Physicians' Desk Reference.
Physicians' Desk Reference. 2004 58:1980-4.
Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac. Agarwal B, Rao CV, Bhendwal S, et al. Gastroenterology. 1999 Oct; 117(4):838-47. BACKGROUND & AIMS: 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (HRIs) were found incidentally to reduce new cases of colon cancer in 2 large clinical trials evaluating coronary events, although most patients in both treatment and control group were taking nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are associated with reduced colon cancer incidence, predominantly by increasing apoptosis. We showed previously that lovastatin induces apoptosis in colon cancer cells. In the present study we evaluated the potential of combining lovastatin with sulindac for colon cancer chemoprevention. RESULTS: Lovastatin, 10-30 micromol/L, augmented sulindac-induced apoptosis up to 5-fold in 3 colon cancer cell lines. This was prevented by mevalonate (100 micromol/L) or geranylgeranylpyrophosphate (10 micromol/L) but not farnesylpyrophosphate (100 micromol/L), suggesting inhibition of geranylgeranylation of target protein(s) as the predominant mechanism. In an azoxymethane rat model of chemical-induced carcinogenesis, the total number of colonic aberrant crypt foci per animal (control, 161 +/- 11) and the number of foci with 4+ crypts (control, 40 +/- 4.5) decreased to 142 +/- 14 (NS) and 43 +/- 2.9 (NS), respectively, with 50 ppm lovastatin alone; to 137 +/- 5.4 (P = 0.053) and 36 +/- 2.1 (NS) with 80 ppm sulindac alone; and to 116 +/- 8.1 (P = 0.004) and 28 +/- 3.4 (P = 0.02) when 50 ppm lovastatin and 80 ppm sulindac were combined. CONCLUSIONS: Addition of an HRI such as lovastatin may augment chemopreventive effects of NSAIDs or/and may allow lower, less toxic doses of these drugs to be used
Chemopreventive effect of Ginkgo biloba extract against benzo(a)pyrene-induced forestomach carcinogenesis in mice: amelioration of doxorubicin cardiotoxicity. Agha AM, El Fattah AA, Al Zuhair HH, et al. J Exp Clin Cancer Res. 2001 Mar; 20(1):39-50. Ginkgo biloba extract (EGb) is a natural product that possesses antioxidant and anticlastogenic properties. The current study was conducted to investigate the effect of EGb on benzo(a)pyrene (BP)-induced forestomach neoplasia, and to explore its possible beneficial effects against doxorubicin (Dox)-induced cardiotoxicity. Tumor was induced in female Swiss albino mice by oral administration of 1 mg BP, twice weekly for four weeks. EGb was given, at a daily oral dose of 150 mg kg(-1), two weeks before and during BP administration. Dox was given ip at a dose of 1.5 mg kg(-1), once weekly, for four weeks, during BP administration. EGb and Dox were given as combined or monotherapies. Results of the present investigation revealed that EGb blunted forestomach tumor multiplicity, as compared to control tumor bearing group. It also exhibited high activity to induce cytosolic glutathione S-transferase and glucose-6-phosphate dehydrogenase (G6PDH) in liver, as well as replenished hepatic glutathione that have been inhibited or depleted by tumorigenesis. Furthermore, it normalized nitric oxide (NO) serum level, without any observed alteration in neither the activity of liver microsomal NADPH-cytochrome P-450 reductase nor serum level of tumor necrosis factor-alpha (TNFalpha). Similar results have been obtained with Dox, but it failed to affect G6PDH activity, while increased serum TNFalpha and NO levels. The combined therapy did not add further to the anticarcinogenic effect of Dox, however it succeeded in ameliorating the deleterious effects of Dox on the heart; as evidenced by the reduction of cardiac lipoperoxidation, with modulation of Dox-induced pathological changes. Therefore, EGb confers a beneficial chemopreventive effect against BP-induced gastric carcinogenesis in mice, and possesses a salutary ameliorating potential on the cardiotoxic effects of Dox
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
Epidermal growth factor receptor dependence in human tumors: more than just expression? Arteaga CL. Oncologist. 2002; 7 Suppl 4:31-9. The epidermal growth factor receptor (EGFR) is a rational target for antitumor strategies. EGFR signaling causes increased proliferation, decreased apoptosis, and enhanced tumor cell motility and neo-angiogenesis. The EGFR is expressed or highly expressed in a variety of human tumors of epithelial origin. ZD1839 (Iressa) is an orally active, selective EGFR tyrosine kinase inhibitor, which blocks signal transduction pathways implicated in proliferation and survival of cancer cells. The lack of a consistent method of evaluating levels of EGFR has caused a disparity in reports of the EGFR as a prognostic factor; however, for some tumors, EGFR is a strong prognostic indicator associated with more aggressive disease and reduced survival. So far, no clear association between EGFR levels and response to EGFR-targeted agents has been found. Preclinical studies with ZD1839 have noted a relationship between the two in some cases, but not others. EGFR signaling may be increased by a number of mechanisms in addition to high expression levels of EGFR, including receptor mutations, heterodimerization with other members of this receptor family such as HER2 (erbB2), increased expression of (autocrine/ paracrine) ligands, and alterations in molecules that control receptor signaling output. Each of these components could be assessed to give an indication of the magnitude of EGFR signal amplification. Evaluation of signaling components downstream from EGFR should provide information on the activation of the EGFR pathway. Until EGFR-based assays predictive of a response to receptor-targeted therapies are available, there is no clear justification for stratifying patients by EGFR status or excluding patients with low EGFR levels from trials with ZD1839 or other EGFR inhibitors
.Arthritis Pills a Cancer Cure? (report on research using COX-2 inhibitors in animal studies). Associated Press. 2002;2002 Mar 30 Associated Press
Granulocyte-macrophage colony-stimulating factor improves immunological parameters in patients with refractory solid tumours receiving second-line chemotherapy: correlation with clinical responses. Baxevanis CN, Tsavaris NB, Papadhimitriou SI, et al. Eur J Cancer. 1997 Jul; 33(8):1202-8. In this report, we studied the immunorestorative properties of subcutaneously administered granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with refractory solid tumours receiving second-line chemotherapy. Such patients exhibit abnormal immune responses in vivo and in vitro and, therefore, it was of interest to examine the effect of GM-CSF-induced immunomodulation on clinical response. We examined patients with primary malignant carcinomas (head and neck, n = 10; urogenital tract, n = 17; penis n = 6; colorectal, n = 8) who were treated with carboplatin (JM8), 300 ng/m2 on days 1 and 22, leucovorin (LV), 200 mg/m2 plus 5-fluoracil (5-FU), 500 mg/m2 on days 8, 15 and 29 and four cycles of daily injections with placebo or GM-CSF, 300 micrograms/day on days 3-6, 10-13, 17-20 and 24-27. Peripheral blood was collected from the patients one day after the end of each of the four-cycle injections with placebo or GM-CSF, namely on days 7, 14, 21 and 28. Peripheral blood mononuclear cells (PBMC) were tested in the autologous mixed lymphocyte reaction (AMLR) and for natural killer (NK) or lymphokine-activated killer (LAK) cell activity. Cytokine levels in serum were measured by immunoenzymatic (ELISA) assay. A total of 21 patients received a four-cycle regimen with GM-CSF (Group 1) and 20 were similarly treated with placebo (Group 2). All received standard chemotherapy as outlined above. Before GM-CSF treatment, all patients exhibited increased serum levels of interleukin-1 (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha), IL-6 and prostaglandin E2 (PGE2) and decreased serum levels of IL-2. Cellular immune responses (AMLR, NK- and LAK-cytotoxicity) were also low in all patients. Five patients from Group 1 had a PR (partial response), 2 patients had CR (complete response), and 14 patients had stable disease. Seven patients from Group 2 showed progressive disease, 3 had a PR and 10 had stable disease. All immune parameters were significantly improved during treatment in Group 1 but remained unchanged or even deteriorated in Group 2. Administration of GM-CSF during treatment of cancer patients with conventional chemotherapeutic drugs results in a marked potentiation of deficient cellular immune responses in vitro and a change towards normalisation of cytokine serum levels. The results reported herein support the use of GM-CSF as immunopotentiator during chemotherapy, but more patients must be studied before definite conclusions can be drawn
Metabolic bone disease induced by prostate cancer: rationale for the use of bisphosphonates. Berruti A, Dogliotti L, Tucci M, et al. J Urol. 2001 Dec; 166(6):2023-31. PURPOSE: Increasing evidences indicate that despite the osteoblastic nature of metastatic bone lesions due to prostate cancer osteolysis is a regular feature and may cause skeletal morbidity. This observation provides the rationale for the use of bisphosphonates for managing bone metastatic prostate cancer. MATERIALS AND METHODS: We reviewed the literature on the mechanisms by which prostate cancer affects bone cell function and disrupts physiological bone turnover. We also summarized the clinical results of bisphosphonate for treating bone pain in patients with prostate cancer. RESULTS: Metastatic prostate cancer in bone interferes with physiological bone remodeling by abnormal release of the hormones and paracrine factors physiologically involved in the modulation of osteoblastic and osteoclastic activity. Tumor induced bone formation and resorption develop within the same metastasis but excessive new bone is deposited away from bone resorption sites and does not contribute to bone strength. The increase in bone resorption may also be a generalized phenomenon that is most likely due to iatrogenic osteoporosis or related to hyperparathyroidism in response to the increased calcium demand. The bone resorption index in patients with bone metastatic prostate cancer correlates with bone pain and is an independent predictor of adverse skeletal events. However, small clinical studies of the efficacy of bisphosphonates for controlling bone pain in patients with prostate cancer show contradictory results. CONCLUSIONS: Improved understanding of the pathophysiology of prostate cancer induced metabolic bone disease implies that bisphosphonates may have a role in the treatment of this disorder. This issue is being addressed by large-scale ongoing randomized studies
Detrimental effect of cancer preventive phytochemicals silymarin, genistein and epigallocatechin 3-gallate on epigenetic events in human prostate carcinoma DU145 cells. Bhatia N, Agarwal R. Prostate. 2001 Feb 1; 46(2):98-107. BACKGROUND: Targeting epigenetic events associated with autonomous growth of advanced prostate cancer (PCA) is a practical approach for its control, prevention, and treatment. Recently we showed that treatment of prostate carcinoma DU145 cells with cancer preventive flavonoid silymarin at 100-200 microM doses inhibits erbB1-Shc mitogenic signaling and modulates cell cycle regulators leading to a G1 arrest and inhibition of cell growth and anchorage-independent colony formation. Here, we asked the question whether these important findings could be extended to other cancer preventive flavonoids and isoflavones such as epigallocatechin 3-gallate (EGCG) and genistein. METHODS: DU145 cells were treated with similar doses (100-200 microM) of silymarin, genistein or EGCG, cell lysates prepared, and levels of activated signaling molecules (erbB1-Shc-ERK1/2) and cell cycle regulators (CDKIs, CDKs, and cyclins) analyzed employing immunoprecipitation and/or immunoblotting techniques. Cell growth studies were done by cell counting during 5 days of treatment with these agents, and cell death was determined by Trypan blue staining. RESULTS: Treatment of cells with silymarin, genistein or EGCG at 100-200 microM resulted in a complete inhibition of TGFalpha-caused activation of erbB1 followed by a moderate to strong inhibition (10-90%) of Shc activation without an alteration in their protein levels. Silymarin and genistein, but not EGCG, also inhibited (10% to complete) ERK1/2 activation suggesting that these agents impair erbB1-Shc-ERK1/2 signaling in DU145 cells. In other studies, silymarin, genistein or EGCG caused a strong induction of Cip1/p21 (up to 2.4-fold) and Kip1/p27 (up to 150-fold), and a strong decrease in CDK4 (40-90%) but had moderate effect on CDK2, and cyclins D1 and E. An enhanced level of CDKIs also led to an increase in their binding to CDK4 and CDK2. Treatment of cells with silymarin, genistein or EGCG also resulted in 50-80% cell growth inhibition at lower doses, and complete inhibition at higher doses. In contrast to silymarin, higher doses of genistein showed cytotoxic effect causing 30-40% cell death. A more profound cytotoxic effect was observed with EGCG accounting for 50% cell death at lower doses and complete loss of viability at higher doses. CONCLUSIONS: These results suggest that similar to silymarin, genistein and EGCG also inhibit mitogenic signaling pathway(s) and alter cell cycle regulators, albeit at different levels, leading to growth inhibition and death of advanced and androgen-independent prostate carcinoma cells. More studies are, therefore, needed with these agents to explore their anti-carcinogenic potential against human prostate cancer
Genotoxicity of idarubicin and its modulation by vitamins C and E and amifostine. Blasiak J, Gloc E, Wozniak K, et al. Chem Biol Interact. 2002 Apr 20; 140(1):1-18. Idarubicin is an anthracycline anticancer drug used in haematological malignancies. The main side effect of idarubicin is free-radicals based cardiotoxicity. Using the comet assay we showed that the drug at concentrations from the range 0.001 to 10 microM induced DNA damage in normal human lymphocytes, measured as the increase in percentage of DNA in the tail (% tail DNA). The effect was dose-dependent. Treated cells were able to recover within a 120-min incubation. Recognised cell protector, amifostine at 14 mM decreased the mean % tail DNA of the cells exposed to idarubicin at all tested concentrations of the drug. So did vitamin C at 10 microM, but vitamin E (alpha-tocopherol) at 50 microM increased the % tail DNA. Lymphocytes exposed to idarubicin and treated with endonuclease III, formamidopyrimidine-DNA glycosylase and 3-methyladenine-DNA glycosylase II, enzymes recognizing oxidized and alkylated bases, displayed greater extent of DNA damage than those not treated with these enzymes. Pretreatment of lymphocytes with nitrone spin traps, N-tert-butyl-alpha-phenylnitrone and alpha-(4-pyridil-1-oxide)-N-tert-butylnitrone decreased the extent of DNA damage evoked by idarubicin. To discuss the influence of vitamins and amifostine in cancer cells we used also murine pro-B lymphoid BaF3 transformed with BCR/ABL oncogene. These cells can be treated as model cells of human acute myelogenous leukemia. The response of these cells to vitamin E was quantitatively the same as human lymphocytes. However, vitamin C did not exert any effect on DNA damage and amifostine, in spite to normal lymphocytes, potentiated this effect. The results obtained suggest that reactive oxygen species, including free radicals, may be involved in the formation of DNA lesions induced by idarubicin. The drug can also methylate DNA bases. Our results indicate that not only cardiotoxicity but also genotoxicity and in consequence induction of secondary malignancies should be taken into account as diverse side effects of idarubicin. Amifostine may potentate DNA-damage effect of idarubicin in cancer cells and decrease this effect in normal cells. Vitamin C can be considered as protective agents against DNA damage in normal cells in persons receiving idarubicin-based chemotherapy, but the use of vitamin E cannot be recommended and at least needs further research
Caffeine inhibits the checkpoint kinase ATM. Blasina A, Price BD, Turenne GA, et al. Curr Biol. 1999 Oct 7; 9(19):1135-8. The basis of many anti-cancer therapies is the use of genotoxic agents that damage DNA and thus kill dividing cells. Agents that cause cells to override the DNA-damage checkpoint are predicted to sensitize cells to killing by genotoxic agents. They have therefore been sought as adjuncts in radiation therapy and chemotherapy. One such compound, caffeine, uncouples cell-cycle progression from the replication and repair of DNA [1] [2]. Caffeine therefore servers as a model compound in establishing the principle that agents that override DNA-damage checkpoints can be used to sensitize cells to the killing effects of genotoxic drugs [3]. But despite more than 20 years of use, the molecular mechanisms by which caffeine affects the cell cycle and checkpoint responses have not been identified. We investigated the effects of caffeine on the G2/M DNA-damage checkpoint in human cells. We report that the radiation-induced activation of the kinase Cds1 [4] (also known as Chk2 [5]) is inhibited by caffeine in vivo and that ATM kinase activity is directly inhibited by caffeine in vitro. Inhibition of ATM provides a molecular explanation of the attenuation of DNA-damage checkpoint responses and for the increased radiosensitivity of caffeine-treated cells [6] [7] [8]
Whey protein concentrate (WPC) and glutathione modulation in cancer treatment. Bounous G. Anticancer Res. 2000 Nov; 20(6C):4785-92. The glutathione (GSH) antioxidant system is foremost among the cellular protective mechanisms. Depletion of this small molecule is a common consequence of increased formation of reactive oxygen species during increased cellular activities. This phenomenon can occur in the lymphocytes during the development of the immune response and in the muscular cells during strenuous exercise. It is not surprising that so much research has been done, and is still being done on this small tripeptide molecule. Whey protein concentrate has been shown to represent an effective and safe cysteine donor for GSH replenishment during GSH depletion in immune deficiency states. Cysteine is the crucial limiting amino acid for intracellular GSH synthesis. Animal experiments showed that the concentrates of whey proteins also exhibit anti-carcinogenesis and anticancer activity. They do this via their effect on increasing GSH concentration in relevant tissues, and may have anti-tumor effect on low volume of tumor via stimulation of immunity through the GSH pathway. It is considered that oxygen radical generation is frequently a critical step in carcinogenesis, hence the effect of GSH on free radicals as well as carcinogen detoxification, could be important in inhibiting carcinogenesis induced by a number of different mechanisms. Case reports are presented which strongly suggest an anti-tumor effect of a whey protein dietary supplement in some urogenital cancers. This non toxic dietary intervention, which is not based on the principles of current cancer chemotherapy, will hopefully attract the attention of laboratory and clinical oncologists
Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Caro JJ, Salas M, Ward A, et al. Cancer. 2001 Jun 15; 91(12):2214-21. BACKGROUND: Anemia is common in cancer patients, although the prevalence is influenced both by the type of malignancy and the choice of treatment. Individual studies have compared the survival of patients with and without anemia and have shown reduced survival times in patients with various malignancies, including carcinoma of the lung, cervix, head and neck, prostate, lymphoma, and multiple myeloma. The objective of this study was to systematically review, to summarize, and to obtain an overall estimate of the effect of anemia on survival in patients with malignant disease. METHODS: A comprehensive literature review was carried out using the MEDLINE data base and reviewing the reference lists from published studies. Two hundred papers were identified. Of these, 60 papers that reported the survival of cancer patients according to either hemoglobin levels or the presence of anemia were included. Among these papers, 25% related to patients with lung carcinoma, 17% related to patients with head and neck carcinoma, 12% related to patients with multiple myeloma, 10% related to patients with prostate carcinoma, 8% related to patients with cervicouterine carcinoma, 7% related to patients with leukemia, 5% related to patients with lymphoma, and 16% related to patients with other types of malignancies. RESULTS: The relative risk of death increased by 19% (95% confidence interval, 10-29%) in anemic patients with lung carcinoma, by 75% (37-123%) in anemic patients with head and neck carcinoma, by 47% (21-78%) in anemic patients with prostate carcinoma, and by 67% (30-113%) in anemic patients with lymphoma. The overall estimate increase in risk was 65% (54-77%). CONCLUSIONS: Anemia is associated with shorter survival times for patients with lung carcinoma, cervicouterine carcinoma, head and neck carcinoma, prostate carcinoma, lymphoma, and multiple myeloma
