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

Vitamin D receptor gene polymorphism was determined in 66 and 60 Japanese patients with prostate cancer and non cancer controls, respectively. In contrast to previous reports showing an association between vitamin D receptor polymorphism of a TaqI restriction fragment length polymorphism at codon 352 (genotype tt) and prostate cancer in an American population, the frequency of genotype tt is less than one percent in the Japanese population. There was no difference between the patients and the controls in the vitamin D receptor TaqI genotype. In patients with metastatic prostate cancer, genotype TT had a tendency to shorter progression free survival compared to genotype Tt, but the number of patients was limited.
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PMID:Vitamin D receptor gene polymorphism in Japanese patients with prostate cancer. 1050 1

Vitamin D receptor gene (VDR) polymorphisms have been reported to be related to prostate cancer risk in the USA. We analyzed the distribution of TaqI RFLP and poly(A) of VDR in 100 prostate cancer patients and 202 urological controls. Among the control, 79.2% were homozygous (TT) for the absence of a TaqI RFLP, while 17.8% were heterozygous (Tt) and 3.0% homozygous (tt) for its presence. The distribution was almost the same in the cancer group; 80% were homozygous TT, 18% heterozygous Tt, and 2.0% homozygous tt. Polymorphism of poly(A) sizes was categorized as a long allele (> or = 18 As) and a short allele (< 18 As). The distribution did not vary between the cancer and control groups; 80, 79.2% were LL, 18, 17.8% LS and 2.0, 3.0% SS, respectively. These results showed no significant association of two VDR polymorphisms with prostate cancer risk, however a different distribution of VDR polymorphisms between Japanese and non-Japanese men.
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PMID:Significance of vitamin D receptor gene polymorphism for prostate cancer risk in Japanese. 1065 Aug 2

Calcitriol, the principal biologically active ligand of the Vitamin D receptor (VDR), has been shown to inhibit cancer cell proliferation in in vitro and in vivo models of prostate cancer and a wide range of other neoplasms. In addition, calcitriol's activity appears to be additive, and in some experimental systems, synergistic with dexamethasone and several cytotoxic chemotherapy agents. While effects on progression through the cell cycle, induction of apoptosis, inhibition of angiogenesis, and reduction in tumor invasiveness have been demonstrated, the exact mechanisms of VDR-mediated antineoplastic activity remain incompletely understood. Antineoplastic activity of calcitriol requires substantially supraphysiologic concentrations of this compound. Dose escalation of calcitriol administered daily was severely limited by predictable hypercalcemia and/or hypercalcuria. This limitation has been overcome with intermittent dosing of calcitriol. At Oregon Health & Science University, weekly oral administration of calcitriol allowed the attainment of peak serum calcitriol concentrations well above 1 nM, a concentration that inhibits prostate cancer proliferation by more than 50% in vitro. Weekly high-dose calcitriol was then combined with weekly docetaxel in a Phase II clinical trial carried out in men with metastatic androgen-independent prostate cancer. Treatment resulted in PSA response (defined as a confirmed 50% reduction) in 81% of patients. This level of activity, as well as the median time to progression of 11.4 months and median survival of 19.5 months, compared favorably to results with docetaxel alone and led to the development of a recently initiated randomized trial of docetaxel with calcitriol or placebo in the same patient population.
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PMID:Development of weekly high-dose calcitriol based therapy for prostate cancer. 1467 May 52

Normal prostate epithelial cells are acutely sensitive to the antiproliferative action of 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)), whilst prostate cancer cell lines and primary cultures display a range of sensitivities. We hypothesised that key antiproliferative target genes of the Vitamin D receptor (VDR) were repressed by an epigenetic mechanism in 1alpha,25(OH)(2)D(3)-insensitive cells. Supportively, we found elevated nuclear receptor co-repressor and reduced VDR expression correlated with reduced sensitivity to the antiproliferative action of 1alpha,25(OH)(2)D(3). Furthermore, the growth suppressive actions of 1alpha,25(OH)(2)D(3) can be restored by co-treatment with low doses of histone deacetylation inhibitors, such as trichostatin A (TSA) to induce apoptosis. Examination of the regulation of VDR target genes revealed that co-treatment of 1alpha,25(OH)(2)D(3) plus TSA co-operatively upregulated GADD45alpha. Similarly in a primary cancer cell culture, the regulation of appeared GADD45alpha repressed. These data demonstrate that prostate cancer cells utilise a mechanism involving deacetylation to suppress the responsiveness of VDR target genes and thus ablate the antiproliferative action of 1alpha,25(OH)(2)D(3).
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PMID:Epigenetic repression of transcription by the Vitamin D3 receptor in prostate cancer cells. 1522 80

