependent manner up to 50 nM. For combined treatment with caffeine and paclitaxel, added caffeine reduced the cytotoxic effect of paclitaxel not only in dose-response but also in time-response curves. Caffeine combined with paclitaxel clearly suppressed cell proliferation in a dose-dependent manner. In the cell cycle analysis, caffeine alone caused early G1 accumulation, whereas paclitaxel alone caused an early increase in G2-M and a decrease in G1. As for the effect of caffeine on paclitaxel, caffeine suppressed the effect of paclitaxel on cell cycle distribution, where a dose-dependent early increase in G2-M and a decrease in G1 were not clear. We suggest that cell cycle modifying agents, such as caffeine, potentially diminish the cytotoxic activity of paclitaxel, and one should be careful when combining such agents

Vitamin E: mechanisms of action as tumor cell growth inhibitors.

Kline K, Yu W, Sanders BG.

J Nutr. 2001 Jan; 131(1):161S-3S.

The sentinel node in breast cancer--a multicenter validation study.

Krag D, Weaver D, Ashikaga T, et al.

N Engl J Med. 1998 Oct 1; 339(14):941-6.

BACKGROUND: Pilot studies indicate that probe-guided resection of radioactive sentinel nodes (the first nodes that receive drainage from tumors) can identify regional metastases in patients with breast cancer. To confirm this finding, we conducted a multicenter study of the method as used by 11 surgeons in a variety of practice settings. METHODS: We enrolled 443 patients with breast cancer. The technique involved the injection of 4 ml of technetium-99m sulfur colloid (1 mCi [37 MBq]) into the breast around the tumor or biopsy cavity. "Hot spots" representing underlying sentinel nodes were identified with a gamma probe. Sentinel nodes subjacent to hot spots were removed. All patients underwent a complete axillary lymphadenectomy. RESULTS: The overall rate of identification of hot spots was 93 percent (in 413 of 443 patients). The pathological status of the sentinel nodes was compared with that of the remaining axillary nodes. The accuracy of the sentinel nodes with respect to the positive or negative status of the axillary nodes was 97 percent (392 of 405); the specificity of the method was 100 percent, the positive predictive value was 100 percent, the negative predictive value was 96 percent (291 of 304), and the sensitivity was 89 percent (101 of 114). The sentinel nodes were outside the axilla in 8 percent of cases and outside of level 1 nodes in 11 percent of cases. Three percent of positive sentinel nodes were in nonaxillary locations. CONCLUSIONS: Biopsy of sentinel nodes can predict the presence or absence of axillary-node metastases in patients with breast cancer. However, the procedure can be technically challenging, and the success rate varies according to the surgeon and the characteristics of the patient

Breast MR imaging screening in 192 women proved or suspected to be carriers of a breast cancer susceptibility gene: preliminary results.

Kuhl CK, Schmutzler RK, Leutner CC, et al.

Radiology. 2000 Apr; 215(1):267-79.

PURPOSE: To compare magnetic resonance (MR) imaging with conventional imaging in screening high-risk women. MATERIALS AND METHODS: This prospective trial included 192 asymptomatic and six symptomatic women who, on the basis of personal or family history or genetic analysis, were suspected or proved to carry a breast cancer susceptibility gene. RESULTS: Fifteen breast cancers were identified: nine in the 192 asymptomatic women (six in the first and three in the second screening round) and six in the symptomatic patients. Concerning the asymptomatic women, four of the nine breast cancers were detected and correctly classified with mammography and ultrasonography (US) combined; another two cancers were visible as well-circumscribed masses and were diagnosed as fibroadenomas. MR imaging allowed the correct classification and local staging of all nine cancers. In 105 asymptomatic women with validation of the 1st-year screening results, the sensitivities of mammography, US, and MR imaging were 33%, 33% (mammography and US combined, 44%), and 100%, respectively; the positive predictive values were 30%, 12%, and 64%, respectively. CONCLUSION: The accuracy of MR imaging is significantly higher than that of conventional imaging in screening high-risk women. Difficulties can be caused by an atypical manifestation of hereditary breast cancers at both conventional and MR imaging and by contrast material enhancement associated with hormonal stimulation

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

The relationship between alcohol use and risk of breast cancer by histology and hormone receptor status among women 65-79 years of age.

Li CI, Malone KE, Porter PL, et al.

Cancer Epidemiol Biomarkers Prev. 2003 Oct; 12(10):1061-6.

Alcohol consumption is associated with a moderate increase in breast cancer risk, possibly because alcohol increases estrogen levels in blood. Certain types of breast carcinomas are more hormonally responsive than others, including those that have a lobular histology or are hormone receptor positive, but few studies evaluating alcohol use and breast cancer risk have stratified results by histology or estrogen receptor (ER)/progesterone receptor (PR) status. We conducted a population-based case-control study of women 65-79 years of age in western Washington State. Women (975) diagnosed with invasive breast cancer during 1997-1999 were compared with 1007 controls. Ever-use of alcohol over the past 20 years was associated with a 1.3-fold [95% confidence interval (CI), 1.0-1.5] increased risk of breast cancer, although this increase was primarily limited to women who consumed > or =30.0 g/day of alcohol [odds ratio (OR), 1.7; 95% CI, 1.1-2.6]. Differences in risk by histology were observed: ever-use of alcohol was associated with a 1.8-fold (95% CI, 1.3-2.5) increased risk of lobular cancer but only a 1.2-fold (95% CI, 0.9-1.4) increased risk of ductal cancer. Ever-users of alcohol had an increase in risk of ER+/PR+ tumors (OR, 1.3; 95% CI, 1.1-1.7), but no change in their risks of ER+/PR- or ER-/PR- tumors. Alcohol use appears to be more strongly associated with risk of lobular carcinomas and hormone receptor-positive tumors than it is with other types of breast cancer. These results are consistent with there being an underlying hormonal basis for the known association between alcohol use and breast cancer incidence

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

Immune effects of preoperative immunotherapy with high-dose subcutaneous interleukin-2 versus neuroimmunotherapy with low-dose interleukin-2 plus the neurohormone melatonin in gastrointestinal tract tumor patients.

Lissoni P, Brivio F, Brivio O, et al.

J Biol Regul Homeost Agents. 1995 Jan; 9(1):31-3.

Surgery-induced immunosuppression could influence tumor/host interactions in surgically treated cancer patients. Previous studies have shown that high-dose IL-2 preoperative therapy may neutralize surgery-induced lymphocytopenia. Moreover, experimental studies have demonstrated that the immunomodulating neurohormone melatonin (MLT) may amplify IL-2 activity and reduce its dose required to activate the immune system. On this basis, we have compared the immune effects of presurgical therapy with high-dose IL-2 with respect to those obtained with preoperative neuroimmunotherapy consisting of low-dose IL-2 plus MLT. The study included 30 patients with gastrointestinal tract tumors, who were randomized to undergo surgery alone, or surgery plus a preoperative biotherapy with high-dose IL-2 (18 million IU/day subcutaneously for 3 days) or low-dose IL-2 (6 million IU/day subcutaneously for 5 days) plus MLT (40 mg/day orally). Patients underwent surgery within 36 hours from IL-2 interruption. Both IL-2 plus MLT were able to prevent surgery-induced lymphocytopenia. However, mean number of lymphocytes, T lymphocytes and T helper lymphocytes observed on day 1 of postoperative period was significantly higher in patients treated with IL-2 plus MLT than in those receiving IL-2 alone. Moreover, toxicity was less in patients treated with IL-2 and MLT. This biological study shows that both immunotherapy with high-dose IL-2 or neuroimmunotherapy with low-dose IL-2 plus MLT preoperatively are tolerated biotherapies, capable of neutralizing surgery-induced lymphocytopenia in cancer patients. Moreover, the study would suggest that the neuroimmunotherapy may induce a more rapid effect on postoperative immune changes with respect to IL-2 alone

Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q10.

Lockwood K, Moesgaard S, Folkers K.

Biochem Biophys Res Commun. 1994 Mar 30; 199(3):1504-8.

Relationships of nutrition and vitamins to the genesis and prevention of cancer are increasingly evident. In a clinical protocol, 32 patients having -"high-risk"- breast cancer were treated with antioxidants, fatty acids, and 90 mg. of CoQ10. Six of the 32 patients showed partial tumor regression. In one of these 6 cases, the dosage of CoQ10 was increased to 390 mg. In one month, the tumor was no longer palpable and in another month, mammography confirmed the absence of tumor. Encouraged, another case having a verified breast tumor, after non-radical surgery and with verified residual tumor in the tumor bed was then treated with 300 mg. CoQ10. After 3 months, the patient was in excellent clinical condition and there was no residual tumor tissue. The bioenergetic activity of CoQ10, expressed as hematological or immunological activity, may be the dominant but not the sole molecular mechanism causing the regression of breast cancer

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

Effects of oral administration of tea, decaffeinated tea, and caffeine on the formation and growth of tumors in high-risk SKH-1 mice previously treated with ultraviolet B light.

Lou YR, Lu YP, Xie JG, et al.

Nutr Cancer. 1999; 33(2):146-53.

Treatment of SKH-1 mice with ultraviolet B light (UV-B, 30 mJ/cm2) twice a week for 22-23 weeks resulted in tumor-free animals with a high risk of developing malignant and nonmalignant tumors during the next several months in the absence of further UV-B treatment (high-risk mice). In three separate experiments, oral administration of green tea or black tea (4-6 mg tea solids/ml) as the sole source of drinking fluid for 18-23 weeks to these high-risk mice inhibited the formation and decreased the size of nonmalignant squamous cell papillomas and keratoacanthomas as well as the formation and size of malignant squamous cell carcinomas. In one experiment all these inhibitory effects of tea were statistically significant, whereas in the two other experiments many but not all of the inhibitory effects of tea were statistically significant. The decaffeinated teas were inactive or less effective inhibitors of tumor formation than the regular teas, and adding caffeine back to the decaffeinated teas restored biological activity. Oral administration of caffeine alone (0.44 mg/ml) as the sole source of drinking fluid for 18-23 weeks inhibited the formation of nonmalignant and malignant tumors, and this treatment also decreased tumor size in these high-risk mice

Dr. Susan Love's Breast Book.

Love S.

1997;

Topical applications of caffeine or (-)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice.

Lu YP, Lou YR, Xie JG, et al.

Proc Natl Acad Sci U S A. 2002 Sep 17; 99(19):12455-60.

SKH-1 hairless mice were irradiated with ultraviolet B (UVB) twice weekly for 20 weeks. These tumor-free mice, which had a high risk of developing skin tumors during the next several months, were then treated topically with caffeine (6.2 micromol) or (-)-epigallocatechin gallate (EGCG; 6.5 micromol) once a day 5 days a week for 18 weeks in the absence of further treatment with UVB. Topical applications of caffeine to these mice decreased the number of nonmalignant and malignant skin tumors per mouse by 44% and 72%, respectively. Topical applications of EGCG decreased the number of nonmalignant and malignant tumors per mouse by 55% and 66%, respectively. Immunohistochemical analysis showed that topical applications of caffeine or EGCG increased apoptosis as measured by the number of caspase 3-positive cells in nonmalignant skin tumors by 87% or 72%, respectively, and in squamous cell carcinomas by 92% or 56%, respectively, but there was no effect on apoptosis in nontumor areas of the epidermis. Topical applications of caffeine or EGCG had a small inhibitory effect on proliferation in nonmalignant tumors as measured by BrdUrd labeling (16-22%), and there was also a similar, but nonsignificant, inhibitory effect on proliferation in malignant tumors. The results suggest a need for further studies to determine whether topical applications of caffeine or EGCG can inhibit sunlight-induced skin cancer in humans

Protection against anthramycin-induced toxicity in mice by coenzyme Q10.

Lubawy WC, Dallam RA, Hurley LH.

J Natl Cancer Inst. 1980 Jan; 64(1):105-9.

Pretreatment of Swiss Webster mice with coenzyme Q10 (CoQ) markedly reduced the lethality of the antitumor antibiotic anthramycin as well as its ability to decrease ventricular weights. In tumor-bearing mice CoQ pretreatment did not produce any consistent alteration of radioactivity levels in blood, heart, tumor, lungs, kidneys, liver, muscles, brain, or spleen after [15-3H]anthramycin administration. Gross alterations in anthramycin distribution is probably not the mechanism by which CoQ alters the cardiotoxicity and lethality of anthramycin

Protection against anthramycin-induced toxicity in mice by coenzyme Q10.

Lubawy WCDRAHLH.

J Natl Cancer Inst. 1980; 64(1):105-9.

Conjugated linoleic acids (CLAs) regulate the expression of key apoptotic genes in human breast cancer cells.

Majumder B, Wahle KW, Moir S, et al.

FASEB J. 2002 Sep; 16(11):1447-9.

Conjugated linoleic acid (CLA) reduces mammary tumorigenesis in rodent models, induces apoptosis in rodent mammary tumor cell lines, and decreases expression of antiapoptotic bcl-2 in rat mammary tissue. This investigation focused on the cell mechanisms underlying the antitumor effects of CLA. Changes (mRNA, protein) in expression of major proapoptotic p53, p21WAF1/CIP1, bax, bcl-Xs genes, and the antiapoptotic bcl-2 gene were observed in malignant MCF-7 and MDA-MB-231 cells and in benign MCF-10a human mammary tumor cells in culture. CLA, but not linoleic acid (LA), inhibited proliferation in all cells; CLA mix was most effective. CLA increased DNA damage (apoptosis). CLA increased mRNA expression of p53 and p21WAF1/CIP1 (three- to fivefold and twofold, respectively) but either decreased bcl-2 by 20-30% or had no effect in MCF-7 and MCF-10a cells, respectively; protein expression reflected mRNA values. In MDA-MBA-231 (mutant p53) cells, mRNA for p53 was not changed, but p21WAF1/CIP1 and bcl-2 mRNA was increased. Protein expression largely reflected mRNA changes but, surprisingly, CLA completely suppressed mutant p53 protein in MDA-MB-231 cells. Apparent antiapoptotic effects of increased bcl-2 expression in MDA-MBA-231 cells were countered by increased proapoptotic p21WAF1/CIP1, Bax, and Bcl-Xs proteins. Findings indicate that CLA elicits mainly proapoptotic effects in human breast tumor cells through both p53-dependent and p53-independent pathways, according to cell type

Dietary fish oil and fish and borage oil suppress intrapulmonary proinflammatory eicosanoid biosynthesis and attenuate pulmonary neutrophil accumulation in endotoxic rats.

Mancuso P, Whelan J, DeMichele SJ, et al.

Crit Care Med. 1997 Jul; 25(7):1198-206.

OBJECTIVE: Proinflammatory eicosanoids and cytokines are important mediators of local inflammation in acute lung injury. We determined if enteral nutrition with anti-inflammatory fatty acids, eicosapentaenoic acid, and gamma-linolenic acid would reduce the intrapulmonary synthesis of proinflammatory eicosanoids and cytokines and pulmonary neutrophil accumulation in a rat model of acute lung injury. DESIGN: Prospective, randomized, controlled, double-blind study. SETTING: Research laboratory at a university medical center. SUBJECTS: Male Long-Evans rats (250 g). INTERVENTIONS: Rats were randomly assigned to three dietary treatment groups and fed nutritionally complete diets (300 kcal/kg/day) containing 55.2% of the total calories from fat with either 97% corn oil, 20% fish oil, or 20% fish and 20% borage oil for 21 days. On day 22, bronchoalveolar lavage was performed 2 hrs after an intravenous injection of Salmonella enteritidis endotoxin (10 mg/kg) or saline. Bronchoalveolar lavage fluid was analyzed for leukotriene B4, leukotriene C4/D4, thromboxane B2, prostaglandin E2, 6 keto-prostaglandin F1alpha, tumor necrosis factor (TNF)-alpha, and macrophage inflammatory protein-2 (MIP-2). Lung myeloperoxidase activity (a marker for neutrophil accumulation) and phospholipid fatty acid composition were also determined. MEASUREMENTS AND MAIN RESULTS: Lung phospholipid concentrations of arachidonic acid were lower and the concentrations of eicosapentaenoic acid and docosahexaenoic acid were higher with fish oil and fish and borage oil as compared with corn oil. Dihomo-gamma-linolenic acid, the desaturated and elongated intermediate of gamma-linolenic acid, increased with fish and borage oil as compared with fish oil and corn oil. The levels of leukotriene B4, leukotriene C4/D4, 6-keto-prostaglandin F1alpha, and thromboxane B2 with corn oil were significantly increased with endotoxin as compared with saline. In contrast to the corn oil group, endotoxin did not significantly increase bronchoalveolar lavage levels of leukotriene B4, leukotriene C4/D4, and thromboxane B2 above those of saline-treated rats with fish oil and fish and borage oil. Lung myeloperoxidase activity was significantly increased in endotoxin-treated rats compared with those rats given saline in all dietary treatment groups. However, lung myeloperoxidase activity was significantly lower with either fish oil or fish and borage oil as compared with corn oil after endotoxin. Although endotoxin increased the levels of TNF-alpha and MIP-2 with all dietary treatment groups as compared with saline-treated rats, there were no significant differences in the levels of either cytokine between the dietary treatment groups. CONCLUSIONS: These results indicate that dietary fish oil and fish and borage oil as compared with corn oil may ameliorate endotoxin-induced acute lung injury by suppressing the levels of proinflammatory eicosanoids (but not TNF-alpha or MIP-2) in bronchoalveolar lavage fluid and reducing pulmonary neutrophil accumulation

Curcumin differentially regulates TGF-beta1, its receptors and nitric oxide synthase during impaired wound healing.