Establishing the dose of the oral NK1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting. Chawla SP, Grunberg SM, Gralla RJ, et al. Cancer. 2003 May 1; 97(9):2290-300. BACKGROUND: The neurokinin-1 antagonist aprepitant (EMEND; Merck Research Laboratories, West Point, PA) has been shown to reduce chemotherapy-induced nausea and vomiting when it is given with a 5-hydroxytryptamine-3 receptor antagonist and dexamethasone. The current study sought to define the most appropriate dose regimen of oral aprepitant. METHODS: This multicenter, randomized, double-blind, placebo-controlled study was conducted in patients with cancer who were receiving initial cisplatin (> or = 70 mg/m(2)) and standard antiemetic therapy (intravenous ondansetron plus oral dexamethasone). Patients were randomized to receive standard therapy plus either aprepitant 375 mg on Day 1 and 250 mg on Days 2-5, aprepitant 125 mg on Day 1 and 80 mg on Days 2-5, or placebo. Due to an apparent interaction with dexamethasone suggested by pharmacokinetic data obtained while the study was ongoing, the aprepitant 375/250 mg dose was discontinued and replaced with aprepitant 40 mg on Day 1 and 25 mg on Days 2-5, and a new randomization schedule was generated. Patients recorded nausea and emesis in a diary. The primary endpoint was complete response (no emesis and no rescue therapy), which was analyzed using an intent-to-treat approach with data obtained after the dose adjustment. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments, and included all available data. RESULTS: The percentages of patients who achieved a complete response in the overall study period were 71.0% for the aprepitant 125/80-mg group (n = 131 patients), 58.8% for the aprepitant 40/25-mg group (n = 119 patients), and 43.7% for the standard therapy group (n = 126 patients; P < 0.05 for either aprepitant regimen vs. standard therapy). Rates for Day 1 were 83.2% for the aprepitant 125/80-mg group, 75.6% for aprepitant 40/25-mg group, and 71.4% for the standard therapy group (P < 0.05 for aprepitant 125/80 mg vs. standard therapy), and rates on Days 2-5 were 72.7% for the aprepitant 125/80-mg group, 63.9% for the aprepitant 40/25-mg group, and 45.2% for the standard therapy group (P < 0.01 for either aprepitant group vs. standard therapy). The efficacy of the aprepitant 375/250-mg regimen was similar to that of the aprepitant 125/80-mg regimen. The overall incidence of adverse events was generally similar across treatment groups: 85% in the aprepitant 375/250-mg group (n = "34" patients), 76% in the aprepitant 125/80-mg group (n = "214" patients), 71% in the aprepitant 40/25-mg group (n = "120" patients), and 72% in the standard therapy group (n = "212" patients), with the exception of a higher incidence of infection in the aprepitant 125/80-mg group (13%) compared with the standard therapy group (4%). CONCLUSIONS: When it was added to a standard regimen of intravenous ondansetron and oral dexamethasone in the current study, aprepitant reduced chemotherapy-induced nausea and vomiting and was generally well tolerated, although increases in infection were noted that were assumed to be due to elevated dexamethasone levels as a result of the pharmacokinetic interaction. The aprepitant 125/80-mg regimen had the most favorable benefit:risk profile
Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21WAF1/CIP1 via C/EBPbeta. Chinery R, Brockman JA, Peeler MO, et al. Nat Med. 1997 Nov; 3(11):1233-41. Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. Five-fluorouracil (5FU) remains the single most effective treatment for advanced disease, despite a response rate of only 20%. Herein, we show that the antioxidants pyrrolidinedithiocarbamate and vitamin E induce apoptosis in CRC cells. This effect is mediated by induction of p21WAF1/CIP1, a powerful inhibitor of the cell cycle, through a mechanism involving C/EBPbeta (a member of the CCAAT/enhancer binding protein family of transcription factors), independent of p53. Antioxidants significantly enhance CRC tumor growth inhibition by cytotoxic chemotherapy in vitro (5FU and doxorubicin) and in vivo (5FU). Thus, chemotherapeutic agents administered in the presence of antioxidants may provide a novel therapy for colorectal cancer
The clinical neuroimmunotherapeutic role of melatonin in oncology. Conti A, Maestroni GJ. J Pineal Res. 1995 Oct; 19(3):103-10. In the past several years, interest in the immunophysiological role of the pineal gland and melatonin has grown to the extent that now their immunoregulatory role is widely recognized. Melatonin has immunoenhancing properties and it is able to counteract the immunodepression induced by acute stress, drug treatment (i.e., anticancer drugs), and viral infections. Here we review the therapeutic efficacy of melatonin alone or in combination with interleukin-2 (IL-2) in cancer patients who did not respond to standard anticancer chemotherapies and/or refused any aggressive treatment. In this review, we summarize a series of reports from 1986 through 1994 in which patients affected by metastatic solid tumors, metastatic non-small-cell lung cancer, advanced solid neoplasms, myelodysplastic syndrome, hepatocellular carcinoma, and advanced endocrine tumors were studied. The conclusion drawn from these studies is that melatonin protects against IL-2 and synergizes with the IL-2 anticancer action. This combined strategy represents a well tolerated intervention to control tumor growth. In most cases performance status and quality of life seem improved
Inhibition by oral N-acetylcysteine of doxorubicin-induced clastogenicity and alopecia, and prevention of primary tumors and lung micrometastases in mice. D'Agostini F, Bagnasco M, Giunciuglio D, et al. Int J Oncol. 1998 Aug; 13(2):217-24. The thiol N-acetylcysteine (NAC), an analog and precursor of glutathione, displays cancer preventive properties not only in early stages of the carcinogenesis process but also in its advanced stages. NAC inhibited type-IV collagenase activity as well as invasion, tumor take, and metastasis of malignant cells in murine models. Previously, we provided evidence for synergistic effects of oral NAC with intravenously injected doxorubicin (DOX). In the present study B16-BL6 melanoma cells were injected s.c. into the footpad of C57BL/6 mice. The animals were divided into 5 groups: i) untreated mice; ii) mice receiving daily NAC with drinking water (12.25 mmol/kg body weight) starting 16 h after injection of cancer cells; iii) mice receiving a single i.v. injection of DOX (2 micromol/kg body weight) 24 h after injection of cancer cells; iv) mice receiving a combination of NAC and DOX, with NAC treatment starting 72 h before injection of cancer cells; and v) mice treated as in iv) but with NAC treatment starting 16 h after injection of cancer cells. Both NAC and DOX, either individually or in combination, significantly enhanced the survival time as compared to controls. The weight of local primary tumors was significantly decreased by either drug, and was further decreased to a significant extent, compared to the individual treatments, in the two groups of mice receiving combinations of NAC and DOX. No lung micrometastases, evaluated by immunohistochemistry as S-100-positive foci of melanocytic cells, were detectable in the two groups of mice receiving the combined treatments. NAC significantly, attenuated the time-related increase of micronucleated polychromatic erythrocytes in the peripheral blood of DOX-treated mice. All mice individually treated with DOX developed a partial but well evident alopecia, diffusely affecting their back hair, which was totally prevented by NAC, irrespective of the combination schedule. Thus, besides preventing DOX cardiotoxicity, as extensively documented in the literature, oral NAC protects mice from DOX-induced myelogenotoxicity and alopecia, and at the same time interacts with this cytotoxic agent in inhibiting cancer cell invasion and metastasis
Synergism between N-acetylcysteine and doxorubicin in the prevention of tumorigenicity and metastasis in murine models. De Flora S, D'Agostini F, Masiello L, et al. Int J Cancer. 1996 Sep 17; 67(6):842-8. The thiol N-acetylcysteine (NAC) is a promising cancer chemopreventive agent which acts through a variety of mechanisms, including its nucleophilic and antioxidant properties. We have recently shown that NAC inhibits type-IV collagenase activity as well as invasion, tumor take and metastasis of malignant cells in mice. NAC is also known to attenuate the cardiotoxicity of the cytostatic drug doxorubicin (DOX, Adriamycin). The present study was designed to evaluate whether the combination of NAC and DOX treatments in mice injected with cancer cells could affect their tumorigenic and metastatic properties. Six separate experiments were carried out, using a total of 291 adult female mice. In experimental metastasis assays, in which B16-F10 melanoma cells were injected i.v. into (CD-1)BR nude mice, DOX significantly reduced the number of lung metastases when administered i.v. at a dose of 10 mg/kg body weight, 3 days after the i.v. injection of cancer cells. NAC inhibited lung metastases when added to the medium of cancer cells before their i.v. injection. The combined treatment with DOX and NAC, under various experimental conditions, was highly effective, showing a synergistic reduction in the number of mestastases. In tumorigenicity and spontaneous metastasis assays, in which B16-BL6 melanoma cells were injected s.c. into the footpad of C57BL/6 mice, DOX decreased the number of lung metastases when given i.p. at 2 mg/kg body weight. Oral NAC exerted significant protective effects, and considerably prolonged survival of mice. The combined treatment with DOX and NAC again showed synergistic effects on the frequency and weight of primary tumors and local recurrences, and completely prevented the formation of lung metastases in the experiment in which these end-points were evaluated at fixed times. While injection of DOX 7 days after implantation of cancer cells failed to improve the cancer-protective effects of NAC, its injection after I day resulted in a striking inhibition of lung metastases. These findings demonstrate an evident synergism between DOX (given parenterally) and NAC (given with drinking water) in preventing tumorigenicity and metastases. The indications of these animal studies warrant further evaluation in clinical trials
Addition of the oral NK1 antagonist aprepitant to standard antiemetics provides protection against nausea and vomiting during multiple cycles of cisplatin-based chemotherapy
16. de Wit R, Herrstedt J, Rapoport B, et al. J Clin Oncol. 2003 Nov 15; 21(22):4105-11. PURPOSE: This analysis evaluated whether the antiemetic efficacy of the NK1 receptor antagonist aprepitant (EMEND trade mark, Merck, Whitehouse Station, NJ) plus standard antiemetics could be sustained for up to six cycles of cisplatin-based chemotherapy. PATIENTS AND METHODS: Patients receiving cisplatin > or = 70 mg/m2 were blindly assigned to receive one of the following three regimens: (1) aprepitant 375 mg 1 hour before cisplatin on day 1 and aprepitant 250 mg on days 2 to 5 (n = 35); (2) aprepitant 125 mg before cisplatin and aprepitant 80 mg on days 2 to 5 (n = 81); or (3) placebo before cisplatin on days 2 to 5 (n = 86). All groups received ondansetron 32 mg and dexamethasone 20 mg before cisplatin, and dexamethasone 8 mg on days 2 to 5. The primary end point was complete response (no emesis and no rescue therapy) over 5 days following cisplatin in up to six cycles. A cumulative probability analysis using a model for transitional probabilities was used to analyze the data. The aprepitant 375/250-mg regimen was discontinued early in light of new pharmacokinetic data. RESULTS: In the first cycle, 64% of patients in the aprepitant group and 49% in the standard therapy group had a complete response. Thereafter, complete response rates for the aprepitant group were still 59% by cycle 6, but decreased to 34% by cycle 6 for the standard therapy group. Reasons for discontinuation were similar across treatment groups. CONCLUSION: Compared with patients who received standard therapy, those who received only the aprepitant regimen had better and more sustained protection against chemotherapy-induced nausea and vomiting over multiple cycles
Oral statins and increased bone-mineral density in postmenopausal women. Edwards CJ, Hart DJ, Spector TD. Lancet. 2000 Jun 24; 355(9222):2218-9. Experimental evidence suggests that the cholesterol-lowering drugs statins increase bone formation. We report a significant increase of bone-mineral density associated with taking statins in postmenopausal women
Statins and bone: myth or reality? Edwards CJ, Russell RG, Spector TD. Calcif Tissue Int. 2001 Aug; 69(2):63-6. In the space of a few weeks, four articles appeared in the The Lancet and JAMA suggesting that using 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) is associated with increased bone mineral density (BMD) and a reduced fracture risk. The stimulus for these case-control studies came from reports that the statins have unexpected effects on bone, increasing bone formation in rodents. These observations offered a new insight into the potential importance of the cholesterol synthesis pathway in bone turnover and future therapeutic opportunities
5-Hydroxymethyluracil excretion, plasma TBARS and plasma antioxidant vitamins in adriamycin-treated patients. Faure H, Coudray C, Mousseau M, et al. Free Radic Biol Med. 1996; 20(7):979-83. The thymine oxidative lesion-5-hydroxymethyluracil (HMUra)-was measured in urine collected from cancer patients. These patients all received chemotherapy using Adriamycin. Adriamycin (ADR) intercalates DNA coils and interferes with normal cell metabolism through diverse biochemical mechanisms that may explain its different actions. The anticancer action of ADR could derive from its interaction with topoisomerase II, resulting in DNA nicking followed by DNA fragmentation and apoptosis. Side effects of ADR-mainly its cardiotoxicity-may derive from the fact that ADR generates superoxide and hydroxyl radicals in two ways: redox-cycling and a Haber-Weiss type reaction due to Fe-ADR complexes. The oxygen free radicals, particularly .OH, are thought to be produced by ADR directly in genomic material and attack all its components. 5-Hydroxymethyluracil is a thymine lesion provoked by these attacks, and it has been proposed as a marker of DNA alterations. In this article, we report the results of a study involving 14 cancer patients treated with ADR. We found that urine HMUra is significantly increased by the anticancer therapy (HMUra (nmol/24 h): 74.4 9.46 vs. 96.3 8.74; p < .01), this increase reveals a higher risk of mutagenesis. Our study is the first to show an in vivo alteration of DNA by ADR. Results also show that thiobarbituric acid reactants increase significantly, and that the vitamin levels for retinol and alpha-tocopherol, which are antioxidant vitamins, are lower at the end of chemotherapy. We suggest to supplement these patients with vitamins A and E, and selenium to reduce the side effects of ADR
Simvastatin inhibits malignant transformation following expression of the Ha-ras oncogene in NIH 3T3 fibroblasts. Furst J, Haller T, Chwatal S, et al. Cell Physiol Biochem. 2002; 12(1):19-30. In previous studies we have shown that the expression of the transforming Ha-ras oncogene in NIH 3T3 fibroblasts stimulates cellular calcium entry, which triggers oscillatory calcium induced calcium release from internal stores. The intracellular calcium oscillations lead to cytoskeletal remodeling by actin stress fiber depolymerization and activation of the Na(+)/H(+) exchanger thus mediating cell swelling and intracellular alkalosis, both important mitogenic signals. This is evidenced by abrogation of Ha-ras induced growth factor independent cell proliferation by interference with any of these events, i.e. by inhibition of cellular calcium entry or inhibition of the Na(+)/H(+) exchanger.As shown in this study, simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme for cholesterol biosynthesis, is able to prevent these events following the expression of the transforming Ha-ras oncogene. We show, that simvastatin inhibits farnesylation dependent membrane translocation of a CAAX motive bearing yellow fluorescent protein and suppresses Ha-ras stimulated cellular calcium influx, which can be identified as capacitative calcium entry. In addition simvastatin is able to block regulatory volume decrease channels and to suppress the cytoskeletal remodeling, intracellular alkalinization, increase in cell volume and growth factor independent cell proliferation induced by the oncogene.Thus simvastatin is able to prevent crucial cellular events following expression of the transforming Ha-ras oncogene
Human prostatic carcinoma cells produce an increase in the synthesis of interleukin-6 by human osteoblasts. Garcia-Moreno C, Mendez-Davila C, de La PC, et al. Prostate. 2002 Mar 1; 50(4):241-6. BACKGROUND: The aim of this work was to evaluate the effect produced by conditioned medium from human prostatic carcinoma cell (PC-3) culture on human osteoblast (HOB) interleukin 6 (IL-6) synthesis. METHODS: PC-3 cells were cultured in Ham's F12K medium with 10% fetal calf serum (FCS) up to confluence. Medium was changed by Dulbecco modified Eagle medium (DMEM)/F12K (1:1) with 0.1% bovine serum albumin. Cells were cultured for 24 hr, and medium (PC-3-CM) was collected. HOBs were cultured up to confluence, and after 48 hr without FCS, medium was removed and PC-3-CM was added to the wells. After 24 hr, supernatant was collected for the determination of IL-6. In another experiment, HOBs were cultured up to confluence in Petri dishes, and after 48 hr without FCS, PC-3-CM or DMEM/F12K (1:1) was added. After different periods of time, medium was removed, and total RNA was extracted. IL-6 mRNA was quantified using reverse transcription polymerase chain reaction. RESULTS: PC-3-CM significantly enhanced IL-6 secretion into HOB culture supernatants (between 1,812% and 372%, depending on the osteoblastic line) with respect to HOBs cultured in DMEM/F12K. PC-3-CM also produced an increase in IL-6 mRNA levels in HOBs. CONCLUSIONS: Prostate carcinoma cells (PC-3) produce a factor or factors that enhance the synthesis and release of IL-6, a known activator of bone resorption
Antiangiogenic scheduling of lower dose cancer chemotherapy. Gately S, Kerbel R. Cancer J. 2001 Sep; 7(5):427-36. Cancer chemotherapy utilized at maximum tolerated, toxic doses, rarely results in sustained total tumor eradication, with patients ultimately failing a variety of chemotherapeutic regimens. If tumors respond, the constituent cancer cells acquire resistance to chemotherapeutic agents, largely due to tremendous genetic instability. Changing the target of these agents to the tumor's proliferating microvasculature, a more genetically stable cell, may provide important therapeutic advantages. Modifying the cyclic schedule and high doses of chemotherapeutic agents to a continuous, lower dose, "metronomic" regimen increases the efficacy of targeting the tumor microvasculature, and produces therapeutic activity with decreased toxicity. Preclinically, the antiangiogenic properties of continuous, lower-dose chemotherapy can be further enhanced by the concurrent administration of a selective angiogenesis inhibitor. Because the target is not exclusively the tumor cell, this antiangiogenic combination strategy provides the opportunity to delay or possibly avoid acquired resistance. Preclinical and clinical observations provide a basis for treating cancer as a chronic disease, using protracted, continuous dosing. Because appropriate chemotherapeutic agents and commercially available compounds that inhibit angiogenesis are readily available, it would be beneficial to initiate clinical trials to evaluate the antiangiogenic scheduling of chemotherapy expeditiously
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.
Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists
24. Hesketh PJ, Van Belle S, Aapro M, et al. Eur J Cancer. 2003 May; 39(8):1074-80. Advances in antiemetic therapy for chemotherapy-induced emesis have resulted in improved protection against symptoms occurring within 24 h of chemotherapy. However, the vomiting which tends to occur beyond 24 h after chemotherapy (delayed-phase vomiting) is still relatively poorly controlled by the currently available drugs, suggesting that more than one mechanism may mediate these symptoms. The standard antiemetic regimen currently recommended for prevention of chemotherapy-induced emesis includes a serotonin (5-HT(3)) antagonist and a corticosteroid. The neurokinin-1 (NK(1)) antagonist aprepitant represents a new class of antiemetic currently in clinical development. Using data obtained in 2 Phase II clinical trials of aprepitant in patients receiving chemotherapy based on the highly emetogenic chemotherapeutic agent cisplatin, we compared the time course of antiemetic effect of aprepitant, a 5-HT(3) antagonist, or a combination of both. Over the entire observation period (up to 7 days post-cisplatin), patients who received the NK(1) antagonist had a superior prevention of emesis. However, in the first 24 h after cisplatin, emesis occurred in fewer patients who received the 5-HT(3) antagonist than in patients who did not receive this class of drug. Furthermore, the majority of treatment failures in patients who received the NK(1) antagonist occurred within the first 8-12 h of chemotherapy, whereas the treatment failures in patients who received a 5-HT(3) antagonist were more evenly distributed over time. Patients who received both drugs had superior control of symptoms compared with patients who received one or the other. The difference in the time course of emesis blockade observed with two different classes of receptor antagonists provides substantial evidence for involvement of separate pathophysiological mechanisms in chemotherapy-induced vomiting. Serotonin mediates the early vomiting process that occurs within 8-12 h following cisplatin-based chemotherapy, after which time substance P acting at NK(1) receptors becomes the dominant mediator of vomiting
The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group
9. Hesketh PJ, Grunberg SM, Gralla RJ, et al. J Clin Oncol. 2003 Nov 15; 21(22):4112-9. PURPOSE: In early clinical trials with patients receiving highly emetogenic chemotherapy, the neurokinin antagonist aprepitant significantly enhanced the efficacy of a standard antiemetic regimen consisting of a type-three 5-hydroxytryptamine antagonist and a corticosteroid. This multicenter, randomized, double-blind, placebo-controlled phase III study was performed to establish definitively the superiority of the aprepitant regimen versus standard therapy in the prevention of chemotherapy-induced nausea and vomiting (CINV). PATIENTS AND METHODS: Patients receiving cisplatin > or = 70 mg/m2 for the first time were given either standard therapy (ondansetron and dexamethasone on day 1; dexamethasone on days 2 to 4) or an aprepitant regimen (aprepitant plus ondansetron and dexamethasone on day 1; aprepitant and dexamethasone on days 2 to 3; dexamethasone on day 4). Patients recorded nausea and vomiting episodes in a diary. The primary end point was complete response (no emesis and no rescue therapy) on days 1 to 5 postcisplatin, analyzed by a modified intent-to-treat approach. Treatment comparisons were made using logistic regression models. Tolerability was assessed by reported adverse events and physical and laboratory assessments. RESULTS: The percentage of patients with complete response on days 1 to 5 was significantly higher in the aprepitant group (72.7% [n = 260] v 52.3% in the standard therapy group [n = 260]), as were the percentages on day 1, and especially on days 2 to 5 (P <.001 for all three comparisons). CONCLUSION: Compared with standard dual therapy, addition of aprepitant was generally well tolerated and provided consistently superior protection against CINV in patients receiving highly emetogenic cisplatin-based chemotherapy
Holland-Frei Cancer Medicine. Holland JFFEIBRCJrPREWRR. 2000; 5th edition
Selective inhibition of cyclooxygenase-2 (COX-2) enhances chemotherapy-induced apoptosis (meeting abstract). Hsueh CKDPSGK. Proc Annu Meet Am Soc Clin Oncol. 1999;(18):A606.
Signal transduction by basic fibroblast growth factor in rat osteoblastic Py1a cells. Hurley MM, Marcello K, Abreu C, et al. J Bone Miner Res. 1996 Sep; 11(9):1256-63. Basic fibroblast growth factor (bFGF) is a potent mitogen for bone. In this study, we utilized the clonal rat osteoblastic cell line, Py1a, to examine signal transduction by bFGF and to determine the role of mitogen activated protein kinases (MAPK) and induction of c-fos mRNA in the mitogenic response to bFGF. Stimulation of [3H]thymidine incorporation (TDR) into DNA by bFGF was determined in the presence of phorbol myristate acetate of (PMA) to down-regulate the protein kinase C (PKC) pathway, genistein, an inhibitor of tyrosine kinase and H-7, a PKC inhibitor, bFGF 10(-8) M and PMA 10(-7) M increased TDR by 242 and 245%, respectively. Treatment with bFGF or PMA for 5 or 30 minutes increased tyrosine phosphorylation of multiple proteins, and immunoblotting with MAPK-specific antibody revealed that two of these bands were the 42 and 44 kD isoforms of MAPK. PMA and bFGF induced c-fos mRNA expression at 30 minutes. Genistein at 10 micrograms/ml blocked the mitogenic effect of bFGF and partially inhibited the mitogenic effect of PMA. Genistein at 100 micrograms/ml also blocked both bFGF- and PMA-induced increases in c-fos mRNA. A 24 h pretreatment with PMA at 10(-7) M inhibited the mitogenic response, tyrosine phosphorylation of MAPK, and induction of c-fos mRNA subsequent to the addition of PMA, but not bFGF. H-7 at 50 microM blocked bFGF-induced mitogenesis and c-fos induction, but did not inhibit bFGF-induced tyrosine phosphorylation of MAPK. In this study, we show that the signaling pathway of bFGF and PMA are similar in that they both induce tyrosine phosphorylation of MAP kinases and activate c-fos. However, the signaling pathways ultimately diverge in that once the PKC pathway is down-regulated by PMA pretreatment or blocked by the PKC inhibitor H-7, tyrosine phosphorylation of MAP kinase, c-fos induction, and the mitogenic effect of PMA is blocked. In contrast, down-regulation of the PKC pathway inhibits c-fos and the mitogenic response to bFGF, but not bFGF's effects on tyrosine phosphorylation of MAP kinase
Protective effect of coenzyme Q10 on anthracyclines cardiotoxicity: control study in children with acute lymphoblastic leukemia and non-Hodgkin lymphoma. Iarussi D, Auricchio U, Agretto A, et al. Mol Aspects Med. 1994; 15 Suppl:s207-s212. Two groups of children with acute lymphoblastic leukemia or non-Hodgkin lymphoma, treated with anthracyclines (ANT), were studied: group I, consisting of 10 patients, with coenzyme Q10 (CoQ) therapy; group II, consisting of 10 patients without CoQ therapy. The ANT cumulative dose was 240 +/- 20.0 mg/m2 in group I and 252.0 +/- 20.1 mg/m2 in group II. Echocardiographic study was performed at the beginning, at the cumulative dose of 180 mg/m2 and at the end of therapy with ANT. Percentage left ventricular fractional shortening (%LVFS) decreased from baseline (40.36 +/- 4.6) to end value (35.82 +/- 5.02) (P < 0.05) in group I; %LVFS decreased from baseline (39.89 +/- 4.37) to end value (33.43 +/- 3.46) (P < 0.002) in group II. Interventricular septum wall thickening decreased only in group II from baseline (46.10 +/- 10.1) to end therapy (27.00 +/- 18.54) (P < 0.01). Septum wall motion abnormalities were detected only in 2 patients of group II. These data demonstrate a protective effect of CoQ on cardiac function during therapy with ANT
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
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
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
Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Kawata S, Yamasaki E, Nagase T, et al. Br J Cancer. 2001 Apr 6; 84(7):886-91. Chemotherapy is not effective for hepatocellular carcinoma (HCC). HMG-CoA redutase inhibitors have cytostatic activity for cancer cells, but their clinical usefulness is unknown. To investigate whether pravastatin, a potent HMG-CoA reductase inhibitor, prolongs survival in patients with advanced HCC, this randomized controlled trial was conducted between February 1990 and February 1998 at Osaka University Hospital. 91 consecutive patients <71 years old (mean age 62) with unresectable HCC were enroled in this study. 8 patients were withdrawn because of progressive liver dysfunction; 83 patients were randomized to standard treatment with or without pravastatin. All patients underwent transcatheter arterial embolization (TAE) followed by oral 5-FU 200 mg(-1)d for 2 months. Patients were then randomly assigned to control (n = "42)" and pravastatin (n = "41)" groups. Pravastatin was administered at a daily dose of 40 mg. The effect of pravastatin on tumour growth was assessed by ultrasonography. Primary endpoint was death due to progression of HCC. The duration of pravastatin administration was 16.5 +/- 9.8 months (mean +/- SD). No patients in either group were lost to follow-up. Median survival was 18 months in the pravastatin group versus 9 months in controls (P = "0.006)." The Cox proportional hazards model showed that pravastatin was a significant factor contributing to survival. Pravastatin prolonged the survival of patients with advanced HCC, suggesting its value for adjuvant treatment
Ginger syrup as an antiemetic in early pregnancy. Keating A, Chez RA. Altern Ther Health Med. 2002 Sep; 8(5):89-91. CONTEXT: Ginger (Zingiber officinale) has been used to ameliorate symptoms of nausea. A beverage containing ginger in a syrup may be easier to consume than a capsule or solid food. OBJECTIVE: To determine if ginger syrup mixed in water is an effective remedy for the relief of nausea and vomiting in the first trimester of pregnancy. DESIGN: Double-blind, placebo-controlled, randomized clinical trial. SETTING: Subjects were enrolled from the University of South Florida department of obstetrics and gynecology private practice office. PATIENTS: 26 subjects in the first trimester of pregnancy. INTERVENTION: Subjects ingested 1 tablespoon of commercially prepared study syrup (or placebo) in 4 to 8 ounces of hot or cold water 4 times daily. MAIN OUTCOME MEASURES: Duration and severity of nausea and vomiting over a 2-week period measured on a 10-point scale. RESULTS: After 9 days, 10 of the 13 (77%) subjects receiving ginger had at least a 4-point improvement on the nausea scale. Only 2 of the 10 (20%) remaining subjects in the placebo group had the same improvement. Conversely, no woman in the ginger group, but 7 (70%) of the women in the placebo group, had a 2-point or less improvement on the nausea scale. Eight of the 12 (67%) women in the ginger group who were vomiting daily at the beginning of the treatment stopped vomiting by day 6. Only 2 of the 10 (20%) women in the placebo group who were vomiting stopped by day 6. CONCLUSION: The ingestion of 1 g of ginger in syrup in a divided dose daily may be useful in some patients experiencing nausea and vomiting in the first trimester of pregnancy
The use of a whey protein concentrate in the treatment of patients with metastatic carcinoma: a phase I-II clinical study. Kennedy RS, Konok GP, Bounous G, et al. Anticancer Res. 1995 Nov; 15(6B):2643-9. Glutathione (GSH) concentration is high in most tumour cells and this may be an important factor in resistance to chemotherapy. Previous in-vitro and animal experiments have shown a differential response of tumour versus normal cells to various cysteine delivery systems. More specifically, an in-vitro assay showed that at concentrations that induce GSH synthesis in normal human cells, a specially prepared whey protein concentrate, Immunocal, caused GSH depletion and inhibition of proliferation in human breast cancer cells. On the basis of this information five patients with metastatic carcinoma of the breast, one of the pancreas and one of the liver were fed 30 grams of this whey protein concentrate daily for six months. In six patients the blood lymphocyte GSH levels were substantially above normal at the outset, reflecting high tumour GSH levels. Two patients (#1, #3) exhibited signs of tumour regression, normalization of haemoglobin and peripheral lymphocyte counts and a sustained drop of lymphocyte GSH levels towards normal. Two patients (#2, #7) showed stabilisation of the tumour, increased haemoglobin levels. In three patients (#4, #5, #6,) the disease progressed with a trend toward higher lymphocyte GSH levels. These results indicate that whey protein concentrate might deplete tumour cells of GSH and render them more vulnerable to chemotherapy
Continuous low-dose anti-angiogenic/ metronomic chemotherapy: from the research laboratory into the oncology clinic. Kerbel RS, Klement G, Pritchard KI, et al. Ann Oncol. 2002 Jan; 13(1):12-5.
Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. Klement G, Baruchel S, Rak J, et al. J Clin Invest. 2000 Apr; 105(8):R15-R24. Various conventional chemotherapeutic drugs can block angiogenesis or even kill activated, dividing endothelial cells. Such effects may contribute to the antitumor efficacy of chemotherapy in vivo and may delay or prevent the acquisition of drug-resistance by cancer cells. We have implemented a treatment regimen that augments the potential antivascular effects of chemotherapy, that is devoid of obvious toxic side effects, and that obstructs the development of drug resistance by tumor cells. Xenografts of 2 independent neuroblastoma cell lines were subjected to either continuous treatment with low doses of vinblastine, a monoclonal neutralizing antibody (DC101) targeting the flk-1/KDR (type 2) receptor for VEGF, or both agents together. The rationale for this combination was that any antivascular effects of the low-dose chemotherapy would be selectively enhanced in cells of newly formed vessels when survival signals mediated by VEGF are blocked. Both DC101 and low-dose vinblastine treatment individually resulted in significant but transient xenograft regression, diminished tumor vascularity, and direct inhibition of angiogenesis. Remarkably, the combination therapy resulted in full and sustained regressions of large established tumors, without an ensuing increase in host toxicity or any signs of acquired drug resistance during the course of treatment, which lasted for >6 months. This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org
Granulocyte-macrophage colony-stimulating factor treatment before doxorubicin and cyclophosphamide chemotherapy priming in women with early-stage breast cancer. Kobrinsky NL, Sjolander DE, Cheang MS, et al. J Clin Oncol. 1999 Nov; 17(11):3426-30. PURPOSE: To determine if inhibition of stem-cell activity induced by granulocyte-macrophage colony-stimulating factor ([GM-CSF]; Sargramostim; Immunex Corporation, Seattle, WA) withdrawal or priming protects hematopoietic stem cells from the cytotoxic effects of adjuvant chemotherapy for early-stage breast cancer. PATIENTS AND METHODS: Serial blood counts were performed in 20 women with early-stage breast cancer receiving four courses of cyclophosphamide and doxorubicin chemotherapy. By a double-blind, placebo-controlled, balanced randomization, subjects received GM-CSF priming on days 5 to 1 for courses 1 and 3 or courses 2 and 4. RESULTS: Compared with before priming, after priming the times to neutrophil nadir (12.8 +/- 2.5 days v 14.8 +/- 1.5 days, respectively; P =.0001) and platelet nadir (mean +/- SD, 10.1 +/- 1.9 days v 11.1 +/- 2.2 days, P <.05) were shorter, indicating a shift of cytotoxicity to later progenitors. The neutrophil nadir was similar with and without priming (mean +/- SD, 490 +/- 310/microL v 550 +/- 350/microL, respectively; P =".2);" however, on day 16 the mean neutrophil count was higher (mean +/- SD, 1030 +/- 580/microL v 690 +/- 370/microL, P =".004)," and the proportion of patients with a neutrophil count less than 500/microL was lower after priming than before (six of 35 or 17. 1% v 12 of 34 or 35.3%, respectively; P =".04)." The platelet nadir was higher (mean +/- SD, 166,000 +/- 51,000/microL after priming v 151,000 +/- 45,000/microL before priming, P =".007)," and the duration of thrombocytopenia, ie, a platelet count less than 150,000/microL, was shorter (1.5 +/- 2.1 days v 2.8 +/- 2.9 days, P =".0025)" after priming. Episodes of fever and neutropenia were not observed. CONCLUSIONS: GM-CSF priming from days 5 to 1 before doxorubicin and cyclophosphamide chemotherapy was associated with an earlier neutrophil and platelet nadir. On day 16, a higher mean neutrophil count and a lower proportion of patients with severe (< 500/microL) neutropenia were observed. Beneficial effects on the severity and duration of thrombocytopenia were also noted. These observations support the hypothesis that GM-CSF priming protects hematopoietic progenitors from the cytotoxic effects of chemotherapy
Ascorbic acid (vitamin C) improves the antineoplastic activity of doxorubicin, cisplatin, and paclitaxel in human breast carcinoma cells in vitro. Kurbacher CM, Wagner U, Kolster B, et al. Cancer Lett. 1996 Jun 5; 103(2):183-9. Utilizing a microplate ATP bioluminescence assay, two human breast carcinoma cell lines, MCF-7 and MDA-MB-231, were tested against doxorubicin (DOX), cisplatin (DDP), and paclitaxel (Tx) alone and in combination with ascorbic acid (Vit C). In both cell lines, Vit C exhibited cytotoxic activity at high concentrations (i.e. 10(2)-10(3) microM). Both cell lines also were resistant to DOX. MCF-7 was found to be DDP-resistant, MDA-MB-231 was moderately sensitive to DDP. Both cell lines were strongly sensitive to Tx. Vit C both at non-cytotoxic (1 microM) and moderately cytotoxic concentrations (10(2) microM) improved the cytotoxicity of DOX, DDP, and Tx significantly. Combination effects between Vit C and DDP or Tx were partly synergistic and partly additive or subadditive whereas a consistent synergism was found between Vit C and DOX. The mechanisms by which Vit C potentiates the cytostatics studied are yet unclear and should be evaluated further
A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state. Lissoni P, Paolorossi F, Ardizzoia A, et al. J Pineal Res. 1997 Aug; 23(1):15-9. Recent studies suggest that the pineal hormone melatonin may reduce chemotherapy-induced immune and bone marrow damage. In addition, melatonin may exert potential oncostatic effects either by stimulating host anticancer immune defenses or by inhibiting tumor growth factor production. On this basis, we have performed a randomized study of chemotherapy alone vs. chemotherapy plus melatonin in advanced non-small cell lung cancer patients (NSCLC) with poor clinical status. The study included 70 consecutive advanced NSCLC patients who were randomized to receive chemotherapy alone with cisplatin (20 mg/m2/day i.v. for 3 days) and etoposide (100 mg/m2/day i.v. for 3 days) or chemotherapy plus melatonin (20 mg/day orally in the evening). Cycles were repeated at 21-day intervals. Clinical response and toxicity were evaluated according to World Health Organization criteria. A complete response (CR) was achieved in 1/34 patients concomitantly treated with melatonin and in none of the patients receiving chemotherapy alone. Partial response (PR) occurred in 10/34 and in 6/36 patients treated with or without melatonin, respectively. Thus, the tumor response rate was higher in patients receiving melatonin (11/34 vs. 6/35), without, however, statistically significant differences. The percent of 1-year survival was significantly higher in patients treated with melatonin plus chemotherapy than in those who received chemotherapy alone (15/34 vs. 7/36, P < 0.05). Finally, chemotherapy was well tolerated in patients receiving melatonin, and in particular the frequency of myelosuppression, neuropathy, and cachexia was significantly lower in the melatonin group. This study shows that the concomitant administration of melatonin may improve the efficacy of chemotherapy, mainly in terms of survival time, and reduce chemotherapeutic toxicity in advanced NSCLC, at least in patients in poor clinical condition
Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Lissoni P, Tancini G, Barni S, et al. Support Care Cancer. 1997 Mar; 5(2):126-9. Experimental data have suggested that the pineal hormone melatonin (MLT) may counteract chemotherapy-induced myelosuppression and immunosuppression. In addition, MLT has been shown to inhibit the production of free radicals, which play a part in mediating the toxicity of chemotherapy. A study was therefore performed in an attempt to evaluate the influence of MLT on chemotherapy toxicity. The study involved 80 patients with metastatic solid tumors who were in poor clinical condition (lung cancer: 35; breast cancer: 31; gastrointestinal tract tumors: 14). Lung cancer patients were treated with cisplatin and etoposide, breast cancer patients with mitoxantrone, and gastrointestinal tract tumor patients with 5-fluorouracil plus folates. Patients were randomised to receive chemotherapy alone or chemotherapy plus MLT (20 mg/day p.o. in the evening). Thrombocytopenia was significantly less frequent in patients concomitantly treated with MLT. Malaise and asthenia were also significantly less frequent in patients receiving MLT. Finally, stomatitis and neuropathy were less frequent in the MLT group, albeit without statistically significant differences. Alopecia and vomiting were not influenced by MLT. This pilot study seems to suggest that the concomitant administration of the pineal hormone MLT during chemotherapy may prevent some chemotherapy-induced side-effects, particularly myelosuppression and neuropathy. Evaluation of the impact of MLT on chemotherapy efficacy will be the aim of future clinical investigations
Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Lissoni P, Barni S, Mandala M, et al. Eur J Cancer. 1999 Nov; 35(12):1688-92. Melatonin (MLT) has been proven to counteract chemotherapy toxicity, by acting as an anti-oxidant agent, and to promote apoptosis of cancer cells, so enhancing chemotherapy cytotoxicity. The aim of this study was to evaluate the effects of concomitant MLT administration on toxicity and efficacy of several chemotherapeutic combinations in advanced cancer patients with poor clinical status. The study included 250 metastatic solid tumour patients (lung cancer, 104; breast cancer, 77; gastrointestinal tract neoplasms, 42; head and neck cancers, 27), who were randomized to receive MLT (20 mg/day orally every day) plus chemotherapy, or chemotherapy alone. Chemotherapy consisted of cisplatin (CDDP) plus etoposide or gemcitabine alone for lung cancer, doxorubicin alone, mitoxantrone alone or paclitaxel alone for breast cancer, 5-FU plus folinic acid for gastro-intestinal tumours and 5-FU plus CDDP for head and neck cancers. The 1-year survival rate and the objective tumour regression rate were significantly higher in patients concomitantly treated with MLT than in those who received chemotherapy (CT) alone (tumour response rate: 42/124 CT + MLT versus 19/126 CT only, P < 0.001; 1-year survival: 63/124 CT + MLT versus 29/126 CT only, P < 0.001). Moreover, the concomitant administration of MLT significantly reduced the frequency of thrombocytopenia, neurotoxicity, cardiotoxicity, stomatitis and asthenia. This study indicates that the pineal hormone MLT may enhance the efficacy of chemotherapy and reduce its toxicity, at least in advanced cancer patients of poor clinical status
Is there a role for melatonin in supportive care? Lissoni P. Support Care Cancer. 2002 Mar; 10(2):110-6. Melatonin (MLT) is the main hormone released from the pineal gland and has proved to have physiological antitumor activity. MLT has been shown to exert anticancer activity through several biological mechanisms: antiproliferative action, stimulation of anticancer immunity, modulation of oncogene expression, and anti-inflammatory, anti-oxidant and anti-angiogenic effects. Several experimental studies have shown that MLT may inhibit cancer cell growth, and preliminary clinical studies seem to confirm its anticancer property in humans. In addition, MLT may have other biological effects, which could be useful in the palliative therapy of cancer, namely anticachectic, anti-asthenic and thrombopoietic activities. On this basis, the present clinical investigation was performed in an attempt at better definition of the therapeutic properties of MLT in human neoplasms. In a first clinical study, we evaluated the effects of MLT in a group of 1,440 patients with untreatable advanced solid tumors, who received supportive care alone or supportive care plus MLT. In a second study, we evaluated the influence of MLT on the efficacy and toxicity of chemotherapy in a group of 200 metastatic patients with chemotherapy-resistant tumor histotype, who were randomized to receive chemotherapy alone or chemotherapy plus MLT. In both studies, MLT was given orally at 20 mg/day during the dark period of the day. The frequency of cachexia, asthenia, thrombocytopenia and lymphocytopenia was significantly lower in patients treated with MLT than in those who received supportive care alone. Moreover, the percentage of patients with disease stabilization and the percentage 1-year survival were both significantly higher in patients concomitantly treated with MLT than in those treated with supportive care alone. The objective tumor response rate was significantly higher in patients treated with chemotherapy plus MLT than in those treated with chemotherapy alone. Moreover, MLT induced a significant decline in the frequency of chemotherapy-induced asthenia, thrombocytopenia, stomatitis, cardiotoxicity and neurotoxicity. These clinical results demonstrate that the pineal hormone MLT may be successfully administered in medical oncology in the supportive care of untreatable advanced cancer patients and for the prevention of chemotherapy-induced toxicity
Immunotherapy with subcutaneous low-dose interleukin-2 plus melatonin as salvage therapy of heavily chemotherapy-pretreated ovarian cancer. Lissoni PAABSTGMMP. Oncol Rep. 1996; 3(5):947-9.