The aim of this study was to investigate effects of 1,25(OH)(2)D(3) (calcitriol), 25OHD(3), and EB1089 on cell growth and on Vitamin D receptor (VDR) mRNA and 1alpha-hydroxylase (1alpha-OHase) mRNA expression in normal canine prostatic primary cultures. Canine prostatic epithelial cells were isolated, cultured, and treated with vehicle (ethanol), calcitriol, 25OHD(3), and EB1089 at 10(-9) and 10(-7)M. The VDR was present in epithelial and stromal cells of the canine prostate gland. 1,25(OH)(2)D(3), 25OHD(3), and EB1089 inhibited epithelial cell growth at 10(-7)M compared to vehicle-treated controls [calcitriol (P < 0.01), EB1089 (P < 0.01), and 25OHD(3) (P < 0.05)]. Epithelial cells treated with calcitriol and EB1089 at 10(-7)M had slightly increased VDR mRNA expression (0.2-0.3-fold) at 6 and 12h compared to controls. There was no difference in 1alpha-OHase mRNA expression in epithelial cells treated with these three compounds. 1,25(OH)(2)D(3) and its analogs may be effective antiproliferative agents of epithelial cells in certain types of prostate cancer.
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PMID:Effects of 1,25(OH)2D3, 25OHD3, and EB1089 on cell growth and Vitamin D receptor mRNA and 1alpha-hydroxylase mRNA expression in primary cultures of the canine prostate. 1522 11

In the US, prostate cancer (PCa) has the highest incidence rate of all cancers in males, with few known modifiable risk factors. Some studies support an association between the Vitamin D metabolites, 1,25-dihydroxyvitamin D (1alpha,25(OH)(2)D(3)) and/or 25-hydroxyvitamin D (25(OH)D(3)), and prostate cancer, while others have yielded conflicting results. 1alpha,25(OH)(2)D(3) has anti-proliferative and pro-differentiating effects in prostate cancer cell lines, and levels of circulating 25(OH)D(3) may be important as PCa cells possess 1-alpha-hydroxylase activity. Using a nested case-control design, we evaluated whether plasma levels of 25(OH)D(3) and 1alpha,25(OH)(2)D(3) were associated with prostate cancer risk in participants from the Nutritional Prevention of Cancer (NPC) trial. With 83 cases and 166 matched controls, we calculated the adjusted odds ratios for increasing plasma levels of 25(OH)D(3) and 1alpha,25(OH)(2)D(3). Compared to the lowest tertile of plasma 25(OH)D(3) levels, the adjusted odds ratios were 1.71 (0.68-4.34) and 0.75 (0.29-1.91); the corresponding odds ratios for 1alpha,25(OH)(2)D(3) were 1.44 (0.59-3.52) and 1.06 (0.42-2.66). Given the pivotal effects of the Vitamin D receptor on gene transcription, it is likely that the anti-carcinogenic effects of Vitamin D that have previously been described are related to the activity and expression of the Vitamin D receptor and should be investigated further.
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PMID:Plasma levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and the risk of prostate cancer. 1522 33

A number of hormonal ligands and/or the nuclear receptors that mediate their actions have been targeted for prostate cancer therapy. Androgens, the ligands for the androgen receptor (AR), are critical for the growth of prostate cancer. Inhibition of androgen production has been the mainstay of treatment for advanced prostate cancer for decades. Other more recently tested targets include retinoid receptors (RAR and RXR), glucocorticoid receptors (GR), estrogen receptors (ER) and peroxisome proliferator-activated receptors (PPAR). Calcitriol, acting through the Vitamin D receptor (VDR), has many tumor suppressive activities in the prostate, including inhibition of proliferation, induction of apoptosis and/or differentiation, and reduction of cellular invasion. Because of these properties, calcitriol and its less hypercalcemic analogs are being evaluated as agents to prevent or treat prostate cancer. Androgens, retinoids, glucocorticoids, estrogens and agonists of PPAR directly or indirectly impact Vitamin D signaling pathways, and vice versa. In order to design the most effective strategies to use calcitriol to prevent or treat prostate cancer, the interactions of other nuclear receptors and their ligands with the Vitamin D signaling pathway need to be considered.
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PMID:Interaction of nuclear receptor ligands with the Vitamin D signaling pathway in prostate cancer. 1566 94

