Oral preneoplasia and chemoprevention of squamous cell carcinoma of the head and neck.
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Antineoplastic Agents↗
Biomedical subjects
Omer Kucuk
Publications and source records attributed to Omer Kucuk.
Folic acid mediated attenuation of loss of heterozygosity of DCC tumor suppressor gene in the colonic mucosa of patients with colorectal adenomas.
Loss of heterozygosity (LOH) and/or inactivation of tumor suppressor genes are implicated in the initiation and progression of many malignancies, including colorectal cancer. Although accumulating evidence suggests a chemopreventive role for folate in colorectal cancer, regulatory mechanisms are poorly understood. The primary objective of the current investigation was to determine whether folic acid would prevent LOH of the three tumor suppressor genes, deleted in colorectal cancer (DCC), adenomatous polyposis coli (APC) and p53 in macroscopically normal appearing rectal mucosa of patients with adenomatous polyps. In addition, the effect of folic acid on rectal mucosal proliferation was determined. Twenty patients were randomized in a double-blind study to receive either folic acid 5mg once daily or identical placebo tablets for 1 year. Genomic DNA and total protein were extracted from the rectal mucosa at baseline and after 1 year of treatment and analyzed for LOH and protein levels of APC, DCC and p53 genes. In addition, paraffin-embedded mucosal specimens were analyzed for proliferating cell nuclear antigen (PCNA) immunoreactivity, as a measure of cellular proliferative activity. Folate supplementation prevented LOH of DCC gene in five out of five (100%) patients who demonstrated baseline heterozygosity, whereas two out of four (50%) placebo-treated patients with baseline heterozygosity demonstrated allelic loss. Mucosal protein levels of DCC were also reduced in 7 of 10 (70%) placebo-treated patients compared to only 2 of 10 (20%) of patients treated with folate. Levels increased, however, in eight and three patients in the folic acid and placebo groups, respectively (P<0.02). Folic acid caused no change in allelic status of either APC or p53 gene. Folate supplementation caused a small, but not statistically significant, 16% reduction in mucosal proliferation, whereas placebo treatment resulted in a 88% (P<0.05) increase in this parameter, when compared with the corresponding baseline values. Our results indicate that folic acid prevents an increase in proliferation and arrests LOH of DCC gene and also stabilizes its protein in normal appearing rectal mucosa of patients with colorectal adenomas. Taken together, our data suggest that one of the ways folate may exert its chemopreventive effect is by stabilizing certain tumor suppressor gene(s) and preventing further increases in proliferation.
Adenoma↗
Expression of EGF-receptor related protein (ERRP) decreases in gastric mucosa during aging and carcinogenesis.
Aging and gastrointestinal malignancies, including that of the stomach are associated with increased activation of EGF-receptor (EGFR). Although the intracellular events that regulate this process are poorly understood, we hypothesize that loss of ERRP (EGFR-related protein; GenBank accession number AF187818), a recently identified negative regulator of EGFR, that possesses a substantial homology to the ligand binding extracellular domain of EGFR, may contribute to this event. In support of our hypothesis, we have observed that in Fischer-344 rats, whereas aging is associated with increased activation of EGFR in the gastric mucosa, expression of ERRP decreases inthis tissue during this period. The latter is accompanied by a concomitant reduction in the amount of TGF-alpha bound to ERRP. In contrast, the amount of TGF-alpha bound to EGFR is found to be higher in the gastric mucosa of aged than in young rats. This is accompanied by a concomitant rise in EGFR levels. In the gastric mucosa, EGFR and ERRP are found to be colocalized. Gastric adenocarcinoma in humans, which has been shown to be associated with increased activation of EGFR, shows a substantial reduction in ERRP expression, when compared with benign tissues. We conclude that increased activation of EGFR in the gastric mucosa during aging and carcinogenesis may partly be due to the loss of ERRP.
Aging↗
Zinc supplementation alleviates heat stress in laying Japanese quail.
The study was conducted to determine whether zinc supplementation could alleviate the detrimental effects of high ambient temperature (34 degrees C) on egg production, digestibility of nutrients and antioxidant status in laying Japanese quail. Quail (n = 180; 52 d old) were divided into six groups (n = 30/group) and were fed a basal diet or the basal diet supplemented with 30 or 60 mg of zinc (ZnSO(4). H(2)O)/kg diet. Birds were kept at 22 degrees C and 58% relative humidity (RH). At 13 wk of age, the thermoneutral (TN) groups remained at the same temperature, whereas the heat-stress (HS) groups were kept in an environmentally controlled room at 34 degrees C and 42% RH for 3 wk. Heat exposure decreased egg production in birds fed the basal diet (P = 0.001). Linear increases in feed intake (P = 0.01) and egg production (P = 0.004) and improved feed efficiency (P = 0.01) and egg quality variables (P 0.05). Results of the present study suggest that supplementation with 60 mg zinc/kg diet protects quail by reducing the negative effects of heat stress.