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
Hematopoietic rescue via T-cell-dependent, endogenous granulocyte-macrophage colony-stimulating factor induced by the pineal neurohormone melatonin in tumor-bearing mice. Maestroni GJ, Covacci V, Conti A. Cancer Res. 1994 May 1; 54(9):2429-32. We investigated whether melatonin can affect tumor growth and/or hematopoiesis in mice transplanted with Lewis lung carcinoma and treated with cyclophosphamide or etoposide. These agents were injected i.p. for 5 days at two different cumulative doses (cyclophosphamide, 40 and 160 mg/kg body weight; etoposide, 20 and 40 mg/kg body weight) from day 8 through day 12 after tumor transplantation. Melatonin was injected s.c. at a dose of 1 mg/kg body weight/day, from day 8 throughout the experiments and from days 8 through 12 or from day 13 onwards. Melatonin did not influence tumor growth but selectively counteracted bone marrow toxicity when administered together with the cancer chemotherapy compounds without interfering with their anticancer action. In vitro, melatonin proved to counteract apoptosis in bone marrow cells incubated with etoposide. Such protection was reflected by an increased frequency of granulocyte/macrophage-colony forming units but not of the pluripotent spleen-colony forming units. The effect of melatonin was neutralized by anti-granulocyte/macrophage-colony-stimulating factor monoclonal antibodies. When athymic, T-cell-deficient mice were used as bone marrow donors, melatonin did not exert any protective effect. This suggested that melatonin is able to stimulate the endogenous production of granulocyte/macrophage-colony-stimulating factor via bone marrow T-cells. Due to the well known lack of toxic and undesirable side effects of melatonin, these findings might have a straightforward clinical application
Colony-stimulating activity and hematopoietic rescue from cancer chemotherapy compounds are induced by melatonin via endogenous interleukin 4. Maestroni GJ, Conti A, Lissoni P. Cancer Res. 1994 Sep 1; 54(17):4740-3. We have reported that melatonin may rescue bone marrow cells from apoptosis induced either in vivo or in vitro by cancer chemotherapy compounds via bone marrow T-cells and endogenous release of granulocyte-macrophage colony-stimulating factor. Here we show that the number of granulocyte/macrophage colony-forming units cultured with suboptimal concentrations of colony-stimulating factor was higher in the presence of melatonin both at physiological and pharmacological concentrations. CD4+,Thy-1.2+ cell depletion or addition of anti-mouse interleukin 4 monoclonal antibodies prevented both effects of melatonin. Upon incubation with etoposide, the concentration of myeloid precursors was 43 +/- 8 per 10(5) cells. The melatonin+etoposide value was 68 +/- 7, whereas that of melatonin+etoposide+anti-interleukin 4 was 38 +/- 6. Melatonin was also ineffective when bone marrow cells were separated in adherent and nonadherent populations. Supernatants from nonadherent cells incubated with melatonin proved to contain interleukin 4 activity which, however, showed its influence on unseparated bone marrow and adherent cells but not on nonadherent cells. It is proposed that melatonin represents a neuroendocrine regulator of interleukin 4 production in bone marrow T-helper cells. Interleukin 4 may then stimulate adherent stromal cells to produce granulocyte/macrophage colony-stimulating factor. Such a neuroendocrine-cytokine mechanism may explain the hematopoietic rescue of melatonin as well as its antitumoral and immunoenhancing properties
kappa-Opioid receptors in marrow stroma mediate the hematopoietic effects of melatonin-induced opioid cytokines. Maestroni GJ. Ann N Y Acad Sci. 1998 May 1; 840:411-9. Melatonin exerts colony-stimulating activity and rescues myeloid progenitors from apoptosis, induced either in vivo or in vitro by cancer chemotherapy compounds in tumor-bearing mice. These effects are mediated mainly by T-helper cell-derived opioid cytokines with an apparent molecular mass of 15 kDa and 67 kDa that are recognized both by anti-interleukin-4 and anti-dynorphin B antibodies. These putative new cytokines were named melatonin-induced-opioid (MIO). The most active and naltrexone-sensitive MIO was the smaller molecule, which was called MIO15 and found to act on an opioid-binding site present in adherent bone marrow cells. However, the hematopoietic action of MIO15 was dependent on the presence of colony-stimulating factors (CSF). To investigate this point, we studied the ability of melatonin to rescue granulocyte/macrophage colony-forming units (GM-CFU) in the bone marrow of tumor-free animals treated with cancer chemotherapeutic compounds. We found that melatonin not only is unable to protect bone marrow GM-CFU unless the mice are transplanted with Lewis lung carcinoma (LLC), but also that melatonin seems to increase the myelotoxicity of cyclophosphamide in tumor-free mice. In both tumor-bearing or healthy mice, the effect of melatonin is negated by naltrexone, indicating the involvement of MIO15. Competition studies classified the target opioid-binding site as a kappa-opioid receptor with low affinity in tumor-free mice and high affinity in LLC-implanted mice. LLC is known to release CSF. Consistently, addition of CSF in the form of lung-conditioned medium (LCM) to adherent bone marrow cells increased the affinity of the kappa-opioid receptor. Addition of antigranulocyte/macrophage colony-stimulating factor (GM-CSF) mAbs neutralized the effect of LCM. In conclusion, the affinity state of the kappa-opioid receptors in stromal bone marrow cells seems to modulate the hematopoietic effect of melatonin and/or MIO15
Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Man S, Bocci G, Francia G, et al. Cancer Res. 2002 May 15; 62(10):2731-5. A number of recent preclinical studies have sparked interest in the concept of exploiting conventional chemotherapeutic drugs as antiangiogenics. Such antiangiogenic activity is achieved or optimized by metronomic-dosing protocols in which the drug is given at comparatively low doses using a frequent schedule of administration (e.g., once to three times per week) with no breaks, particularly when combined with an endothelial cell-specific antiangiogenic drug. The use of p.o. chemotherapeutic drugs is particularly suitable for this type of treatment strategy. We tested one such drug, cyclophosphamide (CTX), in a protocol wherein the drug was administered to mice at low doses, of approximately 10-40 mg/kg on a daily basis through the drinking water. CTX is typically given p.o. to patients, but it has almost always been injected when treating preclinical mouse tumor models. We found p.o. CTX to be a safe and convenient treatment with significant antitumor efficacy. Growth delays were observed for human orthotopic breast or ectopic colon cancer xenografts in nude or SCID mice. Established PC3 human prostate tumor xenografts could be induced to almost fully regress, remaining virtually nonpalpable for > or =2 months of continuous therapy, after which tumors began to grow progressively. These re-emergent tumors were not found to be drug resistant when tested in new hosts, using the same treatment protocol. Regression of spontaneously arising, late-stage pancreatic islet cell carcinomas in Rip Tag transgenic mice was also observed. The effects of continuous p.o. CTX treatment were enhanced significantly in an orthotopic, metastatic breast cancer xenograft model when used in combination with an antivascular endothelial growth factor receptor-2 blocking antibody. Maximum tolerated dose levels established for other mouse strains proved highly toxic to SCID mice, whereas daily p.o. low-dose regimens of CTX were well tolerated. Taken together, the results demonstrate the feasibility of delivering CTX in a p.o. metronomic chemotherapy regimen, which proved safe, reasonably efficacious, and potentially applicable to chronic treatment. Such a regimen may be particularly well suited for integration with antiangiogenic drugs
Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells. Matsumoto S, Imaeda Y, Umemoto S, et al. Br J Cancer. 2002 Jan 21; 86(2):161-7. Cimetidine has been shown to have beneficial effects in colorectal cancer patients. In this study, a total of 64 colorectal cancer patients who received curative operation were examined for the effects of cimetidine treatment on survival and recurrence. The cimetidine group was given 800 mg day(-1) of cimetidine orally together with 200 mg day(-1) of 5-fluorouracil, while the control group received 5-fluorouracil alone. The treatment was initiated 2 weeks after the operation and terminated after 1 year. Robust beneficial effects of cimetidine were noted: the 10-year survival rate of the cimetidine group was 84.6% whereas that of control group was 49.8% (P<0.0001). According to our previous observations that cimetidine blocked the expression of E-selectin on vascular endothelium and inhibited the adhesion of cancer cells to the endothelium, we have further stratified the patients according to the expression levels of sialyl Lewis antigens X (sL(x)) and A (sL(a)). We found that cimetidine treatment was particularly effective in patients whose tumour had higher sL(x) and sL(a) antigen levels. For example, the 10-year cumulative survival rate of the cimetidine group with higher CSLEX staining, recognizing sL(x), of tumours was 95.5%, whereas that of control group was 35.1% (P="0.0001)." In contrast, in the group of patients with no or low levels CSLEX staining, cimetidine did not show significant beneficial effect (the 10-year survival rate of the cimetidine group was 70.0% and that of control group was 85.7% (P="n.s.))." These results clearly indicate that cimetidine treatment dramatically improved survival in colorectal cancer patients with tumour cells expressing high levels of sL(x) and sL(a)
In Vivo Assessment of NF-kB Inhibitors as Chemosensitizers: Study 4967. Paper presented at the Annual Meeting of the American Association for Cancer Research, New Orleans, March 24-28, 2001. Michaels SBDM. 2001;March 24-28, 2001 Study 4967
Clinical and non-invasive assessment of anthracycline cardiotoxicity: perspectives on myocardial protection. Mortensen SA, Aabo K, Jonsson T, et al. Int J Clin Pharmacol Res. 1986; 6(2):137-50. A series of 38 patients with solid tumours (N=29) and haematological malignancies (N=9) and with suspicion of cardiotoxicity (CTX) due to antineoplastic drugs was studied. The series comprised 22 females and 16 males (mean age 52 years). The patients were examined clinically by ECG, chest X-ray and echocardiography. Seventeen patients were classified as having moderate or severe chronic CTX; 16 patients developed either arrhythmias shortly after the administration of chemotherapy (acute CTX) or arrhythmias and/or signs of myocardial dysfunction (without overt congestive heart failure) at a later date, after chemotherapy had been suspended (latent CTX). In 5 cases the suspicion of CTX could not be confirmed. Weak and non-specific symptoms such as unexplained tachycardia or coughing at night should alert the clinician and result in ECG control and further non-invasive cardiological investigations (including radionuclide angiocardiography) before additional anthracycline is administered. Chest X-ray is a very insensitive method with respect to early diagnosis of chronic CTX; in cases of doubt heart catheterization with endomyocardial biopsy should be carried out to obtain a reliable estimate of the extent of morphological damage. As anthracycline CTX may present without prominent clinical symptoms or as latent disease, one should be aware of potential precipitating factors such as volume load (during i.v. chemotherapy), surgical trauma and general anaesthesia and alcohol abuse. Further effects to lessen CTX should be made, using supposed cardio-protective substances in randomized clinical trials. Promising research on coenzyme Q10 and carnitine may usher in a new era in the prevention of anthracycline cardiotoxicity
Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Mukhopadhyay D, Tsiokas L, Zhou XM, et al. Nature. 1995 Jun 15; 375(6532):577-81. Angiogenesis, the formation of new microvasculature by capillary sprouting, is crucial for tumour development. Hypoxic regions of solid tumours produce the powerful and directly acting angiogenic protein VEGF/VPF (vascular endothelial growth factor/vascular permeability factor). We now investigate the signal transduction pathway involved in hypoxic induction of VEGF expression. Hypoxia is known to induce a tyrosine kinase cascade that results in the activation of nitrogen-fixation genes in Rhizobium meliloti, and activation of tyrosine kinases is critical in signalling triggered by growth factors and ultraviolet light. We show here that genistein, an inhibitor of protein tyrosine kinase, blocks VEGF induction. Hypoxia increases the kinase activity of pp60c-src and its phosphorylation on tyrosine 416 but does not activate Fyn or Yes. Expression of either a dominant-negative mutant form of c-Src or of Raf-1 markedly reduces VEGF induction. VEGF induction by hypoxia in c-src(-) cells is impaired, although there is a compensatory activation of Fyn. Our results provide an insight into hypoxia-triggered intracellular signalling, define VEGF as a new downstream target for c-SRC, and suggest a role for c-SRc in promoting angiogenesis
The effect of cimetidine on the pharmacokinetics of epirubicin in patients with advanced breast cancer: preliminary evidence of a potentially common drug interaction. Murray LS, Jodrell DI, Morrison JG, et al. Clin Oncol (R Coll Radiol ). 1998; 10(1):35-8. Epirubicin is known to be metabolized in the liver. Therefore, drugs such as cimetidine, which inhibit the cytochrome P-450 enzyme system or reduce liver blood flow, may reduce the plasma clearance of epirubicin. In a small study, epirubicin 100 mg/m2 every 3 weeks was administered intravenously to eight patients, who also received oral cimetidine (400 mg b.d. for 7 days starting 5 days before chemotherapy) with either the first or second cycles. Epirubicin pharmacokinetics and liver blood flow (idocyanine green clearance) were assessed at each course. The areas under the plasma concentration time curves (AUCs) were used to compare the systemic exposure to epirubicin and its metabolites with each course. The estimated median percentage increase (95% confidence interval CI) in the AUC with cimetidine were: epirubicin 50% (95% CI -18 to 193, epirubicinol 41% (95% CI 1 to 92). Despite the small numbers studied, the increase in the active metabolite epirubicinol was significant (P < 0.05). These changes in exposure were not explained by reduced cytochrome P-450 activity as the 7-deoxy-doxorubicinol aglycone AUC was not reduced (357% increase: 95% CI 17 to 719) or by a decrease in liver blood flow (17% increase: 95% CI -39 to 104). Cimetidine is likely to be coprescribed or self-administered with epirubicin and therefore clinicians should be aware of this potential interaction
Chemoprevention by pravastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, of N-methyl-N-nitrosourea-induced colon carcinogenesis in F344 rats. Narisawa T, Morotomi M, Fukaura Y, et al. Jpn J Cancer Res. 1996 Aug; 87(8):798-804. A potential chemopreventive action of pravastatin (Pr), a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, on colon carcinogenesis was evaluated in F344 rats. All rats at 7 weeks of age received an intrarectal dose of 2 mg of N-methyl-N-nitrosourea 3 times weekly for 2 weeks in experiment I (2 groups of 16 rats each), and for 3 weeks in experiment II (4 groups of 30 rats each). They were given drinking water containing 0 ppm (control) or 200 ppm Pr during weeks 1 to 40 in experiment I, and containing 0 ppm (control), 25 ppm, 5 ppm and 1 ppm Pr during weeks 4 to 40 in experiment II. The body weight gains, and food and water intakes were similar in all the groups. The incidence of colon carcinomas at termination of the experiment at week 40 was not different in the 200 ppm Pr and control groups in experiment I (63% vs. 69%), while it was significantly lower in the 25 ppm and 5 ppm groups, but not in the 1 ppm Pr group, compared with the control group in experiment II (50%, 48%, and 77% vs. 80%). This inhibitory effect of Pr against colon carcinogenesis was not related to the cholesterol-lowering effect of this agent. We postulate that Pr inhibits the promotion stage of colon carcinogenesis, perhaps through modulation of cholesterol synthesis in situ in the colonic mucosa, thereby suppressing farnesyl isoprenylation of growth-regulating proteins such as p21 ras
Dietary curcumin with cisplatin administration modulates tumour marker indices in experimental fibrosarcoma. Navis I, Sriganth P, Premalatha B. Pharmacol Res. 1999 Mar; 39(3):175-9. Curcumin, the active constituent of Curcuma longa, which itself possesses antitumour activity against experimental tumours, enhances the antitumour effect of the widely used anticancer drug cisplatin, when used in combination against fibrosarcoma. Tumour marker enzymes such as aminotransferases, lactate dehydrogenase, gamma-glutamyl transpeptidase, alkaline phosphatase, 5'-nucleotidase were analysed in liver and kidney homogenates of experimental rats. All these enzyme activities were markedly increased in tumour bearing animals. On cisplatin administration, the enzyme levels were decreased but not to near normal values. Curcumin, when treated along with cisplatin brought back the enzyme levels to near the control values. Thus curcumin and cisplatin combination may be worth trying against tumours like fibrosarcoma
Effect of fish oil, arginine, and doxorubicin chemotherapy on remission and survival time for dogs with lymphoma: a double-blind, randomized placebo-controlled study. Ogilvie GK, Fettman MJ, Mallinckrodt CH, et al. Cancer. 2000 Apr 15; 88(8):1916-28. BACKGROUND: Polyunsaturated n-3 fatty acids have been shown to inhibit the growth and metastasis of tumors. This double-blind, randomized study was designed to evaluate the hypothesis that polyunsaturated n-3 fatty acids can improve metabolic parameters, decrease chemical indices of inflammation, enhance quality of life, and extend disease free interval and survival time for dogs treated for lymphoblastic lymphoma with doxorubicin chemotherapy. METHODS: Thirty-two dogs with lymphoma were randomized to receive one of two diets supplemented with menhaden fish oil and arginine (experimental diet) or an otherwise identical diet supplemented with soybean oil (control diet). Diets were fed before and after remission was attained with up to five dosages of doxorubicin. Parameters examined included blood concentrations of glucose, lactic acid, and insulin in response to glucose and diet tolerance tests; alpha-1 acid glycoprotein; tumor necrosis factor; interleukin-6; body weight; amino acid profiles; resting energy expenditure; disease free interval (DFI); survival time (ST); and clinical performance scores. RESULTS: Dogs fed the experimental diet had significantly (P < 0.05) higher mean serum levels of the n-3 fatty acids docosahexaenoic acid (C22:6) and eicosapentaenoic acid (C20:5) compared with controls. Higher serum levels of C22:6 and C20:5 were associated with lesser (P < 0.05) plasma lactic acid responses to intravenous glucose and diet tolerance testing. Increasing C22:6 levels were significantly (P < 0.05) associated with longer DFI and ST for dogs with Stage III lymphoma fed the experimental diet. CONCLUSIONS: Fatty acids of the n-3 series normalize elevated blood lactic acid in a dose-dependent manner, resulting in an increase in DFI and ST for dogs with lymphoma