Vitamin D deficiency increases risk of prostate cancer. According to our recent results, the key Vitamin D hormone involved in the regulation of cell proliferation in prostate is 25(OH) Vitamin D3. It is mainly acting directly through the Vitamin D receptor (VDR), but partially also through its 1alpha-hydroxylation in the prostate. A deficiency of 25(OH) Vitamin D is common especially during the winter season in the Northern and Southern latitudes due to an insufficient sun exposure, but Vitamin D deficient diet may partially contribute to it. A lack of Vitamin D action may also be due to an altered metabolism or Vitamin D resistance. Vitamin D resistance might be brought up by several mechanisms: Firstly, an increased 24-hydroxylation may increase the inactivation of hormonal Vitamin D metabolites resulting in a Vitamin D resistance. This is obvious in the cancers in which an oncogenic amplification of 24-hydroxykase gene takes place, although an amplification of this gene in prostate cancer has not yet been described. During the aging, the activity of 24-hydroxylase increases, whereas 1alpha-hydroxylation decreases. Furthermore, it is possible that a high serum concentration of 25(OH)D3 could induce 24-hydroxylase expression in prostate. Secondly, Vitamin D receptor gene polymorphism or defects may result in a partial or complete Vitamin D resistance. Thirdly, an overexpression or hyperphosphorylation of retinoblastoma protein may result in an inefficient mitotic control by Vitamin D. Fourthly, endogenous steroids (reviewed by [D.M. Peehl, D. Feldman, Interaction of nuclear receptor ligands with the Vitamin D signaling pathway in prostate cancer, J. Steroid Biochem. Mol. Biol. (2004)]) and phytoestrogens may modulate the expression of Vitamin D metabolizing enzymes. In summary, the local metabolism of hormonal Vitamin D seems to play an important role in the development and progression of prostate cancer.
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PMID:The role of Vitamin D3 metabolism in prostate cancer. 1566 95

Governmental and research agencies worldwide have strongly advocated sun avoidance strategies in an attempt to counter marked increases in skin cancer incidence. Concurrently, there are reports describing widespread Vitamin D3 deficiency. Because 1,25-dihydroxyvitamin D3, through interaction with the Vitamin D receptor, exerts pleiotrophic effects, such deficiency might be expected to have clinical consequences. Indeed, various reports indicate that exposure to ultraviolet radiation (UVR) exerts a protective effect on development of some common diseases including internal cancers and multiple sclerosis. We describe studies indicating that modest exposure reduces risk of prostate cancer. The effect of UVR is mediated by skin type; at lower levels of exposure a relative inability to effect skin pigmentation is protective presumably because it allows more efficient Vitamin D3 synthesis. Polymorphic variants in genes associated with pigmentation including melanocyte stimulating hormone receptor and tyrosinase are also associated with prostate cancer risk. Overall, though preliminary and requiring cautious interpretation, these data indicate that moderate UVR exposure together with characteristics linked with less effective tanning confer reduced prostate cancer risk. Clearly, it is important to define safe levels of UVR that do not result in increased risk of skin cancers such as malignant melanoma.
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PMID:Ultraviolet radiation: effects on risks of prostate cancer and other internal cancers. 1574 48

Vitamin D receptor (VDR), a member of the steroid/thyroid hormone nuclear receptor family, is bound by the steroid hormone 1,25-dihydroxyvitamin D3, which is thought to play a role in the etiology and progression of prostate cancer. Polymorphisms in the VDR gene have been associated with prostate cancer risk, although findings are inconclusive. The purpose of this study was to determine if VDR polymorphisms were associated with prostate cancer risk using a large, Australian population-based study of 812 cases and 713 controls frequency-matched by age. As the 3' region polymorphisms are in strong linkage disequilibrium, for joint effects, we only evaluated the common g.60890G > A polymorphism with the unlinked g.27823C > T (5' region) polymorphism. Allele frequencies were similar in cases and controls (g.27823C > T, 36% versus 36%; g.60890 G>A, 41% versus 43%). No genotypes were individually associated with prostate cancer risk (all P > 0.3). All nine possible genotype combinations were evident, and although the g.27823CT/g.60890GA combination was nominally more prevalent in controls (24%) than in cases (19%, P = 0.03), there was no difference in the combined genotype distribution between cases and controls (P = 0.2). The associations of risk with genotype were between 0.91 and 1.03, all with 95% confidence intervals within 0.81 to 1.15. In conclusion, VDR polymorphisms either alone or in combination do not seem to contribute appreciably to prostate cancer risk.
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PMID:Genetic variants in the vitamin D receptor gene and prostate cancer risk. 1582 77


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