Mani H, Sidhu GS, Kumari R, et al.

Biofactors. 2002; 16(1-2):29-43.

Wound healing is a highly ordered process, requiring complex and coordinated interactions involving peptide growth factors of which transforming growth factor-beta (TGF-beta) is one of the most important. Nitric oxide is also an important factor in healing and its production is regulated by inducible nitric oxide synthase (iNOS). We have earlier shown that curcumin (diferuloylmethane), a natural product obtained from the plant Curcuma longa, enhances cutaneous wound healing in normal and diabetic rats. In this study, we have investigated the effect of curcumin treatment by topical application in dexamethasone-impaired cutaneous healing in a full thickness punch wound model in rats. We assessed healing in terms of histology, morphometry, and collagenization on the fourth and seventh days post-wounding and analyzed the regulation of TGF-beta1, its receptors type I (tIrc) and type II (tIIrc) and iNOS. Curcumin significantly accelerated healing of wounds with or without dexamethasone treatment as revealed by a reduction in the wound width and gap length compared to controls. Curcumin treatment resulted in the enhanced expression of TGF-beta1 and TGF-beta tIIrc in both normal and impaired healing wounds as revealed by immunohistochemistry. Macrophages in the wound bed showed an enhanced expression of TGF-beta1 mRNA in curcumin treated wounds as evidenced by in situ hybridization. However, enhanced expression of TGF-beta tIrc by curcumin treatment observed only in dexamethasone-impaired wounds at the 7th day post-wounding. iNOS levels were increased following curcumin treatment in unimpaired wounds, but not so in the dexamethasone-impaired wounds. The study indicates an enhancement in dexamethasone impaired wound repair by topical curcumin and its differential regulatory effect on TGF-beta1, it's receptors and iNOS in this cutaneous wound-healing model

Diet and the risk of breast cancer in a case-control study: does the threat of disease have an influence on recall bias?

Mannisto S, Pietinen P, Virtanen M, et al.

J Clin Epidemiol. 1999 May; 52(5):429-39.

It has been suggested that recall bias may explain the discrepant results between case-control and cohort studies on diet and the risk of breast cancer. Two control groups were used for this case-control study of 25 to 75-year-old breast cancer cases (n = 310). The first group consisted of population controls drawn from the Finnish National Population Register (n = 454). The second group consisted of women who were referred to the same examinations as were the cases because of clinical suspicion of breast disease but who were later diagnosed as healthy (referral controls; n = 506). Because the diagnosis was unknown at the time of interview, it was possible to assess by comparing the two control groups whether the self-reporting of diet changed under the threat of disease. Dietary habits were examined using a validated, self-administered food-frequency questionnaire. Premenopausal women misreported their consumption of liquid milk products, tea, and sugar. Reporting bias was also associated with the intake of fat and vitamins. Postmenopausal women misreported consumption of milk products. When recall bias was taken into consideration, milk was associated with increased risk of premenopausal breast cancer, whereas high consumption of poultry or high intake of monounsaturated fatty acids, n-3 fatty acids, n-6 fatty acids, and vitamin E were related to lower risk. The study suggested that oil, milk, cheese, coffee and beta-carotene may act as protective factors in postmenopausal women, whereas butter and cream may be risk factors for breast cancer. In summary, it is possible that some food items may be overreported or underreported under the threat of disease in health-conscious population. However, most of the results in this study were not modified by recall bias

Risk of breast cancer associated with atypical hyperplasia of lobular and ductal types.

Marshall LM, Hunter DJ, Connolly JL, et al.

Cancer Epidemiol Biomarkers Prev. 1997 May; 6(5):297-301.

Epidemiological studies using the histological classification of Page for benign breast disease consistently demonstrate a positive association between atypical hyperplasia and the subsequent development of breast cancer. However, atypical hyperplasia is of either lobular or ductal types, and breast cancer risk in relation to type of atypical hyperplasia has not been studied extensively. Thus, we investigated prospectively the risk of breast cancer associated with histological subtypes of benign proliferative breast disease, including the types of atypical hyperplasia, among participants in the Nurses' Health Study who had biopsy-confirmed benign breast disease. Women who subsequently developed breast cancer were matched by year of birth and year of biopsy to participants who were free from breast cancer. Benign biopsy slides were classified according to the criteria of Page. Odds ratios (ORs) of breast cancer and 95% confidence intervals (CIs), adjusted for the matching variables and other breast cancer risk factors, were computed using unconditional logistic regression with benign nonproliferative breast disease as the referent group. Atypical ductal hyperplasia (OR = 2.4; 95% CI, 1.3-4.5) or atypical lobular hyperplasia (OR = 5.3; 95% CI, 2.7-10.4) in a prior biopsy were associated with increased breast cancer risk. Atypical lobular hyperplasia was more strongly associated with the risk of premenopausal breast cancer (OR = 9.6; 95% CI, 3.3-27.8) than with the risk of postmenopausal breast cancer (OR = 3.7; 95% CI, 1.3-10.2). The association of atypical ductal hyperplasia and breast cancer risk varied little by menopausal status. The magnitude of breast cancer risk seems to vary according to the type of atypical hyperplasia present at biopsy

Activation of PPARgamma may mediate a portion of the anticancer activity of conjugated linoleic acid.

McCarty MF.

Med Hypotheses. 2000 Sep; 55(3):187-8.

A number of human cancer cell lines express the PPARgamma transcription factor, and agonists for PPARgamma are reported to promote apoptosis in these cell lines and impede their clonal expansion both in vitro and in vivo. Conjugated linoleic acid (CLA) can activate PPARgamma in rat adipocytes, possibly explaining CLA's antidiabetic effects in Zucker fatty rats. It is thus reasonable to suspect that a portion of CLA's broad spectrum anticarcinogenic activity is mediated by PPARgamma activation in susceptible tumors

Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells.

McIntyre BS, Briski KP, Gapor A, et al.

Proc Soc Exp Biol Med. 2000 Sep; 224(4):292-301.

Studies were conducted to determine the comparative effects of tocopherols and tocotrienols on preneoplastic (CL-S1), neoplastic (-SA), and highly malignant (+SA) mouse mammary epithelial cell growth and viability in vitro. Over a 5-day culture period, treatment with 0-120 microM alpha- and gamma-tocopherol had no effect on cell proliferation, whereas growth was inhibited 50% (IC50) as compared with controls by treatment with the following: 13, 7, and 6 microM tocotrienol-rich-fraction of palm oil (TRF); 55, 47, and 23 microM delta-tocopherol; 12, 7, and 5 microM alpha-tocotrienol; 8, 5, and 4 microM gamma-tocotrienol; or 7, 4, and 3 microM delta-tocotrienol in CL-S1, -SA and +SA cells, respectively. Acute 24-hr exposure to 0-250 microM alpha- or gamma-tocopherol (CL-S1, -SA, and +SA) or 0-250 microM delta-tocopherol (CL-S1) had no effect on cell viability, whereas cell viability was reduced 50% (LD50) as compared with controls by treatment with 166 or 125 microM delta-tocopherol in -SA and +SA cells, respectively. Additional LD50 doses were determined as the following: 50, 43, and 38 microM TRF; 27, 28, and 23 microM alpha-tocotrienol; 19, 17, and 14 microM gamma-tocotrienol; or 16, 15, or 12 microM delta-tocotrienol in CL-S1, -SA, and +SA cells, respectively. Treatment-induced cell death resulted from activation of apoptosis, as indicated by DNA fragmentation. Results also showed that CL-S1, -SA, and +SA cells preferentially accumulate tocotrienols as compared with tocopherols, and this may partially explain why tocotrienols display greater biopotency than tocopherols. These data also showed that highly malignant +SA cells were the most sensitive, whereas the preneoplastic CL-S1 cells were the least sensitive to the antiproliferative and apoptotic effects of tocotrienols, and suggest that tocotrienols may have potential health benefits in preventing and/or reducing the risk of breast cancer in women

Sentinel node biopsy: studies should bring needed data.

McNeil C.

J Natl Cancer Inst. 1998 May 20; 90(10):728-30.

Suppression of breast cancer invasion and migration by indole-3-carbinol: associated with up-regulation of BRCA1 and E-cadherin/catenin complexes.

Meng Q, Qi M, Chen DZ, et al.

J Mol Med. 2000; 78(3):155-65.

Indole-3-carbinol (I3C) is a compound occurring naturally in cruciferous vegetables and has been indicated as a promising agent in preventing breast cancer development and progression. In the present study we have investigated the effect of I3C on the cell migration and invasion behavior in estrogen receptor positive MCF-7 and estrogen receptor negative MDA-MB-468 human breast cancer cell lines. Both MCF-7 and MDA-MB-468 were poorly invasive cell lines and exhibited modest invasion and migration capacity in the presence of fibronectin as the chemoattractant. I3C (50 or 100 microM) elicited a significant inhibition of in vitro cell adhesion, migration, and invasion as well as in vivo lung metastasis formation in both cell lines. I3C also suppressed the 17beta-estradiol stimulated migration and invasion in estrogen-responsive MCF-7 cells. These results indicate that anti-invasion and antimigration activities of I3C occur via estrogen-independent and estrogen-dependent pathways. Moreover, I3C significantly caused a dose-dependent increase in E-cadherin, three major catenins (alpha, beta, and gamma-catenin) and BRCA1 expression. Our current finding is the first demonstration that I3C can activate the function of invasion suppressor molecules associated with the suppression of invasion and migration in breast cancer cells. Thus, clinical application of I3C may contribute to the potential benefit for suppression of breast cancer invasion and metastasis

Effects of caffeine as an adjuvant to morphine in advanced cancer patients. A randomized, double-blind, placebo-controlled, crossover study.

Mercadante S, Serretta R, Casuccio A.

J Pain Symptom Manage. 2001 May; 21(5):369-72.

Psychomotor abnormalities are one of the complications of opioid therapy in advanced cancer patients. Caffeine has potential properties to counteract the central effects of morphine. Twelve patients receiving stable doses of slow release morphine with adequate pain relief were scheduled for this double-blind placebo-controlled crossover trial. The treatment consisted of an intravenous dose of 1/6 of the daily morphine dose, using an intravenous/oral conversion ratio of 1:3. The dose calculated was administered in 5 minutes. Patients were randomly divided to received in a double-blind manner an infusion of 200 mg of caffeine or saline solution intravenously over one hour. A crossover took place after 2-3 days. Patients were assessed immediately before the infusion and once at the end (one hour after). Each assessment included pain, nausea, confusion, and drowsiness intensity. Psychomotor tests, including tapping speed with 10-30 seconds trials, arithmetic tests, memory for digits, and visual memory were also performed. Caffeine infusion induced a significant decrease in pain intensity (from 25.3 to 16.3, p =0.003), but this was no different from the placebo. Caffeine increased both tapping speed tests (p = 0.041 and 0.010, respectively) in comparison with placebo treatment. No other significant differences were found in the other parameters examined. Caffeine showed a partial effect on the cognitive performance of advanced cancer patients on chronic morphine treatment who received a bolus of intravenous morphine. Further studies are necessary to evaluate whether higher doses of caffeine may be more effective and to establish the role of tolerance to caffeine in this group of patients

Coffee, tea, and caffeine consumption and breast cancer incidence in a cohort of Swedish women.

Michels KB, Holmberg L, Bergkvist L, et al.

Ann Epidemiol. 2002 Jan; 12(1):21-6.

PURPOSE: Coffee, caffeinated tea, and caffeine have been suggested to play a role in breast carcinogenesis or in the promotion or inhibition of tumor growth. Prior epidemiologic evidence has not supported an overall association between consumption of caffeinated beverages and risk of breast cancer, but consumption in some studies was low. METHODS: We studied this relation in the Swedish Mammography Screening Cohort, a large population-based prospective cohort study in Sweden comprising 59,036 women aged 40-76 years. Sweden has the highest coffee consumption per capita in the world. RESULTS: During 508,267 person-years of follow-up, 1271 cases of invasive breast cancer were diagnosed. Women who reported drinking 4 or more cups of coffee per day had a covariate-adjusted hazard ratio of breast cancer of 0.94 [95% confidence interval (CI) 0.75-1.28] compared to women who reported drinking 1 cup a week or less. The corresponding hazard ratio for tea consumption was 1.13 (95% CI 0.91-1.40). Similarly, women in the highest quintile of self-reported caffeine intake had a hazard ratio of beast cancer of 1.04 (95% CI 0.87-1.24) compared to women in the lowest quintile. CONCLUSIONS: In this large cohort of Swedish women, consumption of coffee, tea, and caffeine was not associated with breast cancer incidence

Altered estrogen metabolism and excretion in humans following consumption of indole-3-carbinol.

Michnovicz JJ, Bradlow HL.

Nutr Cancer. 1991; 16(1):59-66.

Research studies have demonstrated a strong association between estrogen metabolism and the incidence of breast cancer, and we have therefore sought pharmacological means of favorably altering both metabolism and subsequent risk. Indole-3-carbinol (I3C), obtained from cruciferous vegetables (e.g., cabbage, broccoli, etc.), is a known inducer of oxidative P-450 metabolism in animals. We investigated the effects in humans of short-term oral exposure to this compound (6-7 mg/kg/day over 7 days). We used an in vivo radiometric test, which provided a highly specific and reproducible measure of estradiol 2-hydroxylation before and after exposure to I3C. In a group of 12 healthy volunteers, the average extent of reaction increased by approximately 50% during this short exposure (p less than 0.01), affecting men and women equally. We also measured the urinary excretion of two key estrogen metabolites, 2-hydroxyestrone (2OHE1) and estriol (E3). We found that the excretion of 2OHE1 relative to that of E3 was significantly increased by I3C, further confirming the ongoing induction of 2-hydroxylation. These results indicate that I3C predictably alters endogenous estrogen metabolism toward increased catechol estrogen production and may thereby provide a novel "dietary" means for reducing cancer risk

Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans.

Michnovicz JJ, Adlercreutz H, Bradlow HL.

J Natl Cancer Inst. 1997 May 21; 89(10):718-23.

BACKGROUND: The oxidative metabolism of estrogens in humans is mediated primarily by cytochrome P450, many isoenzymes of which are inducible by dietary and pharmacologic agents. One major pathway, 2-hydroxylation, is induced by dietary indole-3-carbinol (I3C), which is present in cruciferous vegetables (e.g., cabbage and broccoli). PURPOSE: Because the pool of available estrogen substrates for all pathways is limited, we hypothesized that increased 2-hydroxylation of estrogens would lead to decreased activity in competing metabolic pathways. METHODS: Urine samples were collected from subjects before and after oral ingestion of I3C (6-7 mg/kg per day). In the first study, seven men received I3C for 1 week; in the second study, 10 women received I3C for 2 months. A profile of 13 estrogens was measured in each sample by gas chromatography-mass spectrometry. RESULTS: In both men and women, I3C significantly increased the urinary excretion of C-2 estrogens. The urinary concentrations of nearly all other estrogen metabolites, including levels of estradiol, estrone, estriol, and 16alpha-hydroxyestrone, were lower after I3C treatment. CONCLUSIONS: These findings support the hypothesis that I3C-induced estrogen 2-hydroxylation results in decreased concentrations of several metabolites known to activate the estrogen receptor. This effect may lower estrogenic stimulation in women. IMPLICATIONS: I3C may have chemopreventive activity against breast cancer in humans, although the long-term effects of higher catechol estrogen levels in women require further investigation

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

Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids.

Mo H, Elson CE.

J Nutr. 1999 Apr; 129(4):804-13.

Diverse classes of phytochemicals initiate biological responses that effectively lower cancer risk. One class of phytochemicals, broadly defined as pure and mixed isoprenoids, encompasses an estimated 22,000 individual components. A representative mixed isoprenoid, gamma-tocotrienol, suppresses the growth of murine B16(F10) melanoma cells, and with greater potency, the growth of human breast adenocarcinoma (MCF-7) and human leukemic (HL-60) cells. beta-Ionone, a pure isoprenoid, suppresses the growth of B16 cells and with greater potency, the growth of MCF-7, HL-60 and human colon adenocarcinoma (Caco-2) cells. Results obtained with diverse cell lines differing in ras and p53 status showed that the isoprenoid-mediated suppression of growth is independent of mutated ras and p53 functions. beta-Ionone suppressed the growth of human colon fibroblasts (CCD-18Co) but only when present at three-fold the concentration required to suppress the growth of Caco-2 cells. The isoprenoids initiated apoptosis and, concomitantly arrested cells in the G1 phase of the cell cycle. Both suppress 3-hydroxy-3-methylglutaryl CoA reductase activity. beta-Ionone and lovastatin interfered with the posttranslational processing of lamin B, an activity essential to assembly of daughter nuclei. This interference, we postulate, renders neosynthesized DNA available to the endonuclease activities leading to apoptotic cell death. Lovastatin-imposed mevalonate starvation suppressed the glycosylation and translocation of growth factor receptors to the cell surface. As a consequence, cells were arrested in the G1 phase of the cell cycle. This rationale may apply to the isoprenoid-mediated G1-phase arrest of tumor cells. The additive and potentially synergistic actions of these isoprenoids in the suppression of tumor cell proliferation and initiation of apoptosis coupled with the mass action of the diverse isoprenoid constituents of plant products may explain, in part, the impact of fruit, vegetable and grain consumption on cancer risk

Circadian-system alterations during cancer processes: a review.

Mormont MC, Levi F.

Int J Cancer. 1997 Jan 17; 70(2):241-7.

