Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although increasing data indicate a role for vitamin D in prostate cancer, little is known about the role of this hormone in the noncancerous prostate. We examined the effect of 1,25-dihydroxyvitamin D3 (1,25 D) on the growth of noncancerous rat prostates in vivo. Rats were castrated and treated with vehicle (controls), 1,25 D, testosterone, or a combination of both hormones for 2 weeks. Histological examination of the harvested prostates revealed that 1,25 D had a selective regressive effect on epithelial cells in treated rats compared to untreated castrated rats and to normal uncastrated rats. However, 1,25 D stimulated stromal growth in the prostate. The mean prostatic weight of the vitamin D-treated rats was twice that of the untreated rats (0.13 +/- SEM 0.005 g versus 0.06 +/- SEM 0.006 g). The histological differences were less marked in the testosterone-supplemented animals. A greater degree of cellular differentiation was observed in the rats treated with testosterone and vitamin D compared to rats that received testosterone supplementation alone. Studies of the nuclear matrix composition revealed differences between the testosterone-supplemented and the testosterone and 1,25 D-treated rat prostates. We conclude that in the absence of testosterone, 1,25 D may exert a growth-promoting effect on the prostatic stroma in vivo. In concert with testosterone, it may play an important role in the growth and differentiation of the normal rat prostate.
 ...
PMID:The role of vitamin D in normal prostate growth and differentiation. 893 Apr 6

Prostate cancer cell lines exhibit variable growth suppression by the hormonal form of vitamin D3, 1,25-Dihydroxyvitamin D3 [1,25 (OH)2D] (1,25 D3). To understand the molecular basis for this differential sensitivity to 1,25 D3, we compared growth response to 1,25 d3, vitamin D receptor (VDR) content and VDR transcriptional activity in four well-characterized human prostate cancer cell lines: LNCaP, DU145, PC-3 and ALVA-31. In PC-3 and DU145 cells, relative lack of growth inhibition by 1,25 D3 (< 10% inhibition) correlates with very low levels of VDR (9-15 fmol/mg protein) compared to classical vitamin D3 target tissues (approximately 75-200 fmol/mg protein). Transfection of DU145 and PC-3 cells with a VDR cDNA expression vector is sufficient to establish growth sensitivity to 1,25 D3, suggesting that low VDR levels are responsible for the failure of these cell lines to respond to 1,24 D3. LNCaP cells are highly sensitive to growth inhibition by 1.25 D3 (approximately 55% inhibition) and contain approximately 2-3-fold more VDR (25 fmol/mg) than the relatively 1,25 D3-insensitive PC-3 and DU145 cell lines. However, ALVA-31 cells display less than 20% growth inhibition to 1.25 D3 although they contain the highest levels of VDR (45 fmol/mg) of the four cell lines. Thus, sensitivity to growth inhibition by 1,25 D3 does not correlate with VDR content in ALVA-31 and LNCaP cells. This lack of correlation between VDR density and growth responses to 1,25 D3 led us to investigate VDR-mediated gene transcription in these cell lines. We employed two different naturally occurring vitamin D response elements (VDREs) linked to a reporter gene. Reporter gene activation by 1,25 D3 correlated well with VDR content in all four cell lines. Therefore, compared to LNCaP cells, decreased sensitivity of ALVA-31 to growth inhibition by 1,25 D3 is not due to a decrease in the general transcriptional activity of VDR. We conclude that growth inhibition by 1,25 D3 in prostate cancer cells requires VDR but that this response is modulated by non-receptor factors that are cell line-specific.
 ...
PMID:Vitamin D receptor content and transcriptional activity do not fully predict antiproliferative effects of vitamin D in human prostate cancer cell lines. 902 66