Animal Nutritional Physiological Phenomena↗
Expression of prostate-specific antigen is transcriptionally regulated by genistein in prostate cancer cells.
Prostate cancer is the second-leading cause of cancer-related deaths in men in the United States. Unfortunately, there is no effective therapy when prostate cancer becomes metastatic and refractory to conventional treatments. For this reason, the identification and exploration of new agents that reduce prostate cancer cell growth are of paramount importance. High consumption of plant-derived phytoestrogens is inversely associated with the incidence and mortality rate of prostate cancer. Previous studies, including our own, have shown that the phytoestrogen genistein inhibits prostate cancer cell growth in vitro and in vivo and decreases secreted and intracellular levels of the androgen-regulated protein prostate-specific antigen (PSA), but the role of genistein as an agonist/antagonist for hormone receptors remains unclear. To elucidate the mechanism by which genistein modulates PSA protein expression in prostate cancer cells, we investigated the effects of genistein on androgen-mediated and estrogen-mediated transcriptional regulation of PSA, androgen receptor (AR) mRNA and protein expression, and the ability of nuclear proteins to bind to androgen-response elements (AREs) in LNCaP cells. We showed that genistein decreased the transcriptional activation of PSA by both androgen-dependent and androgen-independent methods in LNCaP cells. The reduction of androgen-mediated transcriptional activation of PSA was correlated with decreased AR protein and mRNA levels and decreased binding to AREs. In contrast, genistein had differential effects on 17beta-estradiol-mediated PSA expressions. Low concentrations of genistein enhanced 17beta-estradiol-mediated PSA expressions, whereas high concentrations of genistein inhibited estrogen-mediated PSA expression in LNCaP cells. Genistein did not inhibit AR protein expression in the presence of 17beta-estradiol. These results suggest that ligand-dependent differences in the ability to activate PSA expression may contribute to the agonistic/antagonistic responses observed with genistein in prostate cancer cells.
Base Sequence↗
Re: Response of hormone refractory prostate cancer to lycopene.
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Adenocarcinoma↗
Chemoprevention of prostate cancer.
Chemoprevention is prevention of cancer by administering natural or synthetic chemicals. Anti-androgens are among the promising chemopreventive agents for prostate cancer because prostate epithelium is androgen dependent. A National Cancer Institute supported large, randomized, clinical prostate cancer chemoprevention trial has been conducted to test the efficacy of finasteride, an inhibitor of 5-a-reductase, which converts testosterone to 5-hydroxy-testosterone. Now the focus is on micronutrients and phytochemicals, which have potential preventive effects against prostate cancer. Lycopene, soy isoflavones, vitamin E and selenium are among the most promising nutritional chemopreventive agents. Another NCI supported large clinical chemoprevention trial was recently started to investigate the efficacy of selenium and vitamin E, alone or in combination in the prevention of prostate cancer. Inclusion of appropriate biomarkers in clinical trials will help elucidate the mechanisms by which genetic and epigenetic pathways of carcinogenesis are modulated by nutrients and phytochemicals.
Animals↗
Zinc in cancer prevention.
Epidemiologic studies suggest that zinc deficiency may be associated with increased risk of cancer. However, few studies have been conducted with zinc supplementation in animals and humans. Most previous intervention studies have used zinc in combination with several other micronutrients, which make them difficult to interpret. Zinc supplementation is associated with decreased oxidative stress and improved immune function, which may be among the possible mechanisms for its cancer preventive activity. Preclinical and clinical studies need to investigate modulation of genetic and epigenetic pathways of carcinogenesis by zinc.
Animals↗
Cancer chemoprevention.
Chemoprevention means prevention of cancer by administering chemical compounds. Ideal chemopreventive agents are non-toxic, inexpensive and can be taken orally. A large number of natural and synthetic compounds have cancer preventive properties in cell culture or animal model studies. With the demonstration of tamoxifen's ability to prevent breast cancer in women, the feasibility of chemoprevention in humans has now been firmly established. Current challenge is to build on this success and identify non-toxic chemopreventive agents. A promising area of research is clinical studies with botanicals, cancer preventive compounds in fruits, vegetables and other plants.