Murine and human data have indicated that tumors and tumor-bearing hosts may exhibit nearly normal or markedly altered circadian rhythms. Amplitude damping, phase shifts, and/or period (tau) change, including appearance of ultradian rhythms (with tau < 20 hr) usually become more prominent at late stages of cancer development. The extent of rhythm alterations also varies according to tumor type, growth rate and level of differentiation. While "group chronotherapy," i.e., administration of the same chronomodulated schedule to cancer patients, has increased chemotherapy efficacy and/or tolerability, cancer patients' individual circadian rhythms now need to be explored on a large scale, in order to estimate the incidence of cancer-associated circadian-system alterations and to understand the underlying mechanisms. Correlations between such alterations and patient outcome must be established in order to specify the need for individualized chronomodulated delivery schedules and/or specific rhythm-oriented therapy, especially in patients with circadian-system disturbances

Caffeine inhibits the development of Ehrlich ascites carcinoma cells in female mice.

Mukhopadhyay S, Poddarr MK.

Indian J Exp Biol. 2001 Aug; 39(8):735-41.

Long-term administration of caffeine at a dose of 20 mg /kg/day p.o. suppressed the viability, oxygen consumption and [3H]-thymidine incorporation of Ehrlich ascites carcinoma (EAC) cells. Though no significant change in the levels of plasma and adrenal corticosterone as well as both total and reduced adrenal ascorbic acid were observed following long-term caffeine consumption, pretreatment of caffeine and continuation of its treatment in the course of development of EAC cells restored the EAC Cell-induced changes in both corticosterone and ascorbic acid levels to control values. These results, thus, suggest that caffeine may suppress the growth of EAC cells by modulating the adrenal ascorbate level as well as corticosterone status

Flavonoids exert diverse inhibitory effects on the activation of NF-kappaB.

Muraoka K, Shimizu K, Sun X, et al.

Transplant Proc. 2002 Jun; 34(4):1335-40.

Conjugated linoleic acid enhances plasma adiponectin level and alleviates hyperinsulinemia and hypertension in Zucker diabetic fatty (fa/fa) rats.

Nagao K, Inoue N, Wang YM, et al.

Biochem Biophys Res Commun. 2003 Oct 17; 310(2):562-6.

Adiponectin is a recently discovered hormone secreted by adipocytes that has been reported to enhance insulin sensitivity. Although insulin resistance and/or compensatory hyperinsulinemia are considered to be involved with hypertension in obese humans, the relationship between plasma adiponectin level and obesity-related hypertension has not been fully clarified. In this study, we investigated the effect of dietary conjugated linoleic acid (CLA), reported as an insulin sensitizer, on plasma adiponectin, plasma insulin, and blood pressure in Zucker diabetic fatty (ZDF) rats. During the onset of obesity, blood pressure increased in ZDF rats. The increase, however, was prevented by dietary CLA. After 8 weeks, accumulated plasma insulin and glucose were also attenuated by CLA feeding. Dietary CLA increased plasma adiponectin levels in ZDF rats and the increase was attributed to the enhanced mRNA expression in white adipose tissue. This study provides the first evidence that dietary CLA increases plasma adiponectin level through the enhancement of mRNA expression. We speculate that the increase alleviates hyperinsulinemia and prevents the onset of hypertension in CLA-fed ZDF rats

Public Health Service Department of Health and Human Services.

National Cancer Institute.

2003

Cancer Facts: Complementary and Alternative Medicine: Questions and Answers about Coenzyme Q10 2000.

NCCAM.National Center for Complementary and Alternative Medicine.

2000

Breast Cancer: PDQ Information for Health Care Professionals 1998.

NCI.National Cancer Institute.

1998

Tocotrienols inhibit growth of ZR-75-1 breast cancer cells.

Nesaretnam K, Dorasamy S, Darbre PD.

Int J Food Sci Nutr. 2000; 51 Suppl:S95-103.

The vitamin E component of palm oil provides a rich source of tocotrienols which have been shown previously to be growth inhibitory to two human breast cancer cell lines: responsive MCF7 cells and unresponsive MDA-MB-231 cells. Data presented here shows that the tocotrienol-rich fraction (TRF) of palm oil and individual fractions (alpha, gamma and delta) can also inhibit the growth of another responsive human breast cancer cell line, ZR-75-1. At low concentrations in the absence of oestrogen tocotrienols stimulated growth of the ZR-75-1 cells, but at higher concentrations in the presence as well as in the absence of oestradiol, tocotrienols inhibited cell growth strongly. As for MCF7 cells, alpha-tocopherol had no effect on growth of the ZR-75-1 cells in either the absence or presence of oestradiol. In studying the effects of tocotrienols in combination with antioestrogens, it was found that TRF could further inhibit growth of ZR-75-1 cells in the presence of tamoxifen (10(-7) M and 10(-8) M). Individual tocotrienol fractions (alpha, gamma, delta) could inhibit growth of ZR-75-1 cells in the presence of 10(-8) M oestradiol and 10(-8) M pure antioestrogen ICI 164,384. The immature mouse uterine weight bioassay confirmed that TRF could not exert oestrogen antagonist action in vivo. These results provide evidence of wider growth-inhibitory effects of tocotrienols beyond MCF7 and MDA-MB-231 cells, and with an oestrogen-independent mechanism of action, suggest a possible clinical advantage in combining administration of tocotrienols with antioestrogen therapy

Development of HER2-specific humanized antibody Herceptin (trastuzumab).

Nihira S.

Nippon Yakurigaku Zasshi. 2003 Dec; 122(6):504-14.

HER2 is a member of the human epidermal growth factor receptor family, possessing protein kinase activity in its cytoplasmic domain. There were evidences indicating that (1) amplification of HER2/neu gene and HER2 protein over-expression in tumor cells was observed in 25-30% of human breast cancer and (2) amplification of HER2/neu correlated with poor prognosis, including shorter disease-free and overall survival. These evidences suggested HER2 was a promising candidate for novel molecular targets of breast cancer therapy. Herceptin is a recombinant humanized monoclonal antibody generated by Genentech, Inc. for the treatment of HER2 over-expressed/HER2 gene amplified metastatic breast cancer (MBC). Preclinical studies demonstrated that the antibody had anti-tumor activity in vivo and in vitro, and additive or synergistic enhancement of anti-tumor activity of the antibody was observed in combination with various anti-tumor agents in mouse models. In clinical studies, apparent extension of overall survival was observed in HER2 overexpressing MBC patients. Herceptin is the first anticancer drug whose use as a treatment for MBC patients is decided based on the status of the HER2 gene amplification/HER2 protein over-expression. The development and standardization of HER2 test were a key strategy in clinical development of this drug, since appropriate selection of patients with HER2 over-expression was the essential point for success

Efficacy of adjunctive therapy with tamoxifen depends on tumor's hormone receptor status.

ONI.

Oncology News International. 2004;2000 Jun(9):6.

Melatonin and steroid-dependent carcinomas.

Oosthuizen JM, Bornman MS, Barnard HC, et al.

Andrologia. 1989 Sep; 21(5):429-31.

In this study the concentrations of plasma melatonin in patients with either prostatic or breast carcinoma were compared to the levels of controls. The mean melatonin was statistically lower in patients with breast cancer as compared to controls (p less than 0.005). In prostatic carcinoma patients, the mean melatonin was statistically higher than in the control group (p less than 0.005). From the results it would seem that low melatonin levels could possibly play a role in breast carcinoma, but the same did not necessarily applied to prostatic cancer

Atypical hyperplastic lesions of the female breast. A long-term follow-up study.

Page DL, Dupont WD, Rogers LW, et al.

Cancer. 1985 Jun 1; 55(11):2698-708.

A total of 10,542 breast biopsy specimens obtained between 1950 and 1968 were studied. Examples of atypical "ductal" (ADH) and atypical lobular hyperplasia (ALH), defined as having only some features of carcinoma in situ (CIS), were diagnosed in 3.6% of these specimens. In the same series, CIS was diagnosed in 1.7% of biopsy specimens excluding those with invasive cancer. The subsequent risk of invasive breast carcinoma after ALH or ADH was 4-5 times that of the general population. Follow-up was 90% successful and extended 17 years after biopsy. History of breast cancer in a mother, sister, or daughter doubled the risk of subsequent invasive carcinoma development (to 8 times for ALH and 10 times for ADH). The authors conclude that among the epithelial hyperplastic lesions of the human breast, a minority may be recognized by their resemblance to CIS which have a clinically significant elevation of subsequent breast cancer risk. This risk is one-half that of CIS

Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways.

Park JI, Lee MG, Cho K, et al.

Oncogene. 2003 Jul 10; 22(28):4314-32.

Transforming growth factor (TGF)-beta1 acts as a potent growth inhibitor of prostate epithelial cells, and aberrant function of its receptor type I and II correlates with tumor aggressiveness. However, intracellular and serum TGF-beta1 levels are elevated in prostate cancer patients and further increased in patients with metastatic carcinoma, suggesting the oncogenic switch of TGF-beta1 role in prostate tumorigenesis. Recently, we reported the mitogenic conversion of TGF-beta1 effect by oncogenic Ha-Ras in prostate cancer cells. Here, we show that TGF-beta1 activates interleukin (IL)-6, which has been implicated in the malignant progression of prostate cancers, via multiple signaling pathways including Smad2, nuclear factor-kappaB (NF-kappaB), JNK, and Ras. TGF-beta1-induced IL-6 gene expression was strongly inhibited by DN-Smad2 but not by DN-Smad3 while it was further activated by wild-type Smad2 transfection. IL-6 activation by TGF-beta1 was accompanied by nuclear translocation of NF-kappaB, which was blocked by the p38 inhibitors SB202190 and SB203580 or by IkappaBalphaDeltaN transfection, indicating the crucial role for the p38-NF-kappaB signaling in TGF-beta1 induction of IL-6. TGF-beta1 activated c-Jun phosphorylation, and IL-6 induction by TGF-beta1 was severely impeded by DN-c-Jun and DN-JNK or AP-1 inhibitor curcumin, showing that the JNK-c-Jun-AP-1 signaling plays a pivotal role in TGF-beta1 stimulation of IL-6. It was also found that the Ras-Raf-MEK1 cascade is activated by TGF-beta1 and participates in the TGF-beta1 induction of IL-6 in an AP-1-dependent manner. Cotransfection assays demonstrated that TGF-beta1 stimulation of IL-6 results from the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK-c-Jun-AP-1, or Ras-Raf-MEK1 cascades. In addition, a time course IL-6 decay revealed that mRNA stability of IL-6 is modestly increased by TGF-beta1, indicating that TGF-beta1 also regulates IL-6 at the post-transcriptional level. Intriguingly, IL-6 inactivation restored the sensitivity to TGF-beta1-mediated growth arrest and apoptosis, suggesting that elevated IL-6 in advanced prostate tumors might act as a resistance factor against TGF-beta1. Collectively, our data demonstrate that IL-6 expression is stimulated by tumor-producing TGF-beta1 in human prostate cancer cells through multiple signaling pathways including Smad2, p38, JNK, and Ras, and enhanced expression of IL-6 could contribute to the oncogenic switch of TGF-beta1 role for prostate tumorigenesis, in part by counteracting its growth suppression function

Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Parker RA, Pearce BC, Clark RW, et al.

J Biol Chem. 1993 May 25; 268(15):11230-8.

Tocotrienols are natural farnesylated analogues of tocopherols which decrease hepatic cholesterol production and reduce plasma cholesterol levels in animals. For several cultured cell types, incubation with gamma-tocotrienol inhibited the rate of [14C]acetate but not [3H] mevalonate incorporation into cholesterol in a concentration- and time-dependent manner, with 50% inhibition at approximately 2 microM and maximum approximately 80% inhibition observed within 6 h in HepG2 cells. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase total activity and protein levels assayed by Western blot were reduced concomitantly with the decrease in cholesterol synthesis. In HepG2 cells, gamma-tocotrienol suppressed reductase despite strong blockade by inhibitors at several steps in the pathway, suggesting that isoprenoid flux is not required for the regulatory effect. HMG-CoA reductase protein synthesis rate was moderately diminished (57% of control), while the degradation rate was increased 2.4-fold versus control (t1/2 declined from 3.73 to 1.59 h) as judged by [35S]methionine pulse-chase/immunoprecipitation analysis of HepG2 cells treated with 10 microM gamma-tocotrienol. Under these conditions, the decrease in reductase protein levels greatly exceeded the minor decrease in mRNA (23 versus 76% of control, respectively), and the low density lipoprotein receptor protein was augmented. In contrast, 25-hydroxycholesterol strongly cosuppressed HMG-CoA reductase protein and mRNA levels and the low density lipoprotein receptor protein. Thus, tocotrienols influence the mevalonate pathway in mammalian cells by post-transcriptional suppression of HMG-CoA reductase, and appear to specifically modulate the intracellular mechanism for controlled degradation of the reductase protein, an activity that mirrors the actions of the putative non-sterol isoprenoid regulators derived from mevalonate

Bisphosphonates for breast cancer.

Pavlakis N, Stockler M.

Cochrane Database Syst Rev. 2002;(1):CD003474.

BACKGROUND: Bone is the most common site of metastatic disease associated with breast cancer, and affects more than half of women during the course of their disease. Bone metastases are a significant cause of morbidity due to pain, pathological fractures, hypercalcaemia and spinal cord compression, and contribute to mortality. Bisphosphonates, which inhibit osteoclast-mediated bone resorption, are standard care for tumour-associated hypercalcaemia, and have been shown to reduce bone pain, improve quality of life, and to delay skeletal events and reduce their number in patients with multiple myeloma. Several randomized controlled trials have evaluated the role of bisphosphonates in breast cancer. OBJECTIVES: The aim of this systematic review was to identify, describe and summarize high-quality evidence regarding the effect of bisphosphonates on skeletal events, bone pain, quality of life and survival in women with early and advanced breast cancer. SEARCH STRATEGY: Randomized controlled trials were identified in the specialized register maintained by the secretariat of the Cochrane Breast Cancer Group (the search was applied to the databases Medline, Central/CCTR, Embase, CancerLit, and included handsearches from a number of other relevant sources). See: Cochrane Collaboration Collaborative Review Group in Breast Cancer search strategy. SELECTION CRITERIA: Randomized controlled trials evaluating skeletal events in women with metastatic breast cancer and in women with early breast cancer comparing: 1. treatment with a bisphosphonate with the same treatment without a bisphosphonate 2. treatment with one bisphosphonate with treatment with a different bisphosphonate. DATA COLLECTION AND ANALYSIS: Studies were selected by two independent reviewers. Studies fulfilling the eligibility criteria were evaluated for quality, particularly concealment of allocation to randomized groups. Data were extracted from the published papers or abstracts independently by the two primary reviewers for each of the specified endpoints (skeletal events, bone pain, quality of life and survival). Data on skeletal events and survival were presented as numbers of events, risk ratios and ratios of event rates. Meta-analyses were based on the fixed-effects model (Mantel-Haenszel). Subjective qualitative ratings were used to summarize the quality of life and pain data. MAIN RESULTS: From 37 reports considered in detail after screening of the 117 reports identified by our search, 19 randomized studies were included. In eight studies that included 1962 women with advanced breast cancer and existing bone metastases, bisphosphonates reduced the risk of developing a skeletal event by 14% (RR 0.86; 95% confidence interval (CI) 0.80-0.91; P 0.9). In three studies of oral clodronate that included 1680 women with early breast cancer, there was borderline evidence of a reduction in the risk of developing skeletal metastases (RR 0.73; 95% CI 0.55-0.98; P = 0.04), but there was significant heterogeneity among these studies (P = 0.035). Toxicity or adverse events were described in 14 of the 19 studies. In general, few adverse events were reported. REVIEWER'S CONCLUSIONS: In women with advanced breast cancer and clinically evident bone metastases, the use of bisphosphonates (oral or intravenous) in addition to hormone therapy or chemotherapy, when compared with placebo or no bisphosphonates, reduces the risk of developing a skeletal event and the skeletal event rate, as well as increasing the time toskeletal event. Bisphosphonates may also reduce bone pain in women with advanced breast cancer and clinically evident bone metastases. In women with early breast cancer the effectiveness of oral clodronate in reducing the incidence of bone metastases remains an open question for research

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

Coenzyme Q10 concentrations and antioxidant status in tissues of breast cancer patients.

Portakal O, Ozkaya O, Erden IM, et al.

Clin Biochem. 2000 Jun; 33(4):279-84.

OBJECTIVES: An increasing amount of experimental and epidemiological evidence implicates the involvement of oxygen derived radicals in the pathogenesis of cancer development. Oxygen derived radicals are able to cause damage to membranes, mitochondria, and macromolecules including proteins, lipids and DNA. Accumulation of DNA damages has been suggested to contribute to carcinogenesis. It would, therefore, be advantageous to pinpoint the effects of oxygen derived radicals in cancer development. DESIGN AND METHODS: In the present study, we investigated the relationship between oxidative stress and breast cancer development in tissue level. Breast cancer is the most common malignant disease in Western women. Twenty-one breast cancer patients, who underwent radical mastectomy and diagnosed with infiltrative ductal carcinoma, were used in the study. We determined coenzyme Q10 (Q) concentrations, antioxidant enzyme activities (mitochondrial and total superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase), and malondialdehyde (MDA) levels in tumor and surrounding tumor-free tissues. RESULTS: Q concentrations in tumor tissues significantly decreased as compared to the surrounding normal tissues (p < 0.001). Higher MDA levels were observed in tumor tissues than noncancerous tissues (p < 0.001). The activities of MnSOD, total SOD, GSH-Px and catalase in tumor tissues significantly increased (p < 0.001) compared to the controls. CONCLUSIONS: These findings may support that reactive oxygen species increased in malignant cells, and may cause overexpression of antioxidant enzymes and the consumption of coenzyme Q10. Increased antioxidant enzyme activities may be related with the susceptibility of cells to carcinogenic agents and the response of tumor cells to the chemotherapeutic agents. Administration of coenzyme Q10 by nutrition may induce the protective effect of coenzyme Q10 on breast tissue

Caffeine induces TP53-independent G(1)-phase arrest and apoptosis in human lung tumor cells in a dose-dependent manner.