Many anticipate that application of findings in molecular genetics will help to achieve greater precision in defining high-risk populations that may benefit from chemopreventive interventions. We must recognize, however, that genetic susceptibility, environmental factors, and complex gene-environment interactions are all likely to be risk determinants for most cancers. Cohort studies of twins and cancer indicate that having "identical" genes is generally not a very accurate predictor of cancer incidence. Data from twin studies support the suggestion that environmental factors such as tobacco use significantly influence cancer risk. The complexities of the genetic contribution to disease risk are exemplified by the development of Duchenne muscular dystrophy in only one of monozygotic twin girls, hypothesized to be the result of X chromosome inactivation, with the distribution patterns of the X chromosome being skewed to the female X in the manifesting twin and to the male X in the normal twin. Evidence from transgenic and genetic-environmental studies in animals support the possibility of genetic-environmental interactions. Calorie restriction modifies tumor expression in p53 knockout mice; a high-fat, low-calcium, low-vitamin D diet increases prepolyp hyperplasia formation in Apc-mutated mice; and calorie restriction early in life influences development of obesity in the genetically obese Zucker rat (fafa). Such environmental modulation of gene expression suggests that chemoprevention has the potential to reduce risk for both environmentally and genetically determined cancers. In view of the growing research efforts in chemoprevention, the NCI has developed a Prevention Trials Decision Network (PTDN) to formalize the evaluation and approval process for large-scale chemoprevention trials. The PTDN addresses large trial prioritization and the associated issues of minority recruitment and retention; identification and validation of biomarkers as intermediate endpoints for cancer; and chemopreventive agent selection and development. A comprehensive database is being established to support the PTDN's decision-making process and will help to determine which agents investigated in preclinical and early phase clinical trials should move to large-scale testing. Cohorts for large-scale chemoprevention trials include individuals who are determined to be at high risk as a result of genetic predisposition, carcinogenic exposure, or the presence of biomarkers indicative of increased risk. Current large-scale trials in well-defined, high-risk populations include the Breast Cancer Prevention Trial (tamoxifen), the Prostate Cancer Prevention Trial (finasteride), and the N-(4-hydroxyphenyl) retinamide (4-HPR) breast cancer prevention study being conducted in Milan. Biomarker studies will provide valuable information for refining the design and facilitating the implementation of future large-scale trials. For example, potential biomarkers are being assessed at biopsy in women with ductal carcinoma in situ (DCIS). The women are then randomized to either placebo, tamoxifen, 4-HPR, or tamoxifen plus 4-HPR for 2-4 weeks, at which time surgery is performed and the biomarkers reassessed to determine biomarker modulation by the interventions. For prostate cancer, modulation of prostatic intraepithelial neoplasia (PIN) by 4-HPR and difluoromethylornithine is being investigated; similar studies are being planned for oltipraz, dehydroepiandrosterone, and vitamin E plus selenomethionine. The validation of biomarkers as surrogate endpoints for cancer incidence in high-risk cohorts will allow more agents to be evaluated in shorter studies that use fewer subjects to achieve the desired statistical power.
 ...
PMID:Cancer risk factors for selecting cohorts for large-scale chemoprevention trials. 902 95

In this study the effects of a Western-style diet on epithelial cell proliferation in the prostate and bladder of C57BL/6J mice were investigated. The Western-style diet contained increased fat and low calcium and vitamin D, compared with AIN-76A control diet, at levels simulating human Western diets based on nutrient density. After feeding the Western-style and AIN-76A diets for 5 and 16 weeks, mice were infused with bromodeoxyuridine (BrdU) for 72 h using s.c. implanted osmotic pumps. Findings revealed that in bladder epithelium BrdU labeling indices were not significantly different (P > 0.05) between mice on the control and Western-style diets at both time periods. However, significant increases in BrdU labeling indices occurred in epithelial cells of the anterior (P = 0.024) and dorsal (P = 0.049) lobes, but not in the ventral lobe (P = 0.21), of the mouse prostate after feeding the Western-style diet for 16 weeks, compared with mice on the control diet. These findings demonstrate Western-style diet induction of epithelial cell hyperproliferation in anterior and dorsal lobes of the mouse prostate. The findings further suggest that these nutrients may have a role in human prostatic carcinogenesis, since the anterior and dorsal lobes of the mouse prostate are homologous with the human prostate in embryological origin and histological structure and carcinomas induced in rodent models have similar characteristics to those found in human prostatic cancer.
 ...
PMID:Induced hyperproliferation in epithelial cells of mouse prostate by a Western-style diet. 916 86