Bisphosphonates in the management of prostate carcinoma metastatic to the skeleton. Papapoulos SE, Hamdy NA, van der PG. Cancer. 2000 Jun 15; 88(12 Suppl):3047-53. BACKGROUND: Prostate carcinoma metastasizes frequently to the skeleton, causing significant morbidity, particularly severe bone pain. Metastatic lesions typically are osteosclerotic, but there is experimental, histologic, and biochemical evidence of increased bone resorption. Furthermore, bone resorption rates appear to correlate with bone pain. These observations provide the rationale for the use of bisphosphonates in the management of patients with prostate carcinoma and skeletal metastases. METHODS: The authors reviewed the literature and current findings on the use of biphosphonates in the management of patients with prostate carcinoma metastatic to the skeleton. RESULTS: Compared with the large number of studies with bisphosphonates in predominantly osteolytic bone disease, there have been relatively few (mostly uncontrolled) studies in patients with prostate carcinoma. Apart from the lack of appropriate experimental models, the osteoblastic nature of the metastases and the low incidence of objectively assessed endpoints of treatment (e.g., hypercalcemia, pathologic fractures) have delayed developments. Available data, however, strongly suggest that potent bisphosphonates are efficacious in reducing skeletal morbidity in patients with prostate carcinoma. CONCLUSIONS: For the optimal management of patients with skeletal metastases from prostate carcinoma with bisphosphonates their mode of administration, the dose and duration of treatment need to be evaluated. Better understanding of the cellular and molecular mechanisms underlying bone metastases can lead to the design of improved treatment protocols with potent bisphosphonates
Statin use, bone mineral density, and fracture risk: Geelong Osteoporosis Study. Pasco JA, Kotowicz MA, Henry MJ, et al. Arch Intern Med. 2002 Mar 11; 162(5):537-40. BACKGROUND: Recent data suggest that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) decrease fracture risk and increase bone mineral density (BMD). METHODS: This cross-sectional study is set in southeastern Australia. We evaluated the association between statin use, fracture risk, and BMD in 1375 women (573 with incident fractures and 802 without incident fracture, all drawn from the same community). Fractures were identified radiologically. Medication use and lifestyle factors were documented by questionnaire. RESULTS: Unadjusted odds ratio for fracture associated with statin use was 0.40 (95% confidence interval [CI], 0.23-0.71). Adjusting for BMD at the femoral neck, spine, and whole body increased the odds ratio to 0.45 (95% CI, 0.25-0.80), 0.42 (95% CI, 0.24-0.75), and 0.43 (95% CI, 0.24-0.78), respectively. Adjusting for age, weight, concurrent medications, and lifestyle factors had no substantial effect on the odds ratio for fracture. Statin use was associated with a 3% greater adjusted BMD at the femoral neck (P =.08), and BMD tended to be greater at the spine and whole body but did not achieve statistical significance. CONCLUSION: The substantial 60% reduction in fracture risk associated with statin use is greater than would be expected from increases in BMD alone
[Interleukin-6 and bone metastasis of renal cancer: molecular bases and therapeutic implications]. Paule B. Prog Urol. 2001 Apr; 11(2):368-75. Interleukin-6 (IL-6) is a multifunctional cytokine which provides multiple signals on various tissues and cells. In addition, IL-6 is produced by some human renal carcinoma cell lines in vitro and is expressed in a majority of primary renal cell carcinoma (RCC). Serum IL-6 influence the response to immunotherapy. IL-6 appears as a target for rational drug design highly promising for development of new cancer therapies. IL-6 effects are mediated by Stat. Stat (Signal transducers and activators of transcription) signaling pathways represent novel molecular targets for therapeutic implications in metastatic renal cell carcinoma. Inhibitors of Stat signaling pathway will not only block tumor growth by inducing apoptosis, but may also increase the sensitivity of tumors to conventional treatment (immunotherapy). The processes involved in tumor associated angiogenesis should lead to compounds able to interfere with angiogenesis. Il-6 has been implicated in the osteoclastic bone resorption and hypercalcemia associated with metastatic RCC. Different agents were shown to be effective in treating lytic bone disease mediated by osteoclast activation: bisphosphonates and osteoprotegerin
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
Risk of complications from bone metastases in breast cancer. implications for management. Plunkett TA, Smith P, Rubens RD. Eur J Cancer. 2000 Mar; 36(4):476-82. A retrospective analysis of 859 patients who developed bone metastases from breast cancer between 1975 and 1991 was performed in order to identify factors that predict for complications from skeletal disease. The patients were divided into four groups based on the sites of disease at diagnosis of skeletal metastases: bone disease only; bone and soft tissue disease; bone and pleuro-pulmonary disease; bone and liver disease. Patients with metastatic disease confined to the skeleton were most likely to develop a pathological fracture. The time to long bone fracture was similar for all groups, but the least number of such fractures occurred in patients with bone and liver metastases since their survival was shortest (median: 5.5 months; P<0.001). Patients with bone metastases only were most likely to require radiotherapy to painful osseous deposits (P="0.0001)" and most rapidly developed spinal cord compression (P="0.01," data not shown). The results suggest that patients with disease confined to the skeleton at the diagnosis of bone metastases are most likely to develop skeletal-related complications from advanced breast cancer. Such patients may benefit most from treatment with bisphosphonates
Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America
21. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Cancer. 2003 Jun 15; 97(12):3090-8. BACKGROUND: Aprepitant is a novel neurokinin 1 (NK(1)) antagonist that has been shown to improve control of chemotherapy-induced nausea and vomiting (CINV) when added to a standard antiemetic regimen of a 5-hydroxytriptamine-3 antagonist plus a corticosteroid. The authors sought to evaluate further the efficacy and tolerability of aprepitant plus standard therapy in a large clinical trial. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-groups, Phase III study. Patients with cancer who were scheduled to receive treatment with high-dose cisplatin chemotherapy were randomized to receive 1 of 2 treatment regimens; the standard therapy group received intravenous ondansetron 32 mg and oral dexamethasone 20 mg on Day 1, and oral dexamethasone 8 mg twice daily on Days 2-4. The aprepitant group received oral aprepitant 125 mg, intravenous ondansetron 32 mg, and oral dexamethasone 12 mg on Day 1; oral aprepitant 80 mg and oral dexamethasone 8 mg once daily on Days 2-3; and oral dexamethasone 8 mg on Day 4. Patients recorded episodes of emesis, use of rescue therapy, and severity of nausea in a diary. A modified intent-to-treat approach was used to analyze the efficacy data. The primary endpoint was complete response (no emesis and no rescue therapy) during the 5-day period postcisplatin. Treatment comparisons were made using logistic regression models, and reported adverse events and physical and laboratory assessments were used to assess tolerability. RESULTS: A total of 523 patients were evaluated for efficacy, and 568 patients were evaluated for safety. During the 5 days after chemotherapy, the percentages of patients who achieved a complete response were 62.7% in the aprepitant group (163 of 260 patients) versus 43.3% in the standard therapy group (114 of 263 patients; P < 0.001). For Day 1, the complete response rates were 82.8% for the aprepitant group and 68.4% for the standard therapy group (P < 0.001); for Days 2-5, the complete response rates were 67.7% in the aprepitant group and 46.8% in the standard therapy group (P < 0.001). The overall incidence of adverse events was similar between the 2 treatment groups (72.8% in the aprepitant group [206 of 283 patients] and 72.6% in the standard therapy group [207 of 285 patients]) as were rates of serious adverse events, discontinuations due to adverse events, and deaths. CONCLUSIONS: In patients with cancer who are receiving high-dose cisplatin-based chemotherapy, therapy consisting of aprepitant (125 mg on Day 1 and 80 mg on Days 2-3) plus a standard regimen of ondansetron and dexamethasone provided superior antiemetic protection compared with standard therapy alone and was generally well tolerated
Modification of the effect of tamoxifen, cis-platin, DTIC, and interferon-alpha 2b on human melanoma cells in culture by a mixture of vitamins. Prasad KN, Hernandez C, Edwards-Prasad J, et al. Nutr Cancer. 1994; 22(3):233-45. The effect of a mixture of vitamins in modifying the efficacy of commonly used drugs in the treatment of human melanoma has not been studied. Vitamin C and d-alpha-tocopheryl succinate (alpha-TS) alone reduced the growth of human melanoma (SK-30) cells in culture, whereas beta-carotene (BC), 13-cis-retinoic acid (RA), or sodium selenite alone was ineffective. RA caused morphological changes, as evidenced by flattening of cells and formation of short cytoplasmic processes. A mixture of four vitamins (vitamin C, BC, alpha-TS, and RA) was more effective in reducing growth of human melanoma cells than a mixture of three vitamins. The growth-inhibitory effect of cis-platin, decarbazine, tamoxifen, and recombinant interferon-alpha 2b was enhanced by vitamin C alone, a mixture of three vitamins (BC, alpha-TS, and RA), and a mixture of four vitamins (vitamin C, BC, alpha-TS, and RA) that contained 50 micrograms/ml of vitamin C. These data show that a mixture of three or four vitamins can enhance the growth-inhibitory effect of currently used chemotherapeutic agents on human melanoma cells
High doses of multiple antioxidant vitamins: essential ingredients in improving the efficacy of standard cancer therapy. Prasad KN, Kumar A, Kochupillai V, et al. J Am Coll Nutr. 1999 Feb; 18(1):13-25. Numerous articles and several reviews have been published on the role of antioxidants, and diet and lifestyle modifications in cancer prevention. However, the potential role of these factors in the management of human cancer have been largely ignored. Extensive in vitro studies and limited in vivo studies have revealed that individual antioxidants such as vitamin A (retinoids), vitamin E (primarily alpha-tocopheryl succinate), vitamin C (primarily sodium ascorbate) and carotenoids (primarily polar carotenoids) induce cell differentiation and growth inhibition to various degrees in rodent and human cancer cells by complex mechanisms. The proposed mechanisms for these effects include inhibition of protein kinase C activity, prostaglandin E1-stimulated adenylate cyclase activity, expression of c-myc, H-ras, and a transcription factor (E2F), and induction of transforming growth factor-beta and p21 genes. Furthermore, antioxidant vitamins individually or in combination enhance the growth-inhibitory effects of x-irradiation, chemotherapeutic agents, hyperthermia, and biological response modifiers on tumor cells, primarily in vitro. These vitamins, individually, also reduce the toxicity of several standard tumor therapeutic agents on normal cells. Low fat and high fiber diets can further enhance the efficacy of standard cancer therapeutic agents; the proposed mechanisms for these effects include the production of increased levels of butyric acid and binding of potential mutagens in the gastrointestinal tract by high fiber and reduced levels of growth promoting agents such as prostaglandins, certain fatty acids and estrogen by low fat. We propose, therefore, a working hypothesis that multiple antioxidant vitamin supplements together with diet and lifestyle modifications may improve the efficacy of standard and experimental cancer therapies
Scientific rationale for using high-dose multiple micronutrients as an adjunct to standard and experimental cancer therapies. Prasad KN, Cole WC, Kumar B, et al. J Am Coll Nutr. 2001 Oct; 20(5 Suppl):450S-63S. We have hypothesized that high-dose multiple micronutrients, including antioxidants, as an adjunct to standard (radiation therapy and chemotherapy) or experimental therapy (hyperthermia and immunotherapy), may improve the efficacy of cancer therapy by increasing tumor response and decreasing toxicity. Several in vitro studies and some in vivo investigations support this hypothesis. A second hypothesis is that antioxidants may interfere with the efficacy of radiation therapy and chemotherapy. This hypothesis is based on the concept that antioxidants will destroy free radicals that are generated during therapy, thereby protecting cancer cells against death. None of the published data on the effect of antioxidants in combination with radiation or chemotherapeutic agents on tumor cells supports the second hypothesis. Scientific rationale in support of a micronutrient protocol to be used as an adjunct to standard or experimental cancer therapy is presented
Some biological actions of alkylglycerols from shark liver oil. Pugliese PT, Jordan K, Cederberg H, et al. J Altern Complement Med. 1998; 4(1):87-99. Shark liver oil has been used for over 40 years as both a therapeutic and preventive agent. The active ingredients in shark liver oil have been found to be a group of ether-linked glycerols known as alkylglycerols. Initial clinical use was for treating leukemias, and later to prevent radiation sickness from cancer x-ray therapy. Studies over the last 30 years have shown that alkylglycerols are multifunctional. The level of natural alkylglycerols rises within tumor cells, apparently in an effort to control cell growth. Recent studies indicate that the activation of protein kinase C, an essential step in cell proliferation, can be inhibited by alkylglycerols. This action suggests a competitive inhibition of 1.2-diacylglycerol by alkylglycerols. Further studies on the immunostimulatory action of alkylglycerols suggest a primary action on the macrophage. The process of macrophage activation has been demonstrated with both synthetic and natural alkylglycerols. While the exact mechanism has not been found, both an autocrine and paracrine system have been suggested. Shark liver is a major natural source of alkylglycerols, which have no known side effects in dosages of 100 mg three times a day. The information presented in this article suggests that alkylglycerols may be used both as an adjunct therapy in the treatment of neoplastic disorders and as an immune booster in infectious diseases
A selective cyclooxygenase-2 inhibitor, NS-398, enhances the effect of radiation in vitro and in vivo preferentially on the cells that express cyclooxygenase-2. Pyo H, Choy H, Amorino GP, et al. Clin Cancer Res. 2001 Oct; 7(10):2998-3005. It has been proposed that Cyclooxygenase (COX)-2 inhibitors may be able to enhance the effects of chemotherapeutic or radiation treatment; however, currently few studies have been reported that define the radiation-enhancing effect of COX-2 inhibitors. We conducted in vitro radiation survival experiments using rat intestinal epithelial cells which were stably transfected with COX-2 cDNA in the sense (RIE-S) and antisense (RIE-AS) orientations to investigate the potential radiosensitizing effect of the selective COX-2 inhibitor, NS-398. Apoptosis was measured using 7-aminoactinomycin-D with flow cytometry to investigate underlying mechanisms for the effect of NS-398 on radiosensitivity. The same experiments were repeated with NCI-H460 human lung cancer cells, which express COX-2 constitutively, and HCT-116 human colon cancer cells, which lack COX-2 expression. In vivo tumor growth delay assays were also performed with tumors formed by H460 and HCT-116 cells. No difference was observed in the intrinsic radiation sensitivity of RIE-S and RIE-AS cells exposed to radiation alone. However, 150-400 microM of NS-398 enhanced radiosensitivity in a concentration-dependent manner in RIE-S cells with dose enhancement ratios of 1.2-1.9 at a surviving fraction of 0.25. However, this effect was not shown in RIE-AS cells. NS-398 enhanced radiosensitivity in H460 cells with a dose enhancement ratio of 1.8 but protected HCT-116 cells from the effects of radiation. Radiation-induced apoptosis was enhanced by NS-398 in RIE-S and H460 cells but not in RIE-AS and HCT-116 cells. Additionally, this radiation-enhancing effect in RIE-S cells seemed to be attributable to some mechanisms other than the reversal of radioresistance induced by COX-2. NS-398 (36 mg/kg) enhanced the effect of radiation on H460 tumors in vivo by an enhancement factor of 2.5; however, it did not enhance the radiosensitivity of HCT-116 tumors (enhancement factor = 1.04). These in vitro and in vivo results suggest that selective COX-2 inhibitors enhance the effect of radiation on tumors that express COX-2 but not on COX-2-lacking tumors. This effect may be attributable to enhancement of radiation-induced apoptosis. Thus, selective COX-2 inhibitors may have potential as radiosensitizers for treatment of human cancers
Osteoblast-derived survival factors protect PC-3 human prostate cancer cells from adriamycin apoptosis. Reyes-Moreno C, Sourla A, Choki I, et al. Urology. 1998 Aug; 52(2):341-7. OBJECTIVES: Hormone-independent and cytotoxic drug-resistant tumor growth in osteoblastic metastases defines poor survival in patients with advanced prostate cancer. Therefore, we analyzed the ability of human osteoblast-like cells (MG-63 cells) and MG-63 conditioned media (MG-63 CM) to protect PC-3 human prostate cancer cells from adriamycin cytotoxicity in vitro. METHODS: Adriamycin cytotoxicity was assessed in MG-63 osteoblast-like and PC-3 prostate cancer monolayer and three-dimensional collagen coculture systems using the DNA content and trypan blue exclusion assays, analysis of indexes of cell cycle by flow cytometry, determination of DNA fragmentation on simple agarose gel and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay, and immunocytochemistry. RESULTS: Adriamycin (100 nM) arrested both the PC-3 and MG-63 cells at the G2/M phase in the cell cycle but induced apoptosis only in PC-3 cells, as assessed by flow cytometry, trypan blue exclusion, and agarose gel. Optimal doses of MG-63 CM (50 microg/mL), insulin-like growth factor I (50 ng/mL), and transforming growth factor-beta-1 (25 ng/mL), as determined by DNA content assay, partially neutralized the adriamycin cytotoxicity of PC-3 cells detected by flow cytometry and trypan blue exclusion. In addition, MG-63 cells rescued PC-3 cells from adriamycin apoptosis in the three-dimensional type I collagen gel coculture system, as analyzed by TUNEL assay. CONCLUSIONS: These data suggest that osteoblast-like cells and osteoblast-derived growth factors can optimize survival of metastatic prostate cancer cells, thereby helping to develop cytotoxic drug-resistant growth in vitro
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
Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance. Sadzuka Y, Sugiyama T, Sonobe T. Toxicol Lett. 2000 Apr 3; 114(1-3):155-62. Considering of novel biochemical modulation by some foods and beverages, we have performed screening for green tea components that have enhancing effects on doxorubicin (DOX) induced antitumor activity. Components, such as caffeine, theanine, (-)-epigallocatechin gallate (EGCG) and flavonoids have inhibitory effects on the DOX efflux from Ehrlich ascites carcinoma cells. Thus, it is suggested that EGCG and flavonoids may enhance DOX induced antitumor activity and increase the DOX concentrations in tumors through the inhibition of DOX efflux. It is expected that these components in green tea exhibit low toxicity and that there are few side effects of drinking green tea in combination with an antitumor agent. We think that the intake of a favorite beverage favors a positive mental attitude of a patient and increases the efficacy of the chemotherapeutic index, and that this efficacy is useful for improving the quality of life on cancer chemotherapy. In DOX resistant P388 leukemia cell bearing mice theanine increased the DOX induced efficacy through an increase in the DOX concentrations in the tumors. Theanine attacked the same transport process for DOX in both types of cells, elevated the DOX concentration and increased the DOX induced antitumor activity
Improvement of idarubicin induced antitumor activity and bone marrow suppression by theanine, a component of tea. Sadzuka Y, Sugiyama T, Sonobe T. Cancer Lett. 2000 Oct 1; 158(2):119-24. We have examined the effect of theanine, a specific amino acid in green tea, on idarubicin (IDA)-induced antitumor activity and toxicity. In combination with theanine, IDA (0.25 mg/kg per day x4 days, a dose that does not show antitumor activity) had significant antitumor activity in P388-bearing mice. The IDA concentration in the tumors in the theanine plus IDA group increased to twice the level in the IDA alone group. Furthermore, the decrease in tumor weight caused by IDA at 1.0 mg/kg per day x4 days (at this dose IDA exhibits antitumor activity) was significantly amplified by theanine. The numbers of leukocyte and bone marrow cells decreased significantly on IDA injection. Theanine significantly reversed these changes. These results suggest that theanine selectively moderates the IDA-induced toxicities. Until recently, the antitumor activity and related toxicities of this chemotherapeutic agent in leukemia could not be distinguished. Theanine increases the IDA-induced antitumor activity and ameliorates the toxicities
Enhancement of the activity of doxorubicin by inhibition of glutamate transporter. Sadzuka Y, Sugiyama T, Suzuki T, et al. Toxicol Lett. 2001 Sep 15; 123(2-3):159-67. Theanine enhanced doxorubicin (DOX) induced antitumor activity by increasing the concentration of DOX in the tumor through the inhibition of efflux of DOX from tumor cells. As theanine reduced the level of glutamate via suppression of the glutamate transporter in tumor cells, we studied the change in the intracellular concentration of glutathione (GSH) and the correlation with the GSH S-conjugate export (GS-X) pump. The reduction in the concentration of glutamate in tumor cells caused by theanine, induced decreases in the intracellular GSH and GS-DOX levels. The expression of MRP5 in M5076 cells, was confirmed. We concluded that the GS-DOX conjugate was transported extracellularly via the MRP5/GS-X pump in M5076 cells and that theanine affected this route. Namely, theanine increases the concentration of DOX in a tumor in vivo through inhibition of the glutamate transporter via the GS-X pump
Glutathione in the prevention of cisplatin induced toxicities. A prospectively randomized pilot trial in patients with head and neck cancer and non small cell lung cancer. Schmidinger M, Budinsky AC, Wenzel C, et al. Wien Klin Wochenschr. 2000 Jul 28; 112(14):617-23. PURPOSE: Glutathione has been shown to be an effective chemoprotector against cisplatin-induced side effects in patients with ovarian cancer. In view of this fact, we performed a randomized clinical pilot-trial in the management of other solid tumors in order to compare application of Glutathione to intensive hydration in patients undergoing chemotherapy with a regimen including cisplatin. PATIENTS AND METHODS: Twenty patients suffering from advanced non small cell lung cancer (n = 6) or head- and neck cancer (n = 14) were enrolled in the study. All patients received 80 mg/m2 cisplatin along with etoposide or 5-fluorouracil every 4 weeks. Patients randomized to application of Glutathione (n = 11) received 5 g of Glutathione immediately before application of cisplatin followed by 2000 ml of normal saline. Patients in the control group (n = 9) received 2000 ml electrolyte infusion before and 2000 ml of normal saline with forced diuresis after cisplatin. RESULTS: The intensity of hematologic toxicity was significantly less pronounced in patients treated with Glutathione than in the control group (hemoglobin: 10.7 vs 9.5 mg% respectively, p = 0.039; white blood cell count 3.3 vs 2.2 x 103/microliter respectively, p = 0.004; platelets 167 vs 95 x 103/microliter respectively, p = 0.02), whereas in terms of non-hematologic toxicity no difference was observed. Objective remission occurred in 6 out of 11 evaluable patients from the group receiving Glutathione (55%; complete remission: 9%; partial remission: 46%), and in 4 out of 8 evaluable patients from the control group (partial remission: 50%). However, there was no statistical difference in terms of response and overall survival (13.5 months vs. 10.5 months) between the two groups. CONCLUSIONS: Application of Cisplatin and Glutathione seems to be safe and feasible and the antitumoral efficacy of cisplatin is apparently not impaired by the concomitant use of Glutathione in patients with solid tumors
Transcriptional activation of the hepatocyte growth factor receptor (c-met) gene by its ligand (hepatocyte growth factor) is mediated through AP-1. Seol DW, Chen Q, Zarnegar R. Oncogene. 2000 Feb 24; 19(9):1132-7. Hepatocyte Growth Factor (HGF) exerts its biological effects via binding and activating a transmembrane protein tyrosine kinase receptor known as c-Met. Previous studies from our laboratory demonstrated that c-met gene expression is inducible by its own ligand (HGF). However, the molecular mechanism(s) involved in this process are unknown. The present study was carried out to address this question. Transfection of various c-met-CAT promoter constructs into the mouse hepatocellular carcinoma cell line Hepa 1-6 in combination with electrophoretic mobility shift assays (EMSA) identified the responsive element as an activated protein-1 (AP-1) binding site (TGAGTCA) within the c-met core promoter region at position -158 to -152. The c-met AP-1 element binds specifically to AP-1 protein as verified by supershift assays. EMSA studies and mutational analyses of the promoter region also revealed that the members of the Sp family of transcription factors (Sp-1 and Sp-3) bind to the c-met Sp-1 element (located at position -124) which is adjacent to the AP-1 site. We show that Sp binding dampens binding of AP-1 to its cognate site in the c-met promoter region. Stimulation of Hepa 1-6 cells with HGF resulted in a rapid and dramatic enhancement of the AP-1 binding activity as well as an overall increase in the level of AP-1 protein. Cotransfection of AP-1 expression vectors (c-Fos plus c-Jun) with c-met promoter constructs resulted in stimulation of c-met promoter activity. We found that transactivation of the c-met promoter by AP-1 can be blocked by Curcumin, an inhibitor of AP-1. Moreover, we found that the induction of the endogenous c-met gene by HGF is inhibited by the addition of Curcumin. The results demonstrate that the HGF-induced transcription of the c-met gene by HGF is, at least in part, due to activation of the AP-1 pathway
Preoperative plasma levels of transforming growth factor beta(1) (TGF-beta(1)) strongly predict progression in patients undergoing radical prostatectomy. Shariat SF, Shalev M, Menesses-Diaz A, et al. J Clin Oncol. 2001 Jun 1; 19(11):2856-64. PURPOSE: Elevated local and circulating levels of transforming growth factor beta(1) (TGF-beta(1)) have been associated with prostate cancer invasion and metastasis. We tested the hypothesis that preoperative plasma TGF-beta(1) levels would independently predict cancer stage and prognosis in patients who undergo radical prostatectomy. PATIENTS AND METHODS: The study group consisted of 120 consecutive patients who underwent radical prostatectomy for clinically localized prostate cancer (median follow-up, 53.8 months). Preoperative plasma levels of TGF-beta(1) were measured and correlated with pathologic parameters and clinical outcomes. TGF-beta(1) levels also were measured in 44 healthy men without cancer, in 19 men with prostate cancer metastatic to regional lymph nodes, and in 10 men with prostate cancer metastatic to bone. RESULTS: Plasma TGF-beta(1) levels in patients with lymph node metastases (14.2 +/- 2.6 ng/mL) and bone metastases (15.5 +/- 2.4 ng/mL) were higher than those in radical prostatectomy patients (5.2 +/- 1.3 ng/mL) and healthy subjects (4.5 +/- 1.2 ng/mL) (P <.001). In a preoperative analysis, preoperative plasma TGF-beta(1) level and biopsy Gleason sum both were predictors of organ-confined disease (P =".006" and P =".006," respectively) and PSA progression (P <.001 and P =".021," respectively). In a postoperative multivariate analysis, preoperative plasma TGF-beta(1) level, pathologic Gleason sum, and surgical margin status were predictors of PSA progression (P =".020,P" =".020," and P =".022," respectively). In patients who progressed, preoperative plasma TGF-beta(1) levels were higher in those with presumed distant compared with local-only failure (P =".019)." CONCLUSION: Plasma TGF-beta(1) levels are markedly elevated in men with prostate cancer metastatic to regional lymph nodes and bone. In men without clinical or pathologic evidence of metastases, the preoperative plasma TGF-beta(1) level is a strong predictor of biochemical progression after surgery, presumably because of an association with occult metastatic disease present at the time of radical prostatectomy
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
Low bone mineral density in hormone-naive men with prostate carcinoma. Smith MR, McGovern FJ, Fallon MA, et al. Cancer. 2001 Jun 15; 91(12):2238-45. BACKGROUND: The objective of this study was to determine the prevalence of low bone mineral density in men with prostate carcinoma and no history of androgen-deprivation therapy. METHODS: The authors conducted a cross-sectional study in 41 hormone-naive men with locally advanced, lymph node positive, or recurrent prostate carcinoma and no radiographic evidence of bone metastases. Bone mineral density of the total hip, posterior-anterior (PA) lumbar spine, and lateral lumbar spine was determined by dual-energy X-ray absorptiometry (DXA) using a densitometer. Trabecular bone mineral density of the lumbar spine was determined by quantitative computed tomography (QCT). Bone mineral density results were expressed in standard deviation units relative to young adult men (T score) and relative to age-matched men (Z score). RESULTS: Fourteen of 41 men (34%; 95% confidence interval [95% CI], 20-51%) had T scores < -1.0 at one or more skeletal sites by DXA, 12 of 41 men (29%; 95% CI, 16-42%) had T scores between -1.0 and -2.5, and 2 of 41 men (5%; 95% CI, 1-17%) had T scores < -2.5. Thirty-nine of 41 men (95%; 95% CI, 83-99%) had T scores < -1.0 by QCT, 13 of 41 men (31%; 95% CI 18-48%) had T scores between -1.0 and -2.5, and 26 of 41 men (63%; 95% CI, 47-78%) had T scores < -2.5. T scores for trabecular bone mineral density of the lumbar spine were significantly lower than T scores for either the total hip (P < 0.001) or the PA lumbar spine (P < 0.001). The mean Z score for trabecular bone mineral density of the lumbar spine was -0.7 +/- 0.9. Hypogonadism, hypovitaminosis D, and dietary calcium intakes below the Recommended Daily Allowance were observed in 20%, and 17%, and 59% of study participants, respectively. CONCLUSIONS: Many hormone-naive men with prostate carcinoma have low bone mineral density. QCT is a more sensitive method than DXA for diagnosing low bone mineral density in this patient population. Trabecular bone mineral density is lower than expected for age and risk factors for osteoporosis are common
Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Somasundaram S, Edmund NA, Moore DT, et al. Cancer Res. 2002 Jul 1; 62(13):3868-75. Curcumin, the major component of the spice turmeric, is used as a coloring and flavoring additive in many foods and has attracted interest because of its anti-inflammatory and chemopreventive activities. However, this agent also inhibits the generation of reactive oxygen species (ROS) and the c-Jun NH(2)-terminal kinase (JNK) pathway, and because many chemotherapeutic drugs generate ROS and activate JNK in the course of inducing apoptosis, we considered the possibility that curcumin might antagonize their antitumor efficacy. Studies in tissue culture revealed that curcumin inhibited camptothecin-, mechlorethamine-, and doxorubicin-induced apoptosis of MCF-7, MDA-MB-231, and BT-474 human breast cancer cells by up to 70%. Inhibition of programmed cell death was time and concentration dependent, but occurred after relatively brief 3-h exposures, or at curcumin concentrations of 1 microM that have been documented in Phase I chemoprevention trials. Under these conditions, curcumin exhibited antioxidant properties and inhibited both JNK activation and mitochondrial release of cytochrome c in a concentration-dependent manner. Using an in vivo model of human breast cancer, dietary supplementation with curcumin was found to significantly inhibit cyclophosphamide-induced tumor regression. Such dietary supplementation was accompanied by a decrease in the activation of apoptosis by cyclophosphamide, as well as decreased JNK activation. These findings support the hypothesis that dietary curcumin can inhibit chemotherapy-induced apoptosis through inhibition of ROS generation and blockade of JNK function, and suggest that additional studies are needed to determine whether breast cancer patients undergoing chemotherapy should avoid curcumin supplementation, and possibly even limit their exposure to curcumin-containing foods
Enhancing effects of green tea components on the antitumor activity of adriamycin against M5076 ovarian sarcoma. Sugiyama T, Sadzuka Y. Cancer Lett. 1998 Nov 13; 133(1):19-26. We have investigated the combined treatment of components of green tea with adriamycin against M5076 ovarian sarcoma, which exhibits low sensitivity to adriamycin. In M5076 tumor-bearing mice, the injection of adriamycin alone did not inhibit tumor growth, whereas the combination of theanine and adriamycin significantly reduced the tumor weight to 62% of the control level. When combined with theanine, effective antitumor activity of adriamycin was observed without an increase in the dosage. Theanine specifically increased the adriamycin concentration in the tumor by 2.7-fold. In contrast, theanine decreased the adriamycin concentrations in normal tissues. On the other hand, in vitro experiments proved that theanine inhibited the efflux of adriamycin from tumor cells, suggesting a theanine-induced increase in the adriamycin concentration in such tumors in vivo. Furthermore, the oral administration of theanine or green tea similarly enhanced the antitumor activity of adriamycin. In conclusion, the combination of theanine with adriamycin showed antitumor efficacy in spite of the non-effective dose of adriamycin on M5076 ovarian sarcoma. We have found that the modulating action of theanine is useful in clinical cancer chemotherapy
Lamin B, caspase-3 activity, and apoptosis induction by a combination of HMG-CoA reductase inhibitor and COX-2 inhibitors: a novel approach in developing effective chemopreventive regimens. Swamy MV, Cooma I, Reddy BS, et al. Int J Oncol. 2002 Apr; 20(4):753-9. Apoptosis plays a central role in tumor development and it has been hypothesized that lack/failure of apoptosis leads to the development of tumors, including colon tumors. Thus, induction of apoptosis in tumor cells is an effective approach to the regulation of tumor growth. It has been shown by us and other investigators that various chemopreventive agents induce apoptosis and inhibit tumor growth. Identification of agents or combinations of agents that induce tumor cell apoptosis guides the development of novel agents for colon cancer treatment. Experiments were designed to assess the effectiveness of lovastatin, a 3-hydroxy-3-methyl glutaryl-CoA reductase inhibitor, and celecoxib a cyclooxygenase-2 inhibitor, individually or in combination on the induction of apoptosis in human HT-29 colon cancer cells. In addition, we studied the modulatory effect of lovastatin and celecoxib on lamin B levels, caspase-3 activity and expression in relationship to apoptosis in colon cancer cell lines. HT-29 cells exposed to various subtoxic levels of lovastatin or celecoxib or a combination of both were analyzed for apoptosis (by DAPI method), caspase-3 expression (immunoblot analysis) and caspase-3 activity (fluorimetric method). We found that: i) pretreatment with lovastatin (5-30 microM) induces apoptosis in HT-29 cells significantly only at high concentrations (> or = 20 microM) but not at low dose levels; ii) similarly, pretreatment with celecoxib produced apoptosis in colon cancer cells at high concentrations only (> or = 75 microM); iii) caspase-3 protein expression was moderately altered by the treatment with lovastatin or celecoxib at lower concentrations; however, a significant increase (1.6 to 4-fold) in caspase-3 expression and activity was found in HT-29 cells exposed with 20-25 microM lovastatin and/or 5-125 microM celecoxib and iv) importantly, in tumor cells exposed to low doses of (5 or 10 microM) lovastatin, combined with 25-75 microM of celecoxib, apoptosis induction rose 2.5 to 10-fold, caspase-3 expression was 2.3 to 8-fold higher, and enzyme activities were 1.5 to 5.5-fold elevated. This effect was highly synergistic and dose-dependent. Lamin B levels were significantly increased in a dose-dependent manner in cells treated with lovastatin but no such effect was observed with celecoxib. These results indicate that agents with different modes of action when applied in combinations will induce apoptosis synergistically by enhancing caspase-3 activities. These findings further support the hypothesis that HMGCo-R and COX-2 activities play important roles in apoptosis and regulation of apoptosis by selective agents such as lovastatin and celecoxib would provide effective strategies for the prevention of colon cancer
[Chronic cardiotoxicity of anthracycline derivatives and possible prevention by coenzyme Q10]. Tajima M. Gan No Rinsho. 1984 Jul; 30(9 Suppl):1211-6. Adriamycin (ADR), one of the anthracycline derivatives, has the most strong cardiotoxicity. We studied the cardiotoxicity caused by ADR in New Zealand white rabbits and its protection by the medication of CoQ10. The findings of ECG and the myocardial tissue examined by the electron microscope showed the effectiveness of the injection of CoQ10 to prevent the cardiotoxicity caused by ADR. The concomitant injection of CoQ10 dissolved in saline was tried in patients with various kinds of neoplasm who were given more than 200 mg of ADR or DM. Only one patient showed the ST-T change. On the contrary, 3 of patients given more than 200 mg ADR or DM alone showed abnormal change of ECG