Qi W, Qiao D, Martinez JD.

Radiat Res. 2002 Feb; 157(2):166-74.

Caffeine is a model radiosensitizing agent that is thought to work by abrogating the radiation-induced G(2)-phase checkpoint. In this study, we examined the effect that various concentrations of caffeine had on cell cycle checkpoints and apoptosis in cells of a human lung carcinoma cell line and found that a concentration of 0.5 mM caffeine could abrogate the G(2)-phase arrest normally seen after exposure to ionizing radiation. Surprisingly, at a concentration of 5 mM, caffeine not only induced apoptosis by itself and acted synergistically to enhance radiation-induced apoptosis, but also induced a TP53-independent G(1)-phase arrest. Examination of the molecular mechanisms by which caffeine produced these effects revealed that caffeine had opposing effects on different cyclin-dependent kinases. CDK2 activity was suppressed by caffeine, whereas activity of CDC2 was enhanced by suppressing phosphorylation on Tyr15 and by interfering with 14-3-3 binding to CDC25C. These data indicate that the effect of caffeine on cell cycle checkpoints and apoptosis is dependent on dose and that caffeine acts through differential regulation of cyclin-dependent kinase activity

BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis.

Quinn JE, Kennedy RD, Mullan PB, et al.

Cancer Res. 2003 Oct 1; 63(19):6221-8.

We have evaluated the role played by BRCA1 in mediating the phenotypic response to a range of chemotherapeutic agents commonly used in cancer treatment. Here we provide evidence that BRCA1 functions as a differential mediator of chemotherapy-induced apoptosis. Specifically, we demonstrate that BRCA1 mediates sensitivity to apoptosis induced by antimicrotubule agents but conversely induces resistance to DNA-damaging agents. These data are supported by a variety of experimental models including cells with inducible expression of BRCA1, siRNA-mediated inactivation of endogenous BRCA1, and reconstitution of BRCA1-deficient cells with wild-type BRCA1. Most notably we demonstrate that BRCA1 induces a 10-1000-fold increase in resistance to a range of DNA-damaging agents, in particular those that give rise to double-strand breaks such as etoposide or bleomycin. In contrast, BRCA1 induces a >1000-fold increase in sensitivity to the spindle poisons, paclitaxel and vinorelbine. Fluorescence-activated cell sorter analysis demonstrated that BRCA1 mediates G(2)/M arrest in response to both antimicrotubule and DNA-damaging agents. However, poly(ADP-ribose) polymerase and caspase-3 cleavage assays indicate that the differential effect mediated by BRCA1 in response to these agents occurs through the inhibition or induction of apoptosis. Therefore, our data suggest that BRCA1 acts as a differential modulator of apoptosis depending on the nature of the cellular insult

Indole-3-carbinol (I3C) induces apoptosis in tumorigenic but not in nontumorigenic breast epithelial cells.

Rahman KM, Aranha O, Sarkar FH.

Nutr Cancer. 2003; 45(1):101-12.

Recent results from epidemiology, in vitro cell culture and in vivo (animal and human) studies have suggested the benefits of indole-3-carbinol (I3C) for the prevention of many types of cancer, including breast cancer. However, there are no reports, to the best of our knowledge, on the effect of I3C on isogenic nontumorigenic and tumorigenic breast epithelial cells, and there is a significant void in our understanding of the molecular mechanism(s) by which I3C induces apoptotic cell death in breast cancer cells. To fill this gap in our understanding, we conducted experiments to investigate the effects of I3C on an isogenic nontumorigenic (MCF10A) and tumorigenic (MCF10CA1a [CA1a]) breast epithelial cells. Here we show that CA1a cells are more sensitive to low concentration of I3C in terms of cell growth inhibition compared to MCF10A cells. We further report that I3C upregulates Bax/Bcl-2 ratio and downregulates Bcl-xL expression in CA1a cells but not in MCF10A cells. We also report, for the first time, that I3C induces Bax translocation to the mitochondria, causing mitochondrial depolarization, resulting in the loss of mitochondrial potential leading to the release of cytochrome c and subsequent cell death in CA1a cells but not in MCF10A cells. From these results, we conclude that I3C selectively induces apoptosis in breast cancer cells, but not in nontumorigenic breast epithelial cells, suggesting the potential therapeutic benefit of I3C against breast cancer

Differential responsiveness of MCF-7 human breast cancer cell line stocks to the pineal hormone, melatonin.

Ram PT, Yuan L, Dai J, et al.

J Pineal Res. 2000 May; 28(4):210-8.

The estrogen receptor (ER)-positive MCF-7 human breast cancer cell line has been used extensively for the study of estrogen-responsive human breast cancer. However, various levels of estrogen responsiveness have been described in different stocks of MCF-7 cells. Because we have previously shown that the pineal hormone, melatonin, inhibits proliferation of MCF-7 cells and can modulate ER expression and transactivation, we investigated if various stocks of MCF-7 cells exhibit a differential responsiveness to the anti-proliferative effects of melatonin and the possible mechanisms involved. The MCF-7 stocks (M, O, H) were examined for: (1) mitogenic response to estradiol; (2) steady-state ER mRNA levels; (3) expression of the mt1 melatonin membrane receptor; (4) growth inhibition by melatonin; and (5) melatonin's modulation of expression of the ER and the estrogen-regulated genes, PgR, TGFbeta and pS2. For all of these parameters, there was a stock-specific response which showed: MCF-7M > MCF-7O > MCF-7H. These results demonstrate that there are significant differences in the responsiveness of various stocks of MCF-7 breast cancer cells to the growth-inhibitory effects of melatonin which can be correlated with both the level of ER mRNA expression and the degree of estrogen-responsiveness. These findings suggest that not only may these differences have some impact on the cells' estrogen-response pathway, but also that the primary growth-inhibitory effects of melatonin are transduced through the membrane-associated G-protein coupled mt1 melatonin receptor

Effect of melatonin and linolenic acid on mammary cancer in transgenic mice with c-neu breast cancer oncogene.

Rao GN, Ney E, Herbert RA.

Breast Cancer Res Treat. 2000 Dec; 64(3):287-96.

Breast cancer is one of the most common cancers and is a leading cause of mortality in women. The TG.NK transgenic mouse line expresses the c-neu breast cancer oncogene under the control of a MMTV promoter and appears to be a useful animal model for evaluation of intervention strategies to delay/prevent breast cancer. Fiber-rich nonpurified diet (NTP-2000) and some retinoid analogues have been shown to significantly delay the development of mammary cancer in the TG.NK model. Four-week-old hemizygous TG.NK female mice with MMTV/c-neu oncogene fed NTP-2000 diet were gavaged with 0.05-0.2 ml of flaxseed oil as the source of omega-3 rich PUFA, or melatonin at 50-200 mg/kg or a combination of 0.10 ml flaxseed oil and 50 mg/kg melatonin in a gavage volume of 0.2 ml per mouse with corn oil as the vehicle for 30 weeks. The time course of the mammary tumor incidence pattern was advanced by flaxseed oil compared to the control. At the high dose (0.2 ml) of flaxseed oil, when the omega-6: omega-3 PUFA ratio was closer to 1, there was some delay in the growth of mammary tumors. Melatonin delayed the appearance of palpable tumors and the growth of the tumors with a dose-related statistically significant negative trend for the incidence of tumors. The combination of flaxseed oil and melatonin caused a significant decrease in the number of tumors and tumor weight per mouse compared to the control and to flaxseed oil but not to melatonin alone. Flaxseed oil may delay the growth of mammary tumors if the omega-6:omega-3 PUFA ratio of fat consumed is closer to 1. Melatonin has the potential to markedly delay the appearance of palpable mammary tumors. Studies are in progress with the TG.NK mouse model to understand the histological and molecular changes associated with the dose-response pattern of mammary tumor incidence and growth after treatment with a broad range of doses of melatonin

Curcumin is a non-competitive and selective inhibitor of phosphorylase kinase.

Reddy S, Aggarwal BB.

FEBS Lett. 1994 Mar 14; 341(1):19-22.

Recently, we reported that curcumin (diferuloylmethane) inhibits the growth of several different kinds of tumor cells. In order to investigate the mechanism of this inhibition, we examined the effects of curcumin on different protein kinases: highly purified protein kinase A (PkA), protein kinase C (PkC), protamine kinase (cPK), phosphorylase kinase (PhK), autophosphorylation-activated protein kinase (AK) and pp60c-src tyrosine kinase. While all kinases tested were inhibited by curcumin, only PhK was completely inhibited at relatively lower concentrations. At around 0.1 mM curcumin, PhK, pp60c-src, PkC, PkA, AK, and cPK were inhibited by 98%, 40%, 15%, 10%, 1%, and 0.5%, respectively. Lineweaver-Burk plot analysis indicated that curcumin is a non-competitive inhibitor of PhK with a Ki of 0.075 mM. Overall, our results indicate that curcumin is a potent and selective inhibitor of phosphorylase kinase, a key regulatory enzyme involved in the metabolism of glycogen. This has important implications for the anti-proliferative effects of curcumin

Natural products and their derivatives as cancer chemopreventive agents.

Ren S, Lien EJ.

Prog Drug Res. 1997; 48:147-71.

This review summarizes currently available data on the chemopreventive efficacies, proposed mechanisms of action and relationships between activities and structures of natural products like vitamin D, calcium, dehydroepidandrosterone, coenzyme Q10, celery seed oil, parsley leaf oil, sulforaphane, isoflavonoids, lignans, protease inhibitors, tea polyphenols, curcumin, and polysaccharides from Acanthopanax genus

Serum fatty acid imbalance in bone loss: example with periodontal disease.

Requirand P, Gibert P, Tramini P, et al.

Clin Nutr. 2000 Aug; 19(4):271-6.

Among the numerous factors of bone remodelling, the local action of arachidonic acid metabolites together with cytokines, is particularly important, especially that of prostaglandin PGE2. It has been suggested that the alveolar bone destruction in periodontal disease and osteoporosis can be treated by reducing the ratio of arachidonic acid in phospholipids, which would diminish prostaglandin production. The aim of this study was to evaluate the main serum polyunsaturated fatty acids and a possible alteration in the level of arachidonic acid in patients suffering from periodontal bone loss. Of the 105 patients who participated the study, 78 were suffering from periodontal bone loss and 27 served as a control group. The fatty acids were measured in serum by gas-chromatography. The results showed that the level of fatty acids of the n-6 pathway was higher in our patients with bone loss than in the control group, whereas the reverse was observed with fatty acids of the n-3 pathway. In conclusion, our patients' bone losses are linked with an imbalance between n-6 and n-3 fatty acids, which seems to justify a diet increase in 20- and 22-carbon fatty acids

Caffeine-increased radiosensitivity is not dependent on a loss of G2/M arrest or apoptosis in bladder cancer cell lines.

Ribeiro JC, Barnetson AR, Jackson P, et al.

Int J Radiat Biol. 1999 Apr; 75(4):481-92.

PURPOSE: Bladder cancer cell lines UCRU-BL-13, UCRU-BL-17/2 and UCRU-BL-28, with differing p53 status and molecular responses to irradiation, were used to investigate possible mechanisms for caffeine-induced radiosensitization. MATERIALS AND METHODS: After treatment with caffeine and exposure to X-radiation, radiosensitivity was determined by clonogenic assay. Cell-cycle arrest and apoptosis were measured by flow cytometry. RESULTS: Both BL-13 and BL-28 cells (each expressing p53 with a wild-type sequence) fail to arrest at the G2 checkpoint after radiation, but nevertheless caffeine did induce radiosensitization. In contrast, in BL-17/2 cells (expressing p53 with a point mutation in codon 280), caffeine treatment abrogated the radiation-induced G2 arrest but was not accompanied by radiosensitization. No effects on radiosensitivity were seen in RT112 cells (expressing a functionally defective p53) at low caffeine doses (2 mM), but at higher doses (4 mM and 10 mM) caffeine caused both abrogation of radiation-induced G2 arrest and radiosensitization. In none of the cell lines examined did caffeine treatment and/or irradiation result in apoptosis. CONCLUSIONS: In contrast with previous studies, the data suggest that radiosensitization induced by caffeine is not dependent on abrogation of G2 arrest or the induction of apoptosis, and is not selective for cells expressing p53 proteins with mutations

Estrogen receptor reduces CYP1A1 induction in cultured human endometrial cells.

Ricci MS, Toscano DG, Mattingly CJ, et al.

J Biol Chem. 1999 Feb 5; 274(6):3430-8.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exerts its toxic action via the aryl hydrocarbon (Ah) receptor, which induces a battery of xenobiotic-metabolizing enzymes, including the cytochrome P450 isozyme, CYP1A1. TCDD-induced 7-ethoxycoumarin-O-deethylase activity was reduced 75% in cultured human endometrial ECC-1 cells exposed to various concentrations of 17beta-estradiol for up to 72 h, with a half-maximal effective concentration (EC50) of 0.9 nM. Reduced enzyme activity was correlated with decreased CYP1A1 mRNA levels, and transcription. Exposure to TCDD plus 17beta-estradiol also reduced CYP1A1 activity in MCF-7 breast cancer cells but not in Hep-3B human liver cells or HuE primary human keratinocytes, suggesting that the effect was specific to estrogen-regulated cells. Estrogen receptor antagonists 4-hydroxytamoxifen and 7alpha-[9-(4,4, 5,5,5-pentafluoro-pentylsulfinyl)nonyl]estra-1,3,5(10)-tr iene3, 17beta-diol restored TCDD-induced CYP1A1 transcription, steady-state mRNA levels, and enzymatic activity in ECC-1 cells. Gel mobility shift assay showed that 17beta-estradiol had little effect on Ah receptor binding to its DNA-responsive element. 17beta-Estradiol did not alter the induction of another Ah receptor-regulated gene, CYP1B1, suggesting that altered Ah receptor binding to DNA does not mediate reduced CYP1A1 transcription. Transfecting ECC-1 cells with a general transcription factor involved in CYP1A1 induction, nuclear factor-1, reversed 17beta-estradiol antagonism of dioxin induced-CYP1A1. The data suggest that 17beta-estradiol reduced CYP1A1 expression at the transcriptional level by squelching available nuclear factor-1, a transcription factor that interacts with both Ah and estrogen receptors

SEER Cancer Statistics Review 1973-1997.

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2000

[Bisphosphonates, pain and quality of life in metastatic breast cancer patients: a literature review].

Roemer-Becuwe C, Krakowski I, Conroy T.

Bull Cancer. 2003 Dec; 90(12):1097-105.

Bisphosphonates constitute the standard treatment for cancer hypercalcemia and prevention of complications of metastatic bone disease. Various clinical endpoints have been used to evaluate the impact of bisphosphonates on bone metastases. This literature review is focused on the analgesic effect of bisphosphonates and their impact on quality of life (QoL) in patients with bone metastases from breast cancer. Twenty-five randomized trials studying bisphosphonates with pain and/or QoL as primary or secondary endpoints were considered. These studies were analyzed with following criterias : study type, primary cancer, drug scheduling, number of patients included, associated specific treatment, primary and secondary endpoints, pain assessment, and QoL assessment. The results are in favor of an efficacy of bisphosphonates in bone pain, even when not always statistically significant and with an important variability in assessment criterias and tools. QoL assessment with validated, reliable scales (EORTC QLQ-C30, Rotterdam Symptom Checklist.) has been performed in 9 studies. The use of bisphosphonates with systemic and radiation therapy increases QoL or reduces QoL deterioration. Despite some methodological limitations, these studies indicate a beneficial effect on bone pain, and an improvement in the QoL of patients with metastatic bone disease of breast cancer. Because of a lack of systemic data, reliable analysis of the results is difficult. Several questions remain open about which bisphosphonates and route of administration to choose, and the variable effects on different primaries. Copyright John Libbey Eurotext 2003

Light, endocrine systems, and cancer--a view from circadian biologists.

Roenneberg T, Lucas RJ.

Neuroendocrinol Lett. 2002 Jul; 23 Suppl 2:82-3.

IOM says: X-ray mammography remains the gold standard in breast cancer screening technology.

Rollins G.

Rep Med Guidel Outcomes Res. 2001 Apr 19; 12(8):1-2, 5.

An open randomised trial of second-line endocrine therapy in advanced breast cancer. comparison of the aromatase inhibitors letrozole and anastrozole.

Rose C, Vtoraya O, Pluzanska A, et al.

Eur J Cancer. 2003 Nov; 39(16):2318-27.