Although much has been written, little is known about the causes of prostate cancer. Variations between populations in the incidence of invasive cancers, together with changes in the incidence of invasive cancers in migrants, have pointed to environmental (lifestyle) factors that might be amenable to intervention. Conversely, there is a lack of international variation in the prevalence of microscopic tumours, so the essential question is: what causes only some of the common microscopic tumours to become aggressive? Dietary factors hold the most promise in this regard and have been the subject of recent reviews. The strongest and most consistent effects are positive associations with animal products such as red meats, eggs and dairy foods, and possibly by implication, fat. Evidence of a protective effect of fruit and vegetables is weak and inconsistent, as is the relationship with vitamin A and carotenoids, such as beta-carotene. There are some interesting leads. Lycopene, the carotenoid found in tomatoes, has been reported to be protective; alpha-tocopherol supplementation has shown a protective effect in one intervention study; and vitamin D has been shown to be protective in a prospective study. Interest is also growing in phytoestrogens and the extent to which dietary manipulation with these and other phytochemicals might influence prostate cancer by modifying male sex hormone levels or actions. There is limited evidence of associations with obesity. It is not known whether these are related to a particular dietary pattern or to possible physiological effects on the male's hormonal milieu. Associations with lean body mass are likely to be related to the action of androgens during growth and development. Dietary and nutritional effects on prostate cancer do not appear to be strong, but they may be subtle and attenuated by measurement error. To explore these aspects further will require large prospective studies that include improved (repeated) dietary measurements and also blood sampling, so that genetic polymorphisms can be adequately investigated. Such studies are underway.
 ...
PMID:Diet, nutrition and prostate cancer. 920 14

1 alpha,25-Dihydroxyvitamin D (1,25 D; also know as calcitriol), the hormonal form of vitamin D, can inhibit the proliferation and promote the differentiation of human prostate adenocarcinoma cells. However, little is known about the effects of 1,25 D on the invasive ability of prostate cancer cells. We used an in vitro bioassay of cell invasion (Amgel assay) to examine the effects of 1,25 D and a "noncalcemic" vitamin D analogue, 1,25-dihydroxy-16-ene-23-yne-cholecalciferol (16-23-D3), on the invasiveness of three well-characterized human prostate carcinoma cell lines: DU 145, PC-3, and LNCaP. PC-3 and LNCaP cells were poorly invasive in Amgel and were hardly affected by treatment with 1,25 D or 16-23-D3 (< 3%). Conversely, DU 145 cells were highly invasive in Amgel, and their invasion was markedly inhibited by 1,25 D and 16-23-D3 (maximally 66 and 59.4% respectively). This effect was both dose-dependent, with maximal inhibition at 1 x 10(-7) M and 72 h. Significant inhibition of invasion was observed at physiological levels of 1,25 D. Neither proliferative indices nor cell cycle kinetics were altered during the experimental exposure. Treatment with 1,25 D and 16-23-D3 caused a selective decrease in the secreted levels of type IV collagenases (MMP-2 and MMP-9). These findings support the hypothesis that 1,25 D reduces the risk of invasive prostate cancer and suggest a role for vitamin D compounds in the chemoprevention of invasive prostate cancer.
 ...
PMID:1 alpha,25-Dihydroxyvitamin D (calcitriol) inhibits the invasiveness of human prostate cancer cells. 929 81