Suppression by pravastatin, an inhibitor of p21ras isoprenylation, of hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague-Dawley rats. Tatsuta M, Iishi H, Baba M, et al. Br J Cancer. 1998 Feb; 77(4):581-7. The effect of pravastatin, an inhibitor of p21ras isoprenylation, on hepatocarcinogenesis induced by N-nitrosomorpholine and on p21ras isoprenylation were investigated in male Sprague-Dawley rats. Rats received i.p. injections of pravastatin (10 and 20 mg kg(-1) body weight) every other day and, from the beginning of the experiment, were given drinking water containing N-nitrosomorpholine for 8 weeks. Visible white nodules and hepatic lesions staining positively for gamma-glutamyl transpeptidase or glutathione-S-transferase, placental type, were examined macroscopically or histochemically. In week 15, pravastatin at both dosages significantly reduced the incidence, number and volume of visible white nodules. Quantitative histological analysis also showed that prolonged administration of pravastatin at both dosages resulted in significant reductions in the number and percentage area of hepatic lesions positive for gamma-glutamyl transpeptidase and glutathione-S-transferase, placental type. Administration of pravastatin also significantly decreased the amount of membrane-associated p21ras in the tumour and the labelling index of neoplastic nodules and increased the apoptoic indices of neoplastic nodules. These findings indicate that pravastatin suppresses hepatocarcinogenesis and suggest that this effect might be related to pravastatin's inhibition of p21ras isoprenylation and its subsequent inhibition of cell proliferation and induction of apoptosis in neoplastic lesions
Differential effects of polyunsaturated fatty acids on chemosensitivity of NIH3T3 cells and its transformants. Tsai WS, Nagawa H, Muto T. Int J Cancer. 1997 Jan 27; 70(3):357-61. Polyunsaturated fatty acids (PUFAs) have been suggested, on the basis of animal-model studies, to be related not only to cancer development but also to chemotherapeutic effects. Controversy persists, however, as to which types of PUFAs are beneficial in terms of chemosensitivity. In this study, we used the NIH3T3 cell line and its SIC(sigmoid colon cancer)-oncogene transformants to investigate the effects of PUFAs on the chemosensitivity of non-malignant and malignant cells in terms of cell proliferation. We also determined the fatty-acid composition of cells by high-performance liquid chromatography (HPLC). The results revealed that the sensitivity of SIC transformants to mitomycin C (MC) was lower than that of NIH3T3 cells cultured in 10% calf-serum DMEM without PUFA supplementation. When cells were cultured in DMEM supplemented with eicosapentaenoic acid (EPA) at a concentration (2 micrograms/ml) that does not influence cell proliferation, the sensitivity of SIC transformants to MC increased, whereas that of NIH3T3 cells decreased in comparison with the sensitivity of cells cultured without PUFA supplementation (p < 0.05). There was no difference between the 2 cell lines in the chemosensitivity of cells cultured in medium supplemented with arachidonic acid (ARA). The SIC transformants contained more stearic acid (C:18) and less lauric acid (C:12) than NIH3T3 cells cultured without PUFA. Culturing the cells in medium supplemented with EPA or ARA modified the cellular fatty-acid composition. EPA caused the relative combined percentage of lauric acid and myristic acid (C:14) in SIC transformants to decrease significantly, and the SIC transformants tended to accumulate additional EPA, in contrast to the NIH3T3 cells. We conclude that the alterations in fatty-acid composition in malignant transformants caused by exogenous EPA differ from those in non-malignant cells, and that these changes account for the increased chemosensitivity of malignant transformants. Although preliminary, these findings imply that EPA specifically enhances the chemosensitivity of malignant cells
Enchancing effect of patented whey protein isolate (Immunocal) on cytotoxicity of an anticancer drug. Tsai WY, Chang WH, Chen CH, et al. Nutr Cancer. 2000; 38(2):200-8. To determine the enhancing effect of a whey protein isolate on the cytotoxicity of a potential anticancer drug, baicalein, the human hepatoma cell line Hep G2 was assigned to grow in different media for four days, and cell growth and apoptosis were investigated. The control group was grown in normal medium; the other three groups were grown in whey protein isolate (Immunocal) medium, baicalein medium, and a combination of Immunocal and baicalein. As indicated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, survival rate was significantly lower in cells grown in baicalein + Immunocal than in cells grown in baicalein alone. In contrast, there was no significant difference in survival rate of the cells grown in Immunocal. In the investigation of apoptosis, cells grown in baicalein + Immunocal showed a higher phosphatidylserine exposure, lower mitochondrial transmembrane potential, and nearly 13 times more cells undergoing apoptosis than cells grown in baicalein alone. We also demonstrated that Immunocal reduced glutathione (GSH) in Hep G2 cells by 20-40% and regulated the elevation of GSH, which was in response to baicalein. In conclusion, Immunocal seemed to enhance the cytotoxicity of baicalein by inducing more apoptosis; this increase in apoptotic cells may be associated with the depletion of GSH in Hep G2 cells. This is the first study to demonstrate, in vitro, that Immunocal may function as an adjuvant in cancer treatments
Cytotoxicity of simvastatin to pancreatic adenocarcinoma cells containing mutant ras gene. Ura H, Obara T, Nishino N, et al. Jpn J Cancer Res. 1994 Jun; 85(6):633-8. Simvastatin (SV), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, inhibits the synthesis of mevalonic acid. The dose-dependent (0.1-100 micrograms/ml) cytotoxicity of SV towards human (MIAPaCa-2, Panc-1, HPC-1, HPC-3, HPC-4, PK-1, PK-9) and hamster (T2) pancreatic carcinoma cell lines was determined by MTT assay. At up to 20 micrograms/ml of SV, the effect was reversible and was restored by 60 micrograms/ml mevalonic acid. Point mutation of Ki-ras at codon 12 in each cell line was detected by means of the modified polymerase chain reaction. The concentration of SV necessary to achieve 50% cytotoxicity was about 10 micrograms/ml, and at this concentration of SV, DNA synthesis assayed in terms of [3H]thymidine uptake, isoprenylation of p21ras examined by Western blotting and cell progression from G1 to S phase of the cell cycle analyzed by flow cytometry were all inhibited. Isoprenylation inhibitors of p21ras, such as SV, are expected to be useful for the treatment of pancreatic cancer
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
The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells. van de Donk NW, Kamphuis MM, Lokhorst HM, et al. Leukemia. 2002 Jul; 16(7):1362-71. Lovastatin is an irreversible inhibitor of HMG-CoA reductase and blocks the production of mevalonate, a critical compound in the production of cholesterol and isoprenoids. Isoprenylation of target proteins, like the GTP-binding protein Ras, is essential for their membrane localization and subsequent participation in intracellular signaling cascades. Lovastatin effectively decreased the viability of plasma cells from cell lines (n = 10) and myeloma patients' samples (n = 8) in a dose- and time-dependent way. Importantly, co-incubation of lovastatin with dexamethasone had a synergistic effect in inducing plasma cell cytotoxity. This effect was not the consequence of a change in the protein expression levels of Bcl-2 or Bax induced by lovastatin. The decrease in plasma cell viability was the result of induction of apoptosis and inhibition of proliferation. Mevalonate effectively reversed the cytotoxic and cytostatic effects of lovastatin in plasma cells. The cytotoxic activity of lovastatin was higher in Pgp expressing cell lines, but did not correlate with the multidrug resistance (MDR)-related proteins LRP, Bcl-2 and Bax. Lovastatin treatment resulted in a shift of Ras localization from the membrane to the cytosol that was reversed by mevalonate. The data presented in this paper warrant study of lovastatin alone or in combination with therapeutic drugs, in the treatment of myeloma patients
Enhanced resistance of adriamycin-treated MCR-5 lung fibroblasts by increased intracellular glutathione peroxidase and extracellular antioxidants. Vanella A, Campisi A, di Giacomo C, et al. Biochem Mol Med. 1997 Oct; 62(1):36-41. Considerable evidence indicates that reactive oxygen species play an etiological role in both cardiotoxicity and the skin necrosis induced by adriamycin (ADM). An increase in glutathione peroxidase activity on addition of selenium to cultured MCR-5 lung fibroblasts was observed; this increase was accompanied by enhanced cellular resistance to ADM toxicity. Moreover, the presence of exogenous antioxidant systems, such as superoxide dismutase, catalase, vitamin E, dimethylsulfoxide, and desferroxamine, an iron chelating agent, resulted in significant protection from ADM-mediated damage
Cardioprotection in patients undergoing chemo- and/or radiotherapy for neoplastic disease. A pilot study. Wagdi P, Fluri M, Aeschbacher B, et al. Jpn Heart J. 1996 May; 37(3):353-9. OBJECTIVES: To assess the cardioprotective efficiency of an antioxidant regimen (vitamins E, C and N-acetylcysteine) in patients receiving high dose chemo- and/or radiotherapy for malignant disease. METHODS: Prospective, placebo controlled, randomized and double blinded pilot study involving 13 patients receiving chemotherapy and 12 patients receiving radiotherapy. RESULTS: In patients receiving antioxidants, left ventricular ejection fraction did not change (63 +/- 4% to 63 +/- 4%). In the placebo group, ejection fraction changed from 67 +/- 6% to 61 +/- 4% (p = 0.03). No patient in the antioxidant group and 6/13 (46%) patients in the placebo group showed a fall of > 10% in the left ventricular ejection fraction. In the chemotherapy group, the left ventricular ejection fraction changed from 62% (+/- 2) to 63% (+/- 2) in the patients treated with antioxidants (ns) and from 63% (+/- 5) to 61% (+/- 5) in patients treated with placebo (ns). No patient showed a significant fall in ejection fraction in the antioxidant group, whereas 2/7 (29%) in the placebo group showed a reduction > or = 10%. In the radiotherapy group, left ventricular ejection fraction did not change inverted question mark64% (+/- 6) to 64% (+/- 5) inverted question mark in patients treated with antioxidants (ns) and changed from 70% (+/- 8) to 60% (+/- 4) in patients treated with placebo (p = 0.008). No patient in the antioxidant group, but 4/6 (66%) patients in the placebo group showed a fall of > or = 10% in ejection fraction. CONCLUSION: The small number of patients in the study precludes a definitive statement. The preliminary results however suggest efficient cardioprotection by this nontoxic and inexpensive antioxidant combination, so larger studies are warranted for confirmation
ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Wakeling AE, Guy SP, Woodburn JR, et al. Cancer Res. 2002 Oct 15; 62(20):5749-54. The epidermal growth factor receptor (EGFR) is a promising target for anticancer therapy because of its role in tumor growth, metastasis and angiogenesis, and tumor resistance to chemotherapy and radiotherapy. We have developed a low-molecular-weight EGFR tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (Iressa(2) ). ZD1839, a substituted anilinoquinazoline, is a potent EGFR-TKI (IC(50) = 0.033 micro M) that selectively inhibits EGF-stimulated tumor cell growth (IC(50) = 0.054 micro M) and that blocks EGF-stimulated EGFR autophosphorylation in tumor cells. In studies with mice bearing a range of human tumor-derived xenografts, ZD1839 given p.o. once a day inhibited tumor growth in a dose-dependent manner. The level of expression of EGFR did not determine xenograft tumor sensitivity to ZD1839. Long-term ZD1839 (>3 months) treatment of mice bearing A431 xenografts was well tolerated, and ZD1839 completely inhibited tumor growth and induced regression of established tumors. No drug-resistant tumors appeared during ZD1839 treatment, but some tumors regrew after drug withdrawal. These studies indicate the potential utility of ZD1839 in the treatment of many human tumors and indicate that continuous once-a-day p.o. dosing might be a suitable therapeutic regimen
Increased expression of bone sialoprotein in bone metastases compared with visceral metastases in human breast and prostate cancers. Waltregny D, Bellahcene A, de L, X, et al. J Bone Miner Res. 2000 May; 15(5):834-43. The recent demonstration that bone sialoprotein (BSP) is expressed in osteotropic cancers suggests that this bone matrix protein might be implicated in the preferential seed and growth of metastatic cells in bone. High expression of BSP in breast and prostate primary carcinomas is associated with progression and bone metastases development. The exact mechanisms by which BSP may favor bone metastases formation are not clearly established yet. Although BSP expression has been detected in breast, prostate, lung, thyroid, and neuroblastoma primary tumors, no information regarding its expression in metastases is available to date. In this study, we have examined BSP expression in 15 bone and 39 visceral metastatic lesions harvested from 8 breast cancer patients and 7 prostate cancer patients who died of disseminated disease. We were able to retrieve the primary lesions from 5 of the 8 breast cancer patients as well as from all 7 prostate cancer patients. All the primary breast tumor patients and 5 of the 7 primary prostate cancer patients expressed a detectable level of BSP. Bone metastases from all 8 breast cancer patients and from 5 out of 7 prostate cancer patients exhibited detectable levels of the protein. Metastatic cells in close contact with bone trabeculae usually were highly positive for BSP. BSP also was detected in secondary lesions developed at visceral sites including liver, thyroid, lung, and adrenal glands. However, BSP expression was significantly lower in visceral metastases than in skeletal ones (Mann-Whitney test, p < 0.05). Our data represent the first demonstration of an increased expression of BSP in bone metastases compared with nonskeletal metastases in human breast and prostate cancers and add weight to the body of evidence attributing a significant role to this protein in the genesis of bone metastases
Suppression of invasion and MMP-9 expression in NIH 3T3 and v-H-Ras 3T3 fibroblasts by lovastatin through inhibition of ras isoprenylation. Wang IK, Lin-Shiau SY, Lin JK. Oncology. 2000 Sep; 59(3):245-54. Lovastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, was found to block the synthesis of cholesterol and to affect posttranslational modification or isoprenylation, which is essential for membrane localization and biological activity of several proteins including Ras in the signal transduction pathway. Ras activates a multitude of downstream activities with roles in cellular processing, including invasion and metastasis. We investigated the anti-invasive activity of lovastatin in NIH 3T3 and v-H-Ras-transformed NIH 3T3 (v-H-Ras 3T3) cells. Lovastatin suppressed cell invasion in vitro in a dose-dependent manner. By zymographic assay, a decrease in matrix metalloproteinase-9 (MMP-9) activity but not matrix metalloproteinase-2 (MMP-2) activity by lovastatin was detected. RT-PCR demonstrated a reduction in gene expression of MMP-9 after treatment with lovastastin. To confirm the lovastatin-induced down-regulation of MMP-9 expression, we transfected an MMP-9/luciferase reporter vector, under MMP-9 promoter control, into both NIH 3T3 and v-H-Ras 3T3. A reduction in luciferase activity was observed with lovastatin treatment. In addition, lovastatin also reduced AP-1 and NFkappaB binding activities. These anti-invasive features were attenuated by the presence of mevalonate. These results suggest that down-regulation of MMP-9 contributes to the anti-invasive activity of lovastatin. Furthermore, we added exogenous mevalonate, which enhances the potency of cell invasion, and Ras farnesyltransferase inhibitor (manumycin A), which inhibits the potency of cell invasion. In accordance, Western blot analysis showed that lovastatin decreased membrane localization of Ras proteins. These data indicate that the anti-invasion activity of lovastatin happens through a decrease in Ras isoprenylation and functions
Se-methylselenocysteine induces apoptosis through caspase activation and Bax cleavage mediated by calpain in SKOV-3 ovarian cancer cells. Yeo JK, Cha SD, Cho CH, et al. Cancer Lett. 2002 Aug 8; 182(1):83-92. Se-methylselenocysteine (Se-MSC) is a potent chemopreventive agent in many test systems and has been shown to inhibit tumor promotion and induce apoptosis, but its mechanism of action is still not well understood. The present study was designed to assess the mechanism of Se-MSC on the induction of apoptosis in SKOV-3 ovarian cancer cells. Se-MSC displayed strong inhibitory effects on cell proliferation and viability of SKOV-3 cells in dose and time dependent manners and induced apoptosis. Investigation of the mechanism of Se-MSC-induced apoptosis revealed that treatment with Se-MSC produced morphological features of apoptosis and DNA fragmentation. This was associated with caspase-3 activation and cleavage of poly(ADP-ribose) polymerase and phospholipase C-gamma1 proteins. However, SKOV-3 cells treated with Se-MSC did not demonstrate cytochrome c accumulation in the cytosol during apoptosis induction. Pretreatment of cells with the caspase inhibitors (z-VAD-fmk and DEVD-CHO) prevented Se-MSC-induced apoptosis. These results suggested that Se-MSC induces apoptosis through cytochrome c-independent caspase-3 activation in SKOV-3 cells. In late stage of apoptosis, p18kDa fragment of Bax was generated with the down-regulation of the expressions of survivin, X-linked inhibitor of apoptosis protein, and human inhibitor of apoptosis protein 1 following Se-MSC treatment, suggesting that the modulation of Bax and IAP (inhibitors of apoptosis) family proteins play some role in Se-MSC-mediated apoptosis. Pre-treatments of z-VAD-fmk and the calpain inhibitor, calpeptin inhibited Bax cleavage. These results suggested that Bax cleavage is mediated by calpain, and calpain activation may be a caspase-dependent one. Taken together, the chemopreventive effects of Se-MSC may be related in part to the caspase-3 activation, the down-regulation of IAP family proteins, and Bax cleavage mediated by caspase-dependent calpain activation
RRR-alpha-tocopheryl succinate induces MDA-MB-435 and MCF-7 human breast cancer cells to undergo differentiation. You H, Yu W, Sanders BG, et al. Cell Growth Differ. 2001 Sep; 12(9):471-80. RRR-alpha-Tocopheryl succinate (vitamin E succinate, VES) is a potent antitumor agent, inducing DNA synthesis arrest, differentiation, and apoptosis. Because little is known about VES-induced differentiation, studies reported here characterize VES effects on the differentiation status of human breast cancer cell lines and investigate possible molecular mechanisms involved. VES-induced differentiation of human MCF-7 and MDA-MB-435 breast cancer cells was characterized by morphological changes, induction of lipid droplets, induction of beta-casein mRNA expression, and down-regulation of Her2/neu protein. In contrast, VES treatment of normal human mammary epithelial cells, MCF-10A cells, and T-47D cells did not induce differentiation. Studies addressing mechanisms showed that neither antibody neutralization of the transforming growth factor-beta signaling pathway nor expression of a dominant-negative mutant of c-Jun N-terminal kinase blocked the ability of VES to induce differentiation; however, treatment of cells with PD 98059, a chemical inhibitor of mitogen-activated protein kinase kinase (MEK1/2), blocked the ability of VES to induce differentiation
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
|