It was previously shown that letrozole (Femara) was significantly more potent than anastrozole (Arimidex) in inhibiting aromatase activity in vitro and in inhibiting total body aromatisation in patients with breast cancer. The objective of this study was to compare letrozole (2.5 mg per day) and anastrozole (1 mg per day) as endocrine therapy in postmenopausal women with advanced breast cancer previously treated with an anti-oestrogen. This randomised, multicentre and multinational open-label phase IIIb/IV study enrolled 713 patients. Treatment was for advanced breast cancer that had progressed either during anti-oestrogen therapy or within 12 months of completing that therapy. Patients had tumours that were either positive for oestrogen and/or progesterone receptors (48%) or of unknown receptor status (52%). The primary efficacy endpoint was time to progression (TTP). Secondary endpoints included objective response, duration of response, rate and duration of overall clinical benefit (responses and long-term stable disease), time to treatment failure, and overall survival, as well as general safety. There was no difference between the treatment arms in TTP; median times were the same for both treatments. Letrozole was significantly superior to anastrozole in the overall response rate (ORR) (19.1% versus 12.3%, P=0.013), including in predefined subgroups (receptor status-unknown, and soft-tissue- and viscera-dominant site of disease). There were no significant differences between the treatment arms in the rate of clinical benefit, median duration of response, duration of clinical benefit, time to treatment failure or overall survival. Both agents were well tolerated and there were no significant differences in safety. These results support previous data documenting the greater aromatase-inhibiting activity of letrozole and indicate that advanced breast cancer is more responsive to letrozole than to anastrozole as second-line endocrine therapy

Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial.

Rosen LS, Gordon D, Kaminski M, et al.

Cancer. 2003 Oct 15; 98(8):1735-44.

BACKGROUND: The goal of the current study was to compare the long-term (25-month) safety and efficacy of zoledronic acid with pamidronate in patients with bone lesions secondary to advanced breast carcinoma or multiple myeloma. METHODS: Patients (n = 1648) were randomized to receive 4 mg or 8 mg (reduced to 4 mg) zoledronic acid as a 15-minute infusion or to receive 90 mg pamidronate as a 2-hour infusion every 3-4 weeks for 24 months. The primary endpoint was the proportion of patients with at least 1 skeletal-related event (SRE), defined as pathologic fracture, spinal cord compression, radiation therapy, or surgery to bone. Secondary analyses included time to first SRE, skeletal morbidity rate, and multiple-event analysis. Hypercalcemia of malignancy (HCM) was included as an SRE in some secondary analyses. RESULTS: After 25 months of follow-up, zoledronic acid reduced the overall proportion of patients with an SRE and reduced the skeletal morbidity rate similar to pamidronate. Compared with pamidronate, zoledronic acid (4 mg) reduced the overall risk of developing skeletal complications (including HCM) by an additional 16% (P = 0.030). In patients with breast carcinoma, zoledronic acid (4 mg) was significantly more effective than pamidronate, reducing the risk of SREs by an additional 20% (P = 0.025) compared with pamidronate and by an additional 30% in patients receiving hormonal therapy (P = 0.009). Zoledronic acid (4 mg) and pamidronate were tolerated equally well. The most common adverse events included bone pain, nausea, and fatigue. CONCLUSIONS: Long-term follow-up data confirm that zoledronic acid was more effective than pamidronate in reducing the risk of skeletal complications in patients with bone metastases from breast carcinoma and was of similar efficacy in patients with multiple myeloma

Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development.

Rowinsky EK, Windle JJ, Von Hoff DD.

J Clin Oncol. 1999 Nov; 17(11):3631-52.

Ras proteins are guanine nucleotide-binding proteins that play pivotal roles in the control of normal and transformed cell growth and are among the most intensively studied proteins of the past decade. After stimulation by various growth factors and cytokines, Ras activates several downstream effectors, including the Raf-1/mitogen-activated protein kinase pathway and the Rac/Rho pathway. In approximately 30% of human cancers, including a substantial proportion of pancreatic and colon adenocarcinomas, mutated ras genes produce mutated proteins that remain locked in an active state, thereby relaying uncontrolled proliferative signals. Ras undergoes several posttranslational modifications that facilitate its attachment to the inner surface of the plasma membrane. The first-and most critical-modification is the addition of a farnesyl isoprenoid moiety in a reaction catalyzed by the enzyme protein farnesyltransferase (FTase). It follows that inhibiting FTase would prevent Ras from maturing into its biologically active form, and FTase is of considerable interest as a potential therapeutic target. Different classes of FTase inhibitors have been identified that block farnesylation of Ras, reverse Ras-mediated cell transformation in human cell lines, and inhibit the growth of human tumor cells in nude mice. In transgenic mice with established tumors, FTase inhibitors cause regression in some tumors, which appears to be mediated through both apoptosis and cell cycle regulation. FTase inhibitors have been well tolerated in animal studies and do not produce the generalized cytotoxic effects in normal tissues that are a major limitation of most conventional anticancer agents. There are ongoing clinical evaluations of FTase inhibitors to determine the feasibility of administering them on dose schedules like those that portend optimal therapeutic indices in preclinical studies. Because of the unique biologic aspects of FTase, designing disease-directed phase II and III evaluations of their effectiveness presents formidable challenges

Interaction between low dose-rate irradiation, mild hyperthermia and low-dose caffeine in a human lung cancer cell line.

Sakurai H, Mitsuhashi N, Tamaki Y, et al.

Int J Radiat Biol. 1999 Jun; 75(6):739-45.

PURPOSE: To investigate cell killing by means of low dose-rate irradiation (LDRI) combined with concurrent mild hyperthermia and to determine the effect of low-dose caffeine on this combination treatment. MATERIALS AND METHODS: Human lung adenocarcinoma cells, LK87, were treated with LDRI (50 cGy/h) in combination with mild hyperthermia at 41 degrees C and low-dose caffeine (1 mM). Cell survival was estimated by clonogenic assay. Flow-cytometry was performed with PI staining using FACScan. Heat-shock protein (HSP72/73) was measured by the Western blotting method. All treatments were simultaneously performed for up to 48 h (24 Gy). RESULTS: LDRI cytotoxicities were enhanced by hyperthermia at 41 degrees C. D0 calculated from the dose-response curve for LDRI combined with 41 degrees C was 3.46 Gy whereas it was 6.55 Gy for LDRI alone. The survival curve for LDRI +41 degrees C demonstrated no chronic thermotolerance up to 48 h. For LDRI + simultaneous low-dose caffeine, cell killing was also enhanced, where D0 was 3.38 Gy at 37 degrees C. Radiosensitization caused by caffeine was enhanced by combination with simultaneous mild hyperthermia at 41 degrees C, where D0=1.78 Gy. Cell cycle analysis demonstrated remarkable G2 and mild G1 arrest for LDRI alone, but only G1 arrest was observed for LDRI combined with 41 degrees C and for LDRI combined with caffeine. Strong and early G1 arrest was observed in the treatment with LDRI + caffeine at 41 degrees C. The amount of HSP72/73 in the combination of LDRI with caffeine at 41 degrees C was less than that at 41 degrees C alone. CONCLUSION: LDRI cytotoxicity was enhanced by non-lethal hyperthermia. Low dose caffeine produced further cell killing in the combination of LDRI with mild hyperthermia

Melatonin and mammary cancer: a short review.

Sanchez-Barcelo EJ, Cos S, Fernandez R, et al.

Endocr Relat Cancer. 2003 Jun; 10(2):153-9.

Melatonin is an indolic hormone produced mainly by the pineal gland. The former hypothesis of its possible role in mammary cancer development was based on the evidence that melatonin down-regulates some of the pituitary and gonadal hormones that control mammary gland development and which are also responsible for the growth of hormone-dependent mammary tumors. Furthermore, melatonin could act directly on tumoral cells, as a naturally occurring antiestrogen, thereby influencing their proliferative rate. The first reports revealed a low plasmatic melatonin concentration in women with estrogen receptor (ER)-positive breast tumors. However, later studies on the possible role of melatonin on human breast cancer have been scarce and mostly of an epidemiological type. These studies described a low incidence of breast tumors in blind women as well as an inverse relationship between breast cancer incidence and the degree of visual impairment. Since light inhibits melatonin secretion, the relative increase in the melatonin circulating levels in women with a decreased light input could be interpreted as proof of the protective role of melatonin on mammary carcinogenesis. From in vivo studies on animal models of chemically induced mammary tumorigenesis, the general conclusion is that experimental manipulations activating the pineal gland or the administration of melatonin lengthens the latency and reduces the incidence and growth rate of mammary tumors, while pinealectomy usually has the opposite effects. Melatonin also reduces the incidence of spontaneous mammary tumors in different kinds of transgenic mice (c-neu and N-ras) and mice from strains with a high tumoral incidence.In vitro experiments, carried out with the ER-positive MCF-7 human breast cancer cells, demonstrated that melatonin, at a physiological concentration (1 nM) and in the presence of serum or estradiol: (a) inhibits, in a reversible way, cell proliferation, (b) increases the expression of p53 and p21WAF1 proteins and modulates the length of the cell cycle, and (c) reduces the metastasic capacity of these cells and counteracts the stimulatory effect of estradiol on cell invasiveness; this effect is mediated, at least in part, by a melatonin-induced increase in the expression of the cell surface adhesion proteins E-cadherin and beta(1)-integrin.The direct oncostatic effects of melatonin depends on its interaction with the tumor cell estrogen-responsive pathway. In this sense it has been demonstrated that melatonin down-regulates the expression of ERalpha and inhibits the binding of the estradiol-ER complex to the estrogen response element (ERE) in the DNA. The characteristics of melatonin's oncostatic actions, comprising different aspects of tumor biology as well as the physiological doses at which the effect is accomplished, give special value to these findings and encourage clinical studies on the possible therapeutic value of melatonin on breast cancer

Night-shift work and risk of colorectal cancer in the nurses' health study.

Schernhammer ES, Laden F, Speizer FE, et al.

J Natl Cancer Inst. 2003 Jun 4; 95(11):825-8.

Exposure to light at night suppresses the physiologic production of melatonin, a hormone that has antiproliferative effects on intestinal cancers. Although observational studies have associated night-shift work with an increased risk of breast cancer, the effect of night-shift work on the risk of other cancers is not known. We prospectively examined the relationship between working rotating night shifts and the risk of colorectal cancers among female participants in the Nurses' Health Study. We documented 602 incident cases of colorectal cancer among 78 586 women who were followed up from 1988 through 1998. Compared with women who never worked rotating night shifts, women who worked 1-14 years or 15 years or more on rotating night shifts had multivariate relative risks of colorectal cancer of 1.00 (95% confidence interval [CI] = 0.84 to 1.19) and 1.35 (95% CI = 1.03 to 1.77), respectively (P(trend) =.04). These data suggest that working a rotating night shift at least three nights per month for 15 or more years may increase the risk of colorectal cancer in women

Proceedings of the consensus conference on the role of sentinel lymph node biopsy in carcinoma of the breast, April 19-22, 2001, Philadelphia, Pennsylvania.

Schwartz GF, Giuliano AE, Veronesi U.

Cancer. 2002 May 15; 94(10):2542-51.

Proceedings of the consensus conference on the role of sentinel lymph node biopsy in carcinoma of the breast April 19 to 22, 2001, Philadelphia, Pennsylvania.

Schwartz GF, Giuliano AE, Veronesi U.

Hum Pathol. 2002 Jun; 33(6):579-89.

A consensus conference on the role of sentinel node biopsy in breast cancer was held in Philadelphia in April 2001. The participants included many highly respected American and European investigators in this area. This report summarizes the deliberations of the group and promotes its current guidelines for the integration of this new technique into contemporary clinical practice

Does lack of tocopherols and tocotrienols put women at increased risk of breast cancer?

Schwenke DC.

J Nutr Biochem. 2002 Jan; 13(1):2-20.

Breast cancer is the leading site of new cancers in women and the second leading cause (after lung cancer) of cancer mortality in women. Observational studies that have collected data for dietary exposure to alpha-tocopherol with or without the other related tocopherols and tocotrienols have suggested that vitamin E from dietary sources may provide women with modest protection from breast cancer. However, there is no evidence that vitamin E supplements confer any protection whatever against breast cancer. Observational studies that have assessed exposure to vitamin E by plasma or adipose tissue concentrations of alpha-tocopherol have failed to provide consistent support for the idea that alpha-tocopherol provides any protection against breast cancer. In addition, evidence from studies in experimental animals suggest that alpha-tocopherol supplementation alone has little effect on mammary tumors. In contrast, studies in breast cancer cells indicate that alpha- gamma-, and delta-tocotrienol, and to a lesser extent delta-tocopherol, have potent antiproliferative and proapoptotic effects that would be expected to reduce risk of breast cancer. Many vegetable sources of alpha-tocopherol also contain other tocopherols or tocotrienols. Thus, it seems plausible that the modest protection from breast cancer associated with dietary vitamin E may be due to the effects of the other tocopherols and the tocotrienols in the diet. Additional studies will be required to determine whether this may be the case, and to identify the most active tocopherol/tocotrienol

The timing of breast cancer surgery during the menstrual cycle.

Senie RT, Tenser SM.

Oncology (Huntingt). 1997 Oct; 11(10):1509-17.

A number of recent studies have suggested that survival among premenopausal women after primary treatment of breast cancer may be affected by the estimated hormonal milieu at the time of surgery, especially in those with axillary lymph node metastases. The concept has created considerable controversy and has resulted in the publication of many negative reports. However, several biological mechanisms have been suggested for the observed survival advantage. These include cyclical patterns of immune function, as well as cell division and cell death, that correlate with hormonal fluctuations of the menstrual cycle. Comparisons among studies of timing have been complicated by differences in menstrual cycle divisions, variability in the sources of study populations, limited availability of menstrual history data, and changes over the past 2 decades in primary and adjuvant breast cancer therapy. Several recent publications have been enhanced by the availability of serum collected at the time of surgery that enables accurate measurement of the hormonal milieu. In these studies, the likelihood of misclassification by menstrual cycle phase is reduced, and dependence on recalled menstrual history is eliminated. High progesterone levels have been associated with improved survival. These findings have encouraged some to suggest that perioperative administration of progesterone or tamoxifen (Nolvadex) may provide a preventive avenue comparable to scheduling surgery during the luteal phase. Further multidisciplinary studies are needed, however, to clarify the influence of the naturally occurring or medically induced hormonal milieu at the time of breast cancer surgery on survival in premenopausal women

Diurnal cortisol rhythm as a predictor of breast cancer survival.

Sephton SE, Sapolsky RM, Kraemer HC, et al.

J Natl Cancer Inst. 2000 Jun 21; 92(12):994-1000.

BACKGROUND:: Abnormal circadian rhythms have been observed in patients with cancer, but the prognostic value of such alterations has not been confirmed. We examined the association between diurnal variation of salivary cortisol in patients with metastatic breast cancer and subsequent survival. We explored relationships between cortisol rhythms, circulating natural killer (NK) cell counts and activity, prognostic indicators, medical treatment, and psychosocial variables. METHODS: Salivary cortisol levels of 104 patients with metastatic breast cancer were assessed at study entry at 0800, 1200, 1700, and 2100 hours on each of 3 consecutive days, and the slope of diurnal cortisol variation was calculated using a regression of log-transformed cortisol concentrations on sample collection time. NK cell numbers were measured by flow cytometry, and NK cell activity was measured by the chromium release assay. The survival analysis was conducted by the Cox proportional hazards regression model with two-sided statistical testing. RESULTS: Cortisol slope predicted subsequent survival up to 7 years later. Earlier mortality occurred among patients with relatively "flat" rhythms, indicating a lack of normal diurnal variation (Cox proportional hazards, P =. 0036). Patients with chest metastases, as opposed to those with visceral or bone metastases, had more rhythmic cortisol profiles. Flattened profiles were linked with low counts and suppressed activity of NK cells. After adjustment for each of these and other factors, the cortisol slope remained a statistically significant, independent predictor of survival time. NK cell count emerged as a secondary predictor of survival. CONCLUSIONS: Patients with metastatic breast cancer whose diurnal cortisol rhythms were flattened or abnormal had earlier mortality. Suppression of NK cell count and NK function may be a mediator or a marker of more rapid disease progression

Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol.

Serbinova E, Kagan V, Han D, et al.

Free Radic Biol Med. 1991; 10(5):263-75.

d-Alpha-tocopherol (2R,4'R,8'R-Alpha-tocopherol) and d-alpha-tocotrienol are two vitamin E constituents having the same aromatic chromanol "head" but differing in their hydrocarbon "tail": tocopherol with a saturated and toctrienol with an unsaturated isoprenoid chain. d-Alpha-tocopherol has the highest vitamin E activity, while d-alpha-tocotrienol manifests only about 30% of this activity. Since vitamin E is considered to be physiologically the most important lipid-soluble chain-breaking antioxidant of membranes, we studied alpha-tocotrienol as compared to alpha-tocopherol under conditions which are important for their antioxidant function. d-Alpha-tocotrienol possesses 40-60 times higher antioxidant activity against (Fe2+ + ascorbate)- and (Fe2+ + NADPH)-induced lipid peroxidation in rat liver microsomal membranes and 6.5 times better protection of cytochrome P-450 against oxidative damage than d-alpha-tocopherol. To clarify the mechanisms responsible for the much higher antioxidant potency of d-alpha-tocotrienol compared to d-alpha-tocopherol, ESR studies were performed of recycling efficiency of the chromanols from their chromanoxyl radicals. 1H-NMR measurements of lipid molecular mobility in liposomes containing chromanols, and fluorescence measurements which reveal the uniformity of distribution (clusterizations) of chromanols in the lipid bilayer. From the results, we concluded that this higher antioxidant potency of d-alpha-tocotrienol is due to the combined effects of three properties exhibited by d-alpha-tocotrienol as compared to d-alpha-tocopherol: (i) its higher recycling efficiency from chromanoxyl radicals, (ii) its more uniform distribution in membrane bilayer, and (iii) its stronger disordering of membrane lipids which makes interaction of chromanols with lipid radicals more efficient. The data presented show that there is a considerable discrepancy between the relative in vitro antioxidant activity of d-alpha-tocopherol and d-alpha-tocotrienol with the conventional bioassays of their vitamin activity

Serum biochemical markers in carcinoma breast.