Antineoplastic Agents↗
New opportunities in chemoprevention research.
The importance of prevention in reducing the morbidity and mortality from cancer has been widely recognized. With the demonstration of tamoxifen's ability to prevent breast cancer in women, the feasibility of cancer chemoprevention in humans is now established. Future clinical chemoprevention studies should focus on phytochemicals, cancer preventive compounds in fruits, vegetables and other plants. Many phytochemicals are excellent potential chemopreventive agents, because, in addition to their cancer preventive effects, they are relatively non-toxic and inexpensive, they can be taken orally and some of them have other health benefits as well. New opportunities in clinical chemoprevention research include investigating chemopreventive effects of phytochemicals and conducting studies in patients with cancer. There is also a great need to investigate potential benefits and risks of administering phytochemicals before, during or after conventional therapies, such as surgery, chemotherapy, radiation or hormonal therapy. In addition, administration of chemopreventive agents prior to surgery provides an opportunity to investigate the modulation of genetic and epigenetic pathways by putative cancer preventive compounds and nutrients.
Anticarcinogenic Agents↗
Effects of lycopene supplementation in patients with localized prostate cancer.
Epidemiological studies have shown an inverse association between dietary intake of lycopene and prostate cancer risk. We conducted a clinical trial to investigate the biological and clinical effects of lycopene supplementation in patients with localized prostate cancer. Twenty-six men with newly diagnosed prostate cancer were randomly assigned to receive a tomato oleoresin extract containing 30 mg of lycopene (n = 15) or no supplementation (n = 11) for 3 weeks before radical prostatectomy. Biomarkers of cell proliferation and apoptosis were assessed by Western blot analysis in benign and cancerous prostate tissues. Oxidative stress was assessed by measuring the peripheral blood lymphocyte DNA oxidation product 5-hydroxymethyl-deoxyuridine (5-OH-mdU). Usual dietary intake of nutrients was assessed by a food frequency questionnaire at baseline. Prostatectomy specimens were evaluated for pathologic stage, Gleason score, volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia. Plasma levels of lycopene, insulin-like growth factor-1, insulin-like growth factor binding protein-3, and prostate-specific antigen were measured at baseline and after 3 weeks of supplementation or observation. After intervention, subjects in the intervention group had smaller tumors (80% vs 45%, less than 4 ml), less involvement of surgical margins and/or extra-prostatic tissues with cancer (73% vs 18%, organ-confined disease), and less diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia (33% vs 0%, focal involvement) compared with subjects in the control group. Mean plasma prostate-specific antigen levels were lower in the intervention group compared with the control group. This pilot study suggests that lycopene may have beneficial effects in prostate cancer. Larger clinical trials are warranted to investigate the potential preventive and/or therapeutic role of lycopene in prostate cancer.
Adenocarcinoma↗
Methods to increase fruit and vegetable intake with and without a decrease in fat intake: compliance and effects on body weight in the nutrition and breast health study.
Dietary patterns that involve a decrease in fat and an increase in fruit and vegetable (FV) intake have been suggested to decrease cancer risks. In this study, intervention methods to selectively modify dietary fat and/or FV intakes were developed. Compliance to the diets and the effects on body weight are shown, because both of these dietary changes can impact on and be confounded by changes in energy intake. A total of 122 women with a family history of breast cancer were randomized onto one of four diets for 12 mo. Counseling methods were devised to increase amount and variety of FV consumed with or without a decrease in fat intake using modified exchange list diets. Women on the low-fat and combination low-fat/high-FV diet arms decreased their fat intakes to approximately 16% of energy. Women on the high-FV and the combination low-fat/high-FV diet arms increased FV intakes to approximately 11 servings/day. Despite counseling efforts to maintain baseline energy intakes, mean body weight increased significantly by 6 pounds in women in the high-FV diet arm and decreased significantly by 5 pounds in women in the low-fat diet arm. Percent body fat also was increased in the high-FV diet arm and decreased in the low-fat diet arm. Body weight and percent body fat in the combination diet arm did not change significantly. Control of energy intake, therefore, appears to have been achieved only when the addition of FV to the diet was balanced by a decrease in fat intake and both dietary components were enumerated daily. Maintenance of energy intake, therefore, did not appear to be attained intrinsically when individuals were counseled to make changes in the composition of their diets.
Adipose Tissue↗