Laboratory and clinical data indicate an antitumor effect of 1,25(OH)2 vitamin D (1,25(OH)2D) on prostate cancer. High calcium intake suppresses formation of 1,25(OH)2D from 25(OH)D, thereby decreasing the 1,25(OH)2D level. Ingestion of fructose reduces plasma phosphate transiently, and hypophosphatemia stimulates 1,25(OH)2D production. We thus conducted a prospective study among 47,781 men of the Health Professionals Follow-Up Study free of cancer in 1986 to examine whether calcium and fructose intake influenced risk of prostate cancer. Between 1986 and 1994, 1369 non-stage A1 and 423 advanced (extraprostatic) cases of prostate cancer were diagnosed. Higher consumption of calcium was related to advanced prostate cancer [multivariate relative risk (RR), 2.97; 95% confidence interval (CI), 1.61-5.50 for intakes > or = 2000 mg/day versus < 500 mg/day; P, trend, 0.002] and metastatic prostate cancer (RR, 4.57; CI, 1.88-11.1; P, trend, <0.001). Calcium from food sources and from supplements independently increased risk. High fructose intake was related to a lower risk of advanced prostate cancer (multivariate RR, 0.51; CI, 0.33-0.80, for intakes > 70 versus < or = 40 g/day; P, trend, 0.007). Fruit intake was inversely associated with risk of advanced prostate cancer (RR, 0.63; 95% CI, 0.43-0.93; for > 5 versus < or = 1 serving per day), and this association was accounted for by fructose intake. Non-fruit sources of fructose similarly predicted lower risk of advanced prostate cancer. A moderate positive association between energy-adjusted fat intake and advanced prostate cancer was attenuated and no longer statistically significant when controlled for calcium and fructose. Our findings provide indirect evidence for a protective influence of high 1,25(OH)2D levels on prostate cancer and support increased fruit consumption and avoidance of high calcium intake to reduce the risk of advanced prostate cancer.
 ...
PMID:Calcium and fructose intake in relation to risk of prostate cancer. 945 87

The incidence of prostate cancer (CaP) and its increase in the last 10 years vary both from country to country and according to the ethnic group, with the highest incidence reported for Afro-Americans and the lowest for Asian men. To date, only three risk factors have been established for CaP: age; familial aggregation of CaP, and ethnic origins. No dietary or environment-related cause has been established. However, some variations in endogenous genetic factors may help explain differences in risk among ethnic groups or geographic areas. Similarly, certain genetic polymorphisms of genes encoding for 5alpha-reductase, androgen receptor or vitamin D, have been associated with different levels of CaP risk, and could explain the variations observed between populations. Different studies support the view that familial CaP may truly be hereditary, and not due to a similar lifestyle. Thus, familial inheritance is a parameter that needs to be considered in recommending screening for high-risk families. Indeed, when 1, 2, and 3 first-degree relatives are affected, the relative risk of first-degree relatives of CaP patients may increase to 2, 5, and 11%, respectively. Some familial forms appear to be associated with transmission of a rare putative dominant gene with a high penetrance (88% at age 85), with the cumulative proportion of CaP attributable to this gene being more marked for younger patients (a 43 versus a 34% risk of CaP appearing before the age of 55 versus 70 years). Using this transmission model and linkage analysis, a predisposing locus on chromosome 1q24-25 (HPC-1) has been described. Moreover, recessive and X-linked transmission has been suggested, showing that a large proportion of familial CaP may not be due to segregation of a few major gene mutations, but rather to familial sharing of alleles at many loci, each contributing to a small increase in cancer risk. Candidate genes may be the same suppressor genes that are involved in other cancers and in sporadic CaP.
 ...
PMID:Hereditary prostate cancer and other genetic predispositions to prostate cancer. 960 56