Seth LR, Kharb S, Kharb DP.

Indian J Med Sci. 2003 Aug; 57(8):350-4.

BACKGROUND: Despite the extensive research for many years throughout the world, the etiopathogenesis of cancer still remains obscure. For the early detection of carcinoma of various origins, a number of biochemical markers have been studied to evaluate the malignancy. AIM: To analyse serum gamma glutamyl transpeptidase (GGTP), lactate dehydrogenase (LDH) and superoxide dismutase (SOD) in carcinoma breast patients. SETTINGS & DESIGN: The serum biochemical markers were estimated in twenty five histopathologically confirmed patients with carcinoma breast and equal number of healthy age- matched individuals served as control. MATERIAL & METHODS: Serum gamma glutamyl transpeptidase (GGTP), lactate dehydrogenase (LDH) and superoxide dismutase (SOD) were estimated and their sensitivity determined. Statistics: Data was analysed with student's 't'-test and sensitivity score of these markers was determined. RESULTS & CONCLUSIONS: The mean serum GGTP, LDH and SOD activities in patients with carcinoma breast were tremendously increased as compared to controls, and a steady increase was observed in their activities from stage I through stage IV as well as following distant metastasis. Serum GGTP, LDH and SOD might prove to be most sensitive biomarkers in carcinoma breast in early detection of the disease

Antioxidant activity of curcumin and related compounds.

Sharma OP.

Biochem Pharmacol. 1976 Aug 1; 25(15):1811-2.

Intervention in free radical mediated hepatotoxicity and lipid peroxidation by indole-3-carbinol.

Shertzer HG, Berger ML, Tabor MW.

Biochem Pharmacol. 1988 Jan 15; 37(2):333-8.

The cytoprotective effect of the natural dietary constituent indole-3-carbinol (I-3-C) on carbon tetrachloride (CCl4) mediated hepatotoxicity in mice was examined. I-3-C pretreatment by gavage 1 hr prior to intraperitoneal injection of CCl4 produced a 63% decrease in CCl4-mediated centrolobular necrosis and a related 60% decrease in plasma alanine aminotransferase activity (a marker of liver necrosis). Since the toxicological effects of CCl4 are mediated by radical species generated during reductive metabolism by cytochrome P-450, we examined the potential ability of I-3-C to scavenge reactive radicals. Three systems were used to evaluate the ability of I-3-C to intervene in free radical mediated lipid peroxidation. These systems consisted of the following: (1) phospholipid dissolved in chlorobenzene, with peroxidation initiated by the thermal and photo decomposition of azobisisobutyronitrile (AIBN); (2) sonicated phospholipid vesicles in phosphate buffer (pH 7.4), with peroxidation initiated by ferrous/ascorbate; and (3) mouse liver microsomes containing an NADPH-regenerating system, with peroxidation initiated with CCl4. Lipid peroxidation was measured in these three systems as thiobarbiturate-reacting material. In the AIBN and ferrous/ascorbate systems, I-3-C inhibited lipid peroxidation, with greater inhibition under conditions of low rates of free radical generation. I-3-C was not as effective an antioxidant as butylated hydroxytoluene (BHT) or tocopherol, but it inhibited peroxidation in a dose-response manner. I-3-C was most effective as a radical scavenger in the microsomal CCl4-initiated system by inhibiting lipid peroxidation in a dose-dependent fashion, with 50% inhibition at 35-40 microM I-3-C. This concentration is about one-third of the concentration of I-3-C achieved in liver after treatment of mice by gavage with 50 mg I-3-C/kg body weight. These data suggest that I-3-C may be a natural antioxidant in the human diet and, as such, may intervene in toxicological or carcinogenic processes that are mediated by radical mechanisms

Protective effects of various drugs on adriamycin (doxorubicin)-induced toxicity and microsomal lipid peroxidation in mice and rats.

Shinozawa S, Gomita Y, Araki Y.

Biol Pharm Bull. 1993 Nov; 16(11):1114-7.

The protective effects of clinically used drugs on the toxicity and microsomal lipid peroxidation induced by doxorubicin (adriamycin, ADM), an anthracycline type antitumor agent, were studied in mice and rats. Regarding the effects of anthracyclines (aclarubicin, ACL; daunorubicin, DAU; ADM; epirubicin, EPI; pirarubicin, PIR) on rat liver microsomal lipid peroxidation, ACL had the smallest effect, and effectiveness increased in the order of PIR, ADM, DAU and EPI. The increasing effect of lipid peroxidation induced by these drugs was closely correlated with the decrease in the body weight of mice administered intraperitoneally at a dose of 20 mg/kg and in rats at LD50 of the drugs. The survival times of ADM-administered mice (which were injected 15 mg/kg of ADM twice) treated with the following drugs, expressed as a percent of that of the control group, were 236% for adenosine triphosphate, 224% for coenzyme Q10 (Co Q), 235% for dextran sulfate (DS), 123% for dipyridamole, 121% for flavin adenine dinucleotide, 213% for reduced glutathion, 155% for inositol nicotinate, 157% for nicardipin and 297% for nicomol. The rat heart microsomal lipid peroxidation levels in vivo may be one of the indications of ADM-induced toxicity. The levels treated with DS correlated well with the development of ADM-induced toxicity: mouse survival time, change of body weight and tissue wet weight loss. Another type of drug, such as Co Q, may improve the myocardiac mitochondrial functions compared to those of ADM-administered mice

Enhancement of wound healing by curcumin in animals.

Sidhu GS, Singh AK, Thaloor D, et al.

Wound Repair Regen. 1998 Mar; 6(2):167-77.

Tissue repair and wound healing are complex processes that involve inflammation, granulation, and remodeling of the tissue. In this study, we evaluated the in vivo effects of curcumin (difeurloylmethane), a natural product obtained from the rhizomes of Curcuma longa on wound healing in rats and guinea pigs. We observed faster wound closure of punch wounds in curcumin-treated animals in comparison with untreated controls. Biopsies of the wound showed reepithelialization of the epidermis and increased migration of various cells including myofibroblasts, fibroblasts, and macrophages in the wound bed. Multiple areas within the dermis showed extensive neovascularization, and Masson's Trichrome staining showed greater collagen deposition in curcumin-treated wounds. Immunohistochemical localization of transforming growth factor-beta1 showed an increase in curcumin-treated wounds as compared with untreated wounds. In situ hybridization and polymerase chain reaction analysis also showed an increase in the mRNA transcripts of transforming growth factor-beta1 and fibronectin in curcumin-treated wounds. Because transforming growth factor-beta1 is known to enhance wound healing, it may be possible that transforming growth factor-beta1 plays an important role in the enhancement of wound healing by curcumin

Inhibition of cdk2 kinase activity by methylselenocysteine in synchronized mouse mammary epithelial tumor cells.

Sinha R, Medina D.

Carcinogenesis. 1997 Aug; 18(8):1541-7.

Methylselenocysteine (MSC), an organic selenium compound has significant anticarcinogenic activity against mammary tumorigenesis. Previous experiments have demonstrated that MSC and inorganic selenite inhibit mammary cell (TM6 cell line) growth through different pathways. The present investigation demonstrated that MSC arrested cells in S phase during the TM6 cell cycle, which was followed by cells entering apoptosis at 48 h. Methylselenocysteine specifically affected the cdk2 kinase activity of the TM6 cells (54% reduction) at 16 h after release from growth arrest. The cdk4 kinase activity did not change during the cell cycle, confirming that cells had passed the G1 checkpoint and had entered S phase. The amount of cyclin E associated with cdk2 was increased by MSC by the 12 h time point, thereby facilitating entry of cells into S phase. Afterwards, cyclin E and cyclin A associated with cdk2 did not change for the remainder of the cell cycle. The data demonstrate that inhibition of mammary cell growth by MSC is mediated by alterations in progression of cells through S phase. The decrease in cdk2 kinase activity is coincident with prolonged arrest in S phase. One consequence of prolonged arrest may be apoptosis

Effects of methylselenocysteine on PKC activity, cdk2 phosphorylation and gadd gene expression in synchronized mouse mammary epithelial tumor cells.

Sinha R, Kiley SC, Lu JX, et al.

Cancer Lett. 1999 Nov 15; 146(2):135-45.

Methylselenocysteine (MSC), an organic selenium compound is an effective chemopreventive agent against mammary cell growth both in vivo and in vitro but its mechanism of action is still not understood. We have previously demonstrated that MSC is able to inhibit growth in a synchronized TM6 mouse mammary epithelial tumor cell line at 16 h time point followed by apoptosis at 48 h. The decrease in cdk2 kinase activity was coincident with prolonged arrest of cells in S-phase. The present set of experiments showed that cdk2 phosphorylation was reduced by 72% in the MSC-treated cells at 16 h time point. Expression for gadd34, 45 and 153 was elevated 2.5 to 7 fold following MSC treatment only after 16 h time point. In order to investigate a possible upstream target for MSC, we analyzed protein kinase C (PKC) in this model. Total PKC activity was reduced in TM6 cells by MSC (50 microM) within 30 min of treatment, both in cytosolic (55.4 and 77.6%) and membrane (35.2 and 34.1%) fractions for calcium-dependent and independent PKCs, respectively. PMA significantly elevated the PKC activity in membrane fraction (P < 0.01) and MSC inhibited this activation by more than 57%. The effect of MSC was selenium specific as selenomethionine and sulfurmethyl-L-cysteine (SMC) did not alter PKC activity either in cytosolic or membrane fraction. Immunoblot analysis showed that PKC-alpha was translocated to the membrane by PMA and MSC did not alter this translocation. PKC-delta was faintly detectable in membrane fractions of control and MSC-treated cells. MSC treatment slightly reduced levels of PKC-e (in cytosolic and membrane fractions) and PKC-zeta (cytosolic fractions). The data presented herein suggest that PKC is a potential upstream target for MSC that may trigger one or all of the downstream effects; i.e. the decrease of cdk2 kinase activity, decreased DNA synthesis, elevation of gadd gene expression and finally apoptosis

Transforming growth factor-beta and suppression of carcinogenesis.

Sporn MB, Roberts AB, Wakefield LM, et al.

Princess Takamatsu Symp. 1989; 20:259-66.

Transforming growth factor-beta (TGF-beta) plays an important role in controlling proliferation or differentiation in almost all epithelial tissues. The pathophysiology of TGF-beta during carcinogenesis is now an important area of investigation, since it appears that as the process of carcinogenesis progresses, epithelial cells often become refractory to the growth-regulatory actions of TGF-beta. In this article we consider the possible cellular and molecular bases for this phenomenon, and then discuss some pharmacological approaches to enhancing the synthesis or activity of TGF-beta. These approaches may provide new modalities for prevention of carcinogenesis, if they can be applied during the early stages of the disease process, before cells become refractory. We give particular attention to tamoxifen and retinoic acid, since it has been shown that these agents, which are of known efficacy for prevention of cancer, can markedly enhance the secretion of specific isotypes of TGF-beta by several types of cells

In Gross Anatomy of the Breast.

Spratt JSTGR.

1995; fourth edition

The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.

Struewing JP, Hartge P, Wacholder S, et al.

N Engl J Med. 1997 May 15; 336(20):1401-8.

BACKGROUND: Carriers of germ-line mutations in BRCA1 and BRCA2 from families at high risk for cancer have been estimated to have an 85 percent risk of breast cancer. Since the combined frequency of BRCA1 and BRCA2 mutations exceeds 2 percent among Ashkenazi Jews, we were able to estimate the risk of cancer in a large group of Jewish men and women from the Washington, D.C., area. METHODS: We collected blood samples from 5318 Jewish subjects who had filled out epidemiologic questionnaires. Carriers of the 185delAG and 5382insC mutations in BRCA1 and the 6174delT mutation in BRCA2 were identified with assays based on the polymerase chain reaction. We estimated the risks of breast and other cancers by comparing the cancer histories of relatives of carriers of the mutations and noncarriers. RESULTS: One hundred twenty carriers of a BRCA1 or BRCA2 mutation were identified. By the age of 70, the estimated risk of breast cancer among carriers was 56 percent (95 percent confidence interval, 40 to 73 percent); of ovarian cancer, 16 percent (95 percent confidence interval, 6 to 28 percent); and of prostate cancer, 16 percent (95 percent confidence interval, 4 to 30 percent). There were no significant differences in the risk of breast cancer between carriers of BRCA1 mutations and carriers of BRCA2 mutations, and the incidence of colon cancer among the relatives of carriers was not elevated. CONCLUSIONS: Over 2 percent of Ashkenazi Jews carry mutations in BRCA1 or BRCA2 that confer increased risks of breast, ovarian, and prostate cancer. The risks of breast cancer may be overestimated, but they fall well below previous estimates based on subjects from high-risk families

Suppressive effect by melatonin on different phases of 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced rat mammary gland carcinogenesis.

Subramanian A, Kothari L.

Anticancer Drugs. 1991 Jun; 2(3):297-303.

This comprehensive study examines the influence of oral melatonin on the initiation and promotion phases of DMBA-induced mammary tumorigenesis in intact and pinealectomized female Holtzman rats reared in short (light:dark schedule L:D 10:14) and long (L:D 24:0) photoperiods. Melatonin administration in the initiation phase significantly suppressed tumor incidence only in intact animals reared in both photoperiods, indicating that the presence of the pineal was obligatory. On the other hand, during the promotion phase, irrespective of the presence or absence of the pineal, the tumor-suppressive effect of exogenous melatonin was pronounced

Effect of dietary palm oils on mammary carcinogenesis in female rats induced by 7,12-dimethylbenz(a)anthracene.

Sundram K, Khor HT, Ong AS, et al.

Cancer Res. 1989 Mar 15; 49(6):1447-51.

Female Sprague-Dawley rats, 50 days of age, were treated with a single dose of 5 mg of 7,12-dimethylbenz(a)anthracene intragastrically. 3 days after carcinogen treatment, the rats were put on semisynthetic diets containing 20% by weight of corn oil (CO), soybean oil (SBO), crude palm oil (CPO), refined, bleached, deodorized palm oil (RBD PO) and metabisulfite-treated palm oil (MCPO) for 5 months. During the course of experiments, rats fed on different dietary fats had similar rate of growth. Rats fed 20% CO or SBO diet have higher tumor incidence than rats fed on palm oil (PO) diets; however differences of mean tumor latency periods among the groups were not statistically significant. At autopsy, rats fed on high CO or SBO diets had significantly more tumors than rats fed on the three PO diets. Our results showed that high PO diets did not promote chemically induced mammary tumorigenesis in female rats when compared to high CO or SBO diets. CO and SBO differ greatly from the palm oils in their contents of tocopherols, tocotrienols, and carotenes. But further experiments would be required to determine whether the observed differences in tumor incidence and tumor numbers were due to the differences in these minor components or due to the unique triglyceride structure of the palm oils. Analysis of the fatty acid profiles of plasma total lipids of tumor-bearing rats and of the tumor total lipids showed that, with the exception of arachidonic acid, the fatty acid profiles reflect the nature of the dietary fats. At autopsy, there were no differences in the plasma total cholesterol contents among rats fed on different dietary fats, but rats fed on palm oil diets had a significantly higher plasma triglyceride level than that of rats fed CO or SBO diets. As for the tumor lipids, there were no significant differences in the triglyceride, diglyceride, and phospholipid levels when the CO or SBO groups were compared to the palm oil groups

New drug outperforms tamoxifen.

Susman E.

UPI Science News. 2001;Dec 11, 2001

Effects of indole-3-carbinol on the metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in smokers.

Taioli E, Garbers S, Bradlow HL, et al.

Cancer Epidemiol Biomarkers Prev. 1997 Jul; 6(7):517-22.

Indole-3-carbinol (I3C) is a component of the human diet, occurring as a conjugate in certain cruciferous vegetables. I3C protects against carcinogenesis in a variety of animal models by modifying carcinogen metabolism. In mice, I3C decreases lung tumor formation by the tobacco-specific nitrosamine 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by enhancing its hepatic clearance (M. A. Morse et al., Cancer Res., 50: 2613-2617, 1990). In this study, our goal was to determine whether I3C would have similar effects on NNK metabolism in smokers as it did in mice. Thirteen women took 400 mg of I3C on 5 consecutive days and maintained constant smoking habits during this period. Their urine was analyzed before and after the I3C treatment period for two metabolites of NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronide (NNAL-Gluc). I3C treatment resulted in decreased levels of urinary NNAL, NNAL-Gluc, and NNAL plus NNAL-Gluc, and increased NNAL-Gluc:NNAL ratio in 10 of the 13 women. The mean decreases in NNAL (-0.27 +/- 0.09 pmol/mg creatinine, -23.4%) and NNAL plus NNAL-Gluc (-0.43 +/- 0.16 pmol/mg creatinine, -10.9%) were statistically significant as was the increase in NNAL-Gluc:NNAL ratio (1.1 +/- 0.5, 39.9%). These changes in urinary metabolites of NNK were consistent with those seen in mice treated with I3C and NNK; they suggest that I3C increased hepatic metabolism of NNK in our smokers. This is the first study to examine the effects of I3C on metabolism of an exogenous carcinogen in humans

Inhibition of proliferation and modulation of estradiol metabolism: novel mechanisms for breast cancer prevention by the phytochemical indole-3-carbinol.

Telang NT, Katdare M, Bradlow HL, et al.