Prostatic cells express vitamin D receptor (VDR), which mediates the functions of 1,25-dihydroxyvitamin D. Two recent case-control studies suggested strong inverse associations between two VDR polymorphisms, TaqI and poly(A), and risk of prostate cancer. These two and a third polymorphism, BsmI, are closely linked. In a case-control study nested in the Physicians' Health Study, a randomized double-blind trial of aspirin and beta-carotene among 22,071 United States male physicians, we examined the associations between BsmI and TaqI and prostate cancer risk and whether the associations varied according to age and vitamin D metabolite levels among 372 incident cases and 591 controls. Among controls, the BB genotype was significantly associated with higher 1,25-dihydroxyvitamin D (median = 36.2 pg/ml for the BB versus 33.9 pg/ml for the bb genotype; P = 0.02), suggesting an association of the VDR polymorphisms with VDR function. Overall, we observed no significant associations of these VDR polymorphisms with prostate cancer risk: relative risk (RR) = 0.86 [95% confidence interval (CI) = 0.57-1.29] for the BB genotype and RR = 0.92 (95% CI = 0.69-1.22) for the Bb genotype, compared with the bb genotype (results were similar for the TaqI polymorphism). Stratification by age (< or = 61 and > 61 years) and tumor aggressiveness showed no significant associations. However, in an analysis restricted to men with plasma 25-hydroxyvitamin D below the median, we observed a 57% reduction (RR = 0.43, 95% CI = 0.19-0.98) in risk for those with the BB versus the bb genotype; the risk reduction was particularly marked among older men (RR = 0.18, 95% CI = 0.05-0.68). We did not observe this inverse association among men with 25-hydroxyvitamin D levels above the median, nor did we observe it among younger men.
 ...
PMID:Vitamin D receptor polymorphisms, circulating vitamin D metabolites, and risk of prostate cancer in United States physicians. 961 Jul 87

Epidemiological and laboratory data support a role for vitamin D in the growth and differentiation of human prostatic cells. These findings prompted us to ask whether prostatic cells could convert 25-hydroxyvitamin D3 (25-OH-D3), the major circulating metabolite of vitamin D3, to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the hormonally active metabolite, in a manner similar to cultured human keratinocytes. Therefore, we investigated three well-characterized human prostate cancer cell lines, LNCaP, DU 145, and PC-3; two primary cultures of cells derived from noncancerous human prostates (one normal and one benign prostatic hyperplasia); and primary cultures of normal human keratinocytes for their ability to synthesize 1,25(OH)2D3. Assays were performed in the presence of 25-OH-D3 as the enzyme substrate and 1,2-dianilinoethane, an antioxidant and free radical scavenger, and in the presence and absence of clotrimazole, a cytochrome P450 inhibitor. DU 145 and PC-3 cells produced 0.31 +/- 0.06 and 0.07 +/- 0.01 pmol of 1,25(OH)2D3/mg protein/h, respectively. No measurable 1,25(OH)2D3 was detected in LNCaP cells. The normal and benign prostatic hyperplasia primary cultures and keratinocyte cultures produced 3.08 +/- 1.56, 1.05 +/- 0.31, and 2.1 +/- 0.1 pmol of 1,25(OH)2D3/mg protein/h, respectively, using a calf thymus receptor binding assay to measure 1,25(OH)2D3 in the presence of 1,2-dianilinoethane. The identity of the analyte as 1,25(OH)2D3 was supported by high performance liquid chromatography using [3H]25-OH-D3 as the enzyme substrate and a solvent system that is specific for 1,25(OH)2D3. The production of 1,25(OH)2D3 in the prostate cancer cell lines and in the primary cultures was completely inhibited in the presence of clotrimazole. This report demonstrates that two of three human prostate cancer cell lines, as well as primary cultures of noncancerous prostatic cells, possess 1alpha-hydroxylase activity and can synthesize 1,25(OH)2D3 from 25-OH-D3. Together with recent data indicating that 1,25(OH)2D3 inhibits the invasiveness of human prostate cancer cells (G. G. Schwartz et al., Cancer Epidemiol. Biomark. Prev., 6: 727-732, 1997), these data suggest a potential role for 25-OH-D3 in the chemoprevention of invasive prostate cancer.
 ...
PMID:Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3. 961 Jul 88


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>