Proc Soc Exp Biol Med. 1997 Nov; 216(2):246-52.

Aberrant proliferation is an early-occurring intermediate event in carcinogenesis whose inhibition may represent preventive intervention. Indole-3-carbinol (I3C), a glucosinolate metabolite from cruciferous vegetables, inhibits organ site carcinogenesis in rodent models. Clinically relevant biochemical and cellular mechanisms for the anticarcinogenic effects of I3C, however, remain unclear. Experiments were conducted on reduction mammoplasty derived 184-B5 cells initiated with chemical carcinogen (184-B5/BP) or with oncogene (184-B5/HER), and on mammary-carcinoma-derived MDA-MD-231 cells to examine whether (i) I3C inhibits aberrant proliferation in initiated and transformed cells, and (ii) inhibition of aberrant proliferation is associated with altered cell-cycle progression, estradiol (E2) metabolism, and apoptosis. Aberrant proliferation in 184-B5/BP, 184-B5/HER, and MDA-MB-231 cells was evident by a 55%-67% decrease in the ratio of quiescent (Q = G0) to proliferative (P = S + M) phase of the cell cycle, a 72%-90% decrease in apoptosis, and a 76%-106% increase in anchorage-dependent growth. These cells also exhibited a 88%-90% decrease in the ratio of C2 to C16alpha-hydroxylation products of E2. Treatment of 184-B5/BP, 184-B5/HER, and MDA-MB-231 cells to cytostatic dose of 50 microM I3C resulted in an 137%-210% increase in Q/P I3C ratio, a 4- to 18-fold increase in E2 metabolite ratio, a 2-fold increase in cellular apoptosis, and a 54%-61% inhibition of growth. The preventive efficacy of I3C on human mammary carcinogenesis may be due in part to its ability to regulate cell-cycle progression, increase the formation of antiproliferative E2 metabolite, and induce cellular apoptosis

Fish consumption and breast cancer risk.

Terry P, Rohan TE, Wolk A, et al.

Nutr Cancer. 2002; 44(1):1-6.

The omega-3 fatty acids, especially long-chain eicosapentaenoic acid (20:5n-3) and docosahexaenoic (22:6n-3) contained in "fatty" fish, have consistently been shown to retard the growth of breast cancer in vitro and in animal experiments. In contrast, studies of the association between fish consumption and breast cancer risk in human populations have not consistently shown inverse associations. However, previous studies have not considered the specific types of fish consumed. Using data from a large, nationwide case-control study conducted in Sweden, we examined the association between consumption of fatty and lean fish and breast cancer risk. Odds ratios (OR) and 95% confidence intervals were computed from unconditional logistic regression models. High consumption of fish was weakly associated with reduced breast cancer risk, and the association was not statistically significant. With multivariate adjustment, the OR for women with the highest consumption (> or =3.5 servings/wk) compared with women with the lowest (virtually none) was 0.88 (95% confidence interval = 0.60-1.29, P for trend = 0.15). When type of fish was examined separately, the association was similar for fatty and lean fish

Tocotrienol: a review of its therapeutic potential.

Theriault A, Chao JT, Wang Q, et al.

Clin Biochem. 1999 Jul; 32(5):309-19.

OBJECTIVES: To summarize new knowledge surrounding the physiological activity of tocotrienol, a natural analogue of tocopherol. RESULTS: The biological activity of vitamin E has generally been associated with its well-defined antioxidant property, specifically against lipid peroxidation in biological membranes. In the vitamin E group, alpha-tocopherol is considered to be the most active form. However, recent research has suggested tocotrienol to be a better antioxidant. Moreover, tocotrienol has been shown to possess novel hypocholesterolemic effects together with an ability to reduce the atherogenic apolipoprotein B and lipoprotein(a) plasma levels. In addition, tocotrienol has been suggested to have an anti-thrombotic and anti-tumor effect indicating that tocotrienol may serve as an effective agent in the prevention and/or treatment of cardiovascular disease and cancer. CONCLUSION: The physiological activities of tocotrienol suggest it to be superior than alpha-tocopherol in many situations. Hence, the role of tocotrienol in the prevention of cardiovascular disease and cancer may have significant clinical implications. Additional studies on its mechanism of action, as well as, long-term intervention studies, are needed to clarify its function. From the pharmacological point-of-view, the current formulation of vitamin E supplements, which is comprised mainly of alpha-tocopherol, may be questionable

Natural antioxidants. III. Antioxidative components isolated from rhizome of Curcuma longa L.

Toda S, Miyase T, Arichi H, et al.

Chem Pharm Bull (Tokyo). 1985 Apr; 33(4):1725-8.

mt1 Melatonin receptor in the primate adrenal gland: inhibition of adrenocorticotropin-stimulated cortisol production by melatonin.

Torres-Farfan C, Richter HG, Rojas-Garcia P, et al.

J Clin Endocrinol Metab. 2003 Jan; 88(1):450-8.

The pineal hormone melatonin participates in circadian, seasonal, and reproductive physiology. The presence of melatonin binding sites in human brain and peripheral tissues is well documented. However, in the mammalian adrenal gland, low-affinity melatonin binding sites have been detected only in the rat by some but not all authors. Conflicting evidence for a regulatory role of melatonin on adrenal cortisol production, prompted us to investigate this possibility in a New World primate, the capuchin monkey. Expression of melatonin receptors in the adrenal cortex was demonstrated through pharmacological characterization and autoradiographic localization of 2-[125I]iodomelatonin binding sites (dissociation constant = 96.9 +/- 15 pM; maximal binding capacity = 3.8 +/- 0.4 fmol/mg protein). The mt1 identity of these receptors was established by cDNA sequencing. Melatonin treatment of dispersed cells and explants from adrenal gland did not affect basal cortisol production. However, cortisol production stimulated by 100 nM ACTH was significantly inhibited by low melatonin concentrations (0.1-100 nM); this inhibitory effect was reversed by the mt1/MT2 melatonin antagonist luzindole. Melatonin also inhibited dibutyril-cAMP-stimulated cortisol production, suggesting that melatonin acts through a cAMP-independent signaling pathway. The present data demonstrate that the primate adrenal gland cortex expresses functional mt1 melatonin receptors and shows that melatonin inhibits ACTH-stimulated cortisol production

The effect of short intermittent light exposures on the melatonin circadian rhythm and NMU-induced breast cancer in female F344/N rats.

Travlos GS, Wilson RE, Murrell JA, et al.

Toxicol Pathol. 2001 Jan; 29(1):126-36.

We investigated the effects of altered endogenous nighttime melatonin concentrations on mammary tumor production in an N-nitroso-N-methylurea (NMU)-induced breast cancer model in female Fischer 344 (F344)/N rats. Experiments were designed 1) to evaluate whether short-duration intermittent exposures to light at night would affect the nocturnal rise of melatonin, resulting in a decrease in nighttime serum melatonin concentrations, 2) to evaluate whether any suppression of nighttime serum melatonin concentrations could be maintained for a period of weeks, and 3) to determine the effects of suppressed serum melatonin concentrations on the incidence and progression of NMU-induced breast cancer. In vivo studies were used to assess serum melatonin concentrations after 1 day and 2 and 10 weeks of nightly administration of short-duration intermittent light exposure at night and incidence of NMU-induced tumors. Five 1-minute exposures to incandescent light every 2 hours after the start of the dark phase of the light: dark cycle decreased the magnitude of the nocturnal rise of serum melatonin concentrations in rats by approximately 65%. After 2 weeks of nightly intermittent light exposures, an average decrease of the peak nighttime serum melatonin concentrations of approximately 35% occurred. The amelioration continued and, at 10 weeks, peak nighttime serum melatonin concentrations were still decreased, by approximately 25%. Because peak endogenous nighttime serum melatonin values could be moderately suppressed for at least 10 weeks, a 26-week NMU mammary tumor study was conducted. Serum melatonin concentrations and incidence, multiplicity, and weight of NMU-induced mammary tumors were assessed. A group of pinealectomized (Px) animals was also included in the tumor study. No effect on the development of mammary tumors in an NMU-induced tumor model in rats occurred when endogenous nighttime serum melatonin concentrations were moderately suppressed by short-duration intermittent light exposures at night. At necropsy, there were no alterations in mammary tumor incidence (28/40 NMU controls, 28/40 NMU + light, 31/40 NMU + Px), multiplicity (2.18 tumors/tumor-bearing NMU control, 1.89 NMU + light, 2.39 NMU + Px), or average tumor weight (1.20 g NMU control, 1.19 g NMU + light, 0.74 g NMU + Px). Tumor burden had no effect on the serum melatonin cycle. At 26 weeks, however, animals exposed to intermittent light at night exhibited approximately 3-fold higher serum melatonin concentrations as compared with controls. Additionally, rats that had been pinealectomized at 4 weeks of age had serum melatonin concentrations that were markedly higher than the expected baseline concentrations for pinealectomized rats (<15 pg/ml), suggesting the reestablishment of a melatonin cycle. This finding was unexpected and suggests that melatonin can be produced by an organ or tissue other than the pineal gland

Caffeine-potentiated radiochemotherapy and function-saving surgery for high-grade soft tissue sarcoma.

Tsuchiya H, Yamamoto N, Asada N, et al.

Anticancer Res. 2000 May; 20(3B):2137-43.

Caffeine, which has a DNA-repair inhibiting effect, enhances the cytocidal effects of anticancer drugs and radiation. We present a preliminary report on the results of a new treatment, "radiochemotherapy combined with caffeine" (K3 protocol), for high-grade soft tissue sarcomas. Seventeen patients with various high-grade soft tissue sarcomas were included in this study. Preoperatively, three to five courses of intra-arterial chemotherapy using cisplatin, caffeine and doxorubicin after radiation therapy were administered. Following the preoperative therapy, function-saving surgery was performed for all cases. Complete response was observed in six patients, partial response in six and no change in five. The effectiveness rate of caffeine-potentiated radiochemotherapy was therefore 71%. The histological response for radiochemotherapy was better than that for chemotherapy alone, that is, total tumor necrosis was identified in six patients and over 90% necrosis in another six. Complications resulting from the preoperative radiation comprised of serious inflammation in three patients and skin necrosis in another three. Twelve patients have remained free of disease, two patients are alive with disease and three have died of metastatic disease with a mean follow-up period of 36 months. There was no local tumor recurrence. These preliminary findings suggest that caffeine-potentiated radiochemotherapy contributed to a satisfactory local response and the success of function-saving surgery for high-grade soft tissue sarcomas

Histopathologic validation of the sentinel lymph node hypothesis for breast carcinoma.

Turner RR, Ollila DW, Krasne DL, et al.

Ann Surg. 1997 Sep; 226(3):271-6.

BACKGROUND AND OBJECTIVE: The sentinel node hypothesis assumes that a primary tumor drains to a specific lymph node in the regional lymphatic basin. To determine whether the sentinel node is indeed the node most likely to harbor an axillary metastasis from breast carcinoma, the authors used cytokeratin immunohistochemical staining (IHC) to examine both sentinel and nonsentinel lymph nodes. METHODS: From February 1994 through October 1995, patients with breast cancer were staged with sentinel lymphadenectomy followed by completion level I and II axillary dissection. If the sentinel node was free of metastasis by hematoxylin and eosin staining (H&E), then sentinel and nonsentinel nodes were examined with IHC. RESULTS: The 103 patients had a median age of 55 years and a median tumor size of 1.8 cm (58.3% T1, 39.8% T2, and 1.9% T3). A mean of 2 sentinel (range, 1-8) and 18.9 nonsentinel (range, 7-37) nodes were excised per patient. The H&E identified 33 patients (32%) with a sentinel lymph node metastasis and 70 patients (68%) with tumor-free sentinel nodes. Applying IHC to the 157 tumor-free sentinel nodes in these 70 patients showed an additional 10 tumor-involved nodes, each in a different patient. Thus, 10 (14.3%) of 70 patients who were tumor-free by H&E actually were sentinel node-positive, and the IHC lymph node conversion rate from sentinel node-negative to sentinel node-positive was 6.4% (10/157). Overall, sentinel node metastases were detected in 43 (41.8%) of 103 patients. In the 60 patients whose sentinel nodes were metastasis-free by H&E and IHC, 1087 nonsentinel nodes were examined at 2 levels by IHC and only 1 additional tumor-positive lymph node was identified. Therefore, one H&E sentinel node-negative patient (1.7%) was actually node-positive (p < 0.0001), and the nonsentinel IHC lymph node conversion rate was 0.09% (1/1087; p < 0.0001). CONCLUSIONS: If the sentinel node is tumor-free by both H&E and IHC, then the probability of nonsentinel node involvement is <0.1%. The true false-negative rate of this technique using multiple sections and IHC to examine all nonsentinel nodes for metastasis is 0.97% (1/103) in the authors' hands. The sentinel lymph node is indeed the most likely axillary node to harbor metastatic breast carcinoma

Guide to Clinical Preventive Services.

USPSTF, U.S.Preventive Services Task Force.

1996; Second Edition

Possible prevention from the progression of cardiotoxicity in adriamycin-treated rabbits by coenzyme Q10.

Usui T, Ishikura H, Izumi Y, et al.

Toxicol Lett. 1982 Jun; 12(1):75-82.

The cumulative dose-dependent cardiotoxicity induced by doxorubicin (adriamycin, ADR) and its possible prevention by coenzyme Q10 (CoQ10) were studied in rabbits. In the group that received ADR alone, ADR dose-dependent electrocardiography (ECG) abnormalities and severe myocardial damage on electron microscopic examination were observed. In the group that received ADR + CoQ10, these alterations occurred in lesser degree, and ECG changes seemed to be improved. The results indicated that CoQ10 might prevent the progression of cardiotoxicity in ADR treated rabbits

University of Texas-Houston and Center for Alternative Medicine Research in Cancer. Hydrazine Sulfate 1998.

UTH.

1998

Variation in sensitizing effect of caffeine in human tumour cell lines after gamma-irradiation.

Valenzuela MT, Mateos S, Ruiz de Almodovar JM, et al.

Radiother Oncol. 2000 Mar; 54(3):261-71.

BACKGROUND AND PURPOSE: We have investigated whether the protective role of the G2 checkpoint has increasing importance when the p53-dependent G1 checkpoint is inactivated. MATERIALS AND METHODS: We have studied the differential effect of caffeine by clonogenic assays and flow cytometry in three human tumour cell lines with different functionality of p53 protein. RESULTS: The radiosensitizing effect of caffeine (2 mM) expressed itself as a significant decrease in surviving fraction at 2 Gy and a significant increase in alpha-values in RT112 and TE671, both with non-functional p53. However, no radiosensitizing effect was seen in cells with a normal p53 function (MCF-7 BUS). Two millimoles of caffeine also caused important changes in the cell cycle progression after irradiation. MCF-7 BUS showed a G1 arrest after irradiation and an early G2 arrest but those cells that reached the second G2 did not arrest significantly. In contrast, TE671 exhibited radiosensitization by caffeine, no G1 arrest, a G2 arrest in those cells irradiated in G2, no significant accumulation in the second G2 but an overall delay in release from the first cell cycle, which could be abrogated by caffeine. RT112 was similar to TE671 except that the emphasis in a G2 arrest was shifted from the block in cells irradiated in G2 to those irradiated at other cell cycle phases. CONCLUSION: The data presented confirm that p53 status can be a significant determinant of the efficacy of caffeine as radiosensitizer in these tumour cell lines, and document the importance of the G2 checkpoint in this effect

Intake of conjugated linoleic acid, fat, and other fatty acids in relation to postmenopausal breast cancer: the Netherlands Cohort Study on Diet and Cancer.

Voorrips LE, Brants HA, Kardinaal AF, et al.

Am J Clin Nutr. 2002 Oct; 76(4):873-82.

BACKGROUND: Conjugated linoleic acid (CLA), which is present in milk products and meat from ruminants, appears to have anticarcinogenic activity against breast cancer in animal and in vitro experiments. To date, few epidemiologic data are available in humans. OBJECTIVE: This study evaluated the relation between intakes of CLA and other fatty acids and breast cancer incidence in the Netherlands Cohort Study. DESIGN: Intake data derived from a validated 150-item food-frequency questionnaire were linked to an existing database with analytic data on specific fatty acids in European foods (the TRANSFAIR study). With 6.3 y of follow-up and 941 incident cases of breast cancer, multivariate rate ratios and 95% CIs were calculated for energy-adjusted intakes of fatty acids and CLA-containing food groups (eg, butter, cheese, milk, other milk products, and meat). RESULTS: CLA intake showed a weak, positive relation with breast cancer incidence (rate ratio for highest compared with lowest quintile: 1.24, 95% CI: 0.91, 1.69; P for trend = 0.02). Statistically significant positive associations were found with total trans fatty acids and (borderline) with saturated fatty acids. Significant inverse associations were found with monounsaturated and cis unsaturated fatty acids, whereas total fat and energy intake of CLA-containing food groups were not related to breast cancer incidence. CONCLUSION: The suggested anticarcinogenic property of CLA in animal and tissue culture models could not be confirmed in this epidemiologic study in humans

Comparison of breast magnetic resonance imaging, mammography, and ultrasound for surveillance of women at high risk for hereditary breast cancer.

Warner E, Plewes DB, Shumak RS, et al.

J Clin Oncol. 2001 Aug 1; 19(15):3524-31.

PURPOSE: Recommended surveillance for BRCA1 and BRCA2 mutation carriers includes regular mammography and clinical breast examination, although the effectiveness of these screening techniques in mutation carriers has not been established. The purpose of the present study was to compare breast magnetic resonance imaging (MRI) with ultrasound, mammography, and physical examination in women at high risk for hereditary breast cancer. PATIENTS AND METHODS: A total of 196 women, aged 26 to 59 years, with proven BRCA1 or BRCA2 mutations or strong family histories of breast or ovarian cancer underwent mammography, ultrasound, MRI, and clinical breast examination on a single day. A biopsy was performed when any of the four investigations was judged to be suspicious for malignancy. RESULTS: Six invasive breast cancers and one noninvasive breast cancer were detected among the 196 high-risk women. Five of the invasive cancers occurred in mutation carriers, and the sixth occurred in a woman with a previous history of breast cancer. The prevalence of invasive or noninvasive breast cancer in the 96 mutation carriers was 6.2%. All six invasive cancers were detected by MRI, all were 1.0 cm or less in diameter, and all were node-negative. In contrast, only three invasive cancers were detected by ultrasound, two by mammography, and two by physical examination. The addition of MRI to the more commonly available triad of mammography, ultrasound, and breast examination identified two additional invasive breast cancers that would otherwise have been missed. CONCLUSION: Breast MRI may be superior to mammography and ultrasound for the screening of women at high risk for hereditary breast cancer

Pathologic analysis of sentinel and nonsentinel lymph nodes in breast carcinoma: a multicenter study.

Weaver DL, Krag DN, Ashikaga T, et al.

Cancer. 2000 Mar 1; 88(5):1099-107.

BACKGROUND: Axillary lymph node status is a powerful prognostic factor in breast carcinoma; however, complications after axillary lymph node dissection are common. Sentinel lymph node biopsy is an alternative staging procedure. The sentinel lymph node postulate is that tumor cells migrating from the primary tumor colonize one or a few lymph nodes before colonizing subsequent lymph nodes. To validate this hypothesis, the distribution of occult and nonoccult metastases in sentinel and nonsentinel lymph nodes was evaluated. METHODS: Original pathology material was reviewed from 431 patients enrolled on a multicenter validation study of sentinel lymph node biopsy in breast carcinoma patients. Paraffin embedded tissue blocks of sentinel and nonsentinel lymph nodes were obtained for 214 lymph node negative patients. Additional sections from 100 and 200 microm deeper into the paraffin block were examined for the presence of occult metastatic carcinoma. Both routine and cytokeratin immunohistochemical stains were employed. RESULTS: Metastases were identified in 15.9% of sentinel lymph nodes and 4.2% of nonsentinel lymph nodes (odds ratio [OR] 4.3[ P < 0.001]; 95% confidence interval [95% CI], 3.5-5.4). Occult metastases were identified in 4. 09% of sentinel lymph nodes and 0.35% of nonsentinel lymph nodes (OR 12.3 [P < 0.001]; 95% CI, 5.6-28.6). The overall case conversion rate was 10.3%. All the occult metastases identified were < or = "1" mm in greatest individual dimension. The likelihood (OR) of metastases in nonsentinel lymph nodes was 13.4 times higher for sentinel lymph node positive than for sentinel lymph node negative patients (P < 0. 001; 95% CI, 6.7-28.1). CONCLUSIONS: The distribution of occult and nonoccult metastases in axillary lymph nodes validates the sentinel lymph node hypothesis. In addition, pathology review of cases confirmed the authors' previously reported finding that the sentinel lymph nodes are predictive of the final axillary lymph node status. Occult metastatic disease is more likely to be identified in sentinel lymph nodes, allowing future studies to focus attention on one or a few sentinel lymph nodes. However, the relation between occult metastatic disease in sentinel lymph nodes, disease free survival, and overall survival must be evaluated prior to endorsing the intensive analysis of sentinel lymph nodes in routine practice. [See editorial on pages 971-7, this issue.] Copyright 2000 American Cancer Society

Vitamin D-3 receptor as a target for breast cancer prevention.

Welsh J, Wietzke JA, Zinser GM, et al.

J Nutr. 2003 Jul; 133(7 Suppl):2425S-33S.

The vitamin D-3 receptor (VDR) is a nuclear receptor that modulates gene expression when complexed with its ligand 1-alpha,25-dihydroxycholecalciferol [1,25(OH)(2)-D(3)], which is the biologically active form of vitamin D-3. The cellular effects of VDR signaling include growth arrest, differentiation and/or induction of apoptosis, which indicate that the vitamin D pathway participates in negative-growth regulation. Although much attention has been directed in recent years toward the development of synthetic vitamin D analogs as therapeutic agents for a variety of human cancers including those derived from the mammary gland, studies on vitamin D as a chemopreventive agent for breast cancer have been quite limited. The VDR is expressed in normal mammary gland, where it functions to oppose estrogen-driven proliferation and maintain differentiation; this suggests that 1,25(OH)(2)-D(3) participates in negative-growth regulation of mammary epithelial cells. Furthermore, preclinical studies show that vitamin D compounds can reduce breast cancer development in animals, and human data indicate that both vitamin D status and genetic variations in the VDR may affect breast cancer risk. Collectively, findings from cellular, molecular and population studies suggest that the VDR is a nutritionally modulated growth-regulatory gene that may represent a molecular target for chemoprevention of breast cancer

Risk of breast cancer in carriers of BRCA gene mutations.

Whittemore AS.

N Engl J Med. 1997 Sep 11; 337(11):788-9.

Identification of a novel inhibitor of breast cell growth that is down-regulated by estrogens and decreased in breast tumors.

Wittmann BM, Wang N, Montano MM.

Cancer Res. 2003 Aug 15; 63(16):5151-8.

Lifetime exposure to estrogens is a major risk factor in breast cancer, but the mechanism for this action is not fully defined. To better determine this mechanism, the activation domain of estrogen receptor (ER) alpha was used in yeast two-hybrid screenings. These screenings resulted in the identification of a novel antiproliferative protein, estrogen down-regulated gene 1 (EDG1), of which the mRNA and protein were shown to be down-regulated directly by estrogens. Our studies additionally suggested an important role for EDG1 in ER alpha-mediated breast cancer development. Analysis of 43 invasive breast cancer samples and 40 adjacent normal breast samples demonstrated EDG1 protein levels to be significantly higher in normal breast epithelial tissue as compared with breast epithelial tumor tissue. EDG1 expression levels were also correlated with the proliferation activity and ER alpha status of the tumors to examine the prognostic value of EDG1 in invasive breast tumors. EDG1 expression was more disassociated from proliferative activity as compared with ER alpha expression in tumor cells. A growth regulatory function for EDG1 is additionally indicated by studies wherein overexpression of EDG1 protein in breast cells resulted in decreased cell proliferation and decreased anchorage-independent growth. Conversely, inhibiting EDG1 expression in breast cells resulted in increased breast cell growth. Thus, we have identified a novel growth inhibitor that is down-regulated by estrogens and colocalizes with ER alpha in breast tissue. These studies support a role for EDG1 in breast cancer

Dose-ranging study of indole-3-carbinol for breast cancer prevention.

Wong GY, Bradlow L, Sepkovic D, et al.

J Cell Biochem Suppl. 1997; 28-29:111-6.

Sixty women at increased risk for breast cancer were enrolled in a placebo-controlled, double-blind dose-ranging chemoprevention study of indole-3-carbinol (I3C). Fifty-seven of these women with a mean age of 47 years (range 22-74) completed the study. Each woman took a placebo capsule or an I3C capsule daily for a total of 4 weeks; none of the women experienced any significant toxicity effects. The urinary estrogen metabolite ratio of 2-hydroxyestrone to 16 alpha-hydroxyestrone, as determined by an ELISA assay, served as the surrogate endpoint biomarker (SEB). Perturbation in the levels of SEB from baseline was comparable among women in the control (C) group and the 50, 100, and 200 mg low-dose (LD) group. Similarly, it was comparable among women in the 300 and 400 mg high-dose (HD) group. Regression analysis showed that peak relative change of SEB for women in the HD group was significantly greater than that for women in the C and LD groups by an amount that was inversely related to baseline ratio; the difference at the median baseline ratio was 0.48 with 95% confidence interval (0.30, 0.67). No other factors, such as age and menopausal status, were found to be significant in the regression analysis. The results in this study suggest that I3C at a minimum effective dose schedule of 300 mg per day is a promising chemopreventive agent for breast cancer prevention. A larger study to validate these results and to identify an optimal effective dose schedule of I3C for long-term breast cancer chemoprevention will be necessary

The accuracy and effectiveness of routine population screening with mammography, prostate-specific antigen, and prenatal ultrasound: a review of published scientific evidence.

Woolf SH.

Int J Technol Assess Health Care. 2001; 17(3):275-304.

OBJECTIVE: To review published data regarding the accuracy and effectiveness of three screening tests: mammography, prostate-specific antigen (PSA), and prenatal ultrasound. METHODS: Published evidence regarding the accuracy and effectiveness of the three tests was collected by computerized literature search and supplemented by manual review of relevant bibliographies. RESULTS: Screening mammograms lower breast cancer mortality by about 20%. Most data come from women aged 50-64 years; women aged 40-49 years may also benefit, but the absolute risk reduction is lower. Up to 1,500 to 2,500 women must undergo screening to prevent one death from breast cancer. Mammograms miss approximately 12% to 37% of cancers, generate false-positive results, and cause anxiety while abnormal results are evaluated. PSA screening can detect 80% to 85% of prostate cancers but has a high false-positive rate. There is little direct evidence that early detection reduces morbidity or mortality. Indirect evidence includes a trend toward earlier stage tumors and steadily declining mortality rates in geographic areas where PSA screening has become common. Potential harms include the morbidity associated with evaluating abnormal results, and complications from treatment (e.g., impotence, incontinence). The overall balance of benefits and harms remains uncertain in the absence of better evidence. Prenatal ultrasound may reduce perinatal mortality, primarily through elective abortions for congenital anomalies, but does not appear to lower live birth rates. Although ultrasound has no proven effect on neonatal morbidity, it provides more accurate estimates of gestational age that prevent unnecessary inductions for post-term pregnancy. Screening detects multiple gestations, congenital anomalies, and intrauterine growth retardation, but direct health benefits from having this knowledge are unproved. Ultrasound has both positive and negative psychological effects on parents. The scans do not appear to harm childhood development. CONCLUSIONS: Even for the most established screening tests, the appropriateness of routine testing depends on subjective value judgments about the quality of supporting evidence and about the trade-offs between benefits and harms. Individuals, clinicians, policy makers, and governments must weigh the evidence in light of these values and the constraints imposed by available resources

Reassessment of breast cancers missed during routine screening mammography: a community-based study.

Yankaskas BC, Schell MJ, Bird RE, et al.

AJR Am J Roentgenol. 2001 Sep; 177(3):535-41.

OBJECTIVE: The purpose of this study was to have a series of screening mammograms from routine practice, including false-negative results, reviewed by peer community-based experienced radiologists to determine the percentage of these false-negative findings that might be considered detectable. MATERIALS AND METHODS: All screening cases for 1997 and 1998 were identified from the Carolina Mammography Registry. Mammographic assessments from community mammography practices were linked with population-based cancer outcomes. The findings of four community-based radiologists who reviewed the mammograms of 339 asymptomatic women were 93 false-negatives, 180 true-negatives, and 66 false-positives. The percentage of false-negative, true-negative and false-positive findings on breast films that reviewers evaluated was determined. The findings of the reviewers were compared with the original interpreting radiologists' assessments. RESULTS: The overall breast-specific workup rate by the reviewing radiologists was 21%. The average workup rate for the false-negative findings was 42% (range, 35-51%). Adjusting for the 13% workup rate in the cancer-free breasts, the percentage of false-negative findings that were detectable was estimated to be 29%. CONCLUSION: This peer review of screening mammograms from a population-based screening registry estimated a missed detectable cancer rate of 29%. Thus, 71% of cancers missed at screening would not have been worked up by peers in the same community

Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols.

Yu W, Simmons-Menchaca M, Gapor A, et al.

Nutr Cancer. 1999; 33(1):26-32.

The apoptosis-inducing properties of RRR-alpha-, beta-, gamma-, and delta-tocopherols, alpha-, gamma-, and delta-tocotrienols, RRR-alpha-tocopheryl acetate (vitamin E acetate), and RRR-alpha-tocopheryl succinate (vitamin E succinate) were investigated in estrogen-responsive MCF7 and estrogen-nonresponsive MDA-MB-435 human breast cancer cell lines in culture. Apoptosis was characterized by two criteria: 1) morphology of 4,6-diamidino-2-phenylindole-stained cells and oligonucleosomal DNA laddering. Vitamin E succinate, a known inducer of apoptosis in several cell lines, including human breast cancer cells, served as a positive control. The estrogen-responsive MCF7 cells were more susceptible than the estrogen-nonresponsive MDA-MB-435 cells, with concentrations for half-maximal response for tocotrienols (alpha, gamma, and delta) and RRR-delta-tocopherol of 14, 15, 7, and 97 micrograms/ml, respectively. The tocotrienols (alpha, gamma, and delta) and RRR-delta-tocopherol induced MDA-MB-435 cells to undergo apoptosis, with concentrations for half-maximal response of 176, 28, 13, and 145 micrograms/ml, respectively. With the exception of RRR-delta-tocopherol, the tocopherols (alpha, beta, and gamma) and the acetate derivative of RRR-alpha-tocopherol (RRR-alpha-tocopheryl acetate) were ineffective in induction of apoptosis in both cell lines when tested within the range of their solubility, i.e., 10-200 micrograms/ml. In summary, these studies demonstrate that naturally occurring tocotrienols and RRR-delta-tocopherol are effective apoptotic inducers for human breast cancer cells

Curcumin inhibits cyclooxygenase-2 transcription in bile acid- and phorbol ester-treated human gastrointestinal epithelial cells.

Zhang F, Altorki NK, Mestre JR, et al.

Carcinogenesis. 1999 Mar; 20(3):445-51.

We investigated whether curcumin, a chemopreventive agent, inhibited chenodeoxycholate (CD)- or phorbol ester (PMA)-mediated induction of cyclooxygenase-2 (COX-2) in several gastrointestinal cell lines (SK-GT-4, SCC450, IEC-18 and HCA-7). Treatment with curcumin suppressed CD- and PMA-mediated induction of COX-2 protein and synthesis of prostaglandin E2. Curcumin also suppressed the induction of COX-2 mRNA by CD and PMA. Nuclear run-offs revealed increased rates of COX-2 transcription after treatment with CD or PMA and these effects were inhibited by curcumin. Treatment with CD or PMA increased binding of AP-1 to DNA. This effect was also blocked by curcumin. In addition to the above effects on gene expression, we found that curcumin directly inhibited the activity of COX-2. These data provide new insights into the anticancer properties of curcumin

Effects of treatment of rats with indole-3-carbinol on apoptosis in the mammary gland and mammary adenocarcinomas.

Zhang X, Malejka-Giganti D.

Anticancer Res. 2003 May; 23(3B):2473-9.

Induction of apoptosis is an approach to suppress carcinogenesis. The effects of a 12-week treatment of female Sprague-Dawley rats with indole-3-carbinol (I3C), beta-naphthoflavone or vehicle (40% ethanol in corn oil), by oral gavages starting 3 weeks after initiation of mammary tumorigenesis with 7,12-dimethylbenz[alpha]anthracene, on apoptotic activities in the mammary adenocarcinomas were examined. Apoptotic cells in tumor sections were detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and quantitated by light microscopy and an Image-Plus Program. Activities of caspase-3, caspase-8 and caspase-9 were determined by colorimetric assays using the specific substrate and total tumor protein. There were no significant treatment-related effects on the numbers of apoptotic cells and caspase activities in the mammary adenocarcinomas. Likewise, protein expression levels of Bcl-2 and Bax genes in these tumors, determined by Western blot analysis, showed no treatment-related stimulation of apoptotic process. In the absence of tumorigenesis, the activities of caspase-3, caspase-8 and caspase-9 were increased up to approximately 3.6-fold in the mammary gland of rats treated with I3C at 5 or 25 mg/kg of body weight for 4 or 10 days. The I3C-effected induction of caspase-3 activity in the mammary gland was further confirmed by the cleavage of poly (ADP-ribose) polymerase. Treatment of rats with 3,3'-diindolylmethane, a major product of I3C in vivo, at the dose levels equimolar to those of I3C above, did not increase the caspase activities in the mammary gland. Thus, this I3C dimer does not seem to account for the increases of apoptotic activities in the mammary gland observed with I3C. The results suggest that increase of apoptosis in the mammary gland induced by I3C before initiation of tumorigenesis may contribute to suppression of tumor development

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

Vitamin E concentration in breast adipose tissue of breast cancer patients (Kuopio, Finland).

Zhu Z, Parviainen M, Mannisto S, et al.

Cancer Causes Control. 1996 Nov; 7(6):591-5.

Previous data on animals and humans suggest that vitamin E may be a protective factor against cancer. A low dietary vitamin E intake has been suggested to increase the risk of breast cancer. We examined the dietary intake and the concentration of vitamin E in breast adipose tissue of women in Kuopio, Finland, diagnosed between 1990 and 1992 with benign breast disease (n = 34) and with breast cancer (n = 32). In postmenopausal women, lower dietary intake (P = 0.006) and a smaller concentration of vitamin E in breast adipose tissue (P = 0.024) were observed in breast cancer patients than in subjects with benign breast disease. Partial correlation showed that the vitamin E concentration in the breast adipose tissue correlated positively with the dietary intake of vitamin E (r = 0.25, P = 0.023), indicating that the vitamin E concentration in breast adipose tissue reflects the dietary intake of vitamin E