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)

A brief description of physicochemical properties of the androgen receptors in the various target tissues is given. It is suggested that androgen receptors in all organs and species are very similar if not identical. It is also suggested that apparent differences in steroid binding are not due to differences in steroid specificity of receptors, but rather due to organ specific differences in target tissue metabolism. A short discussion of our studies on androgen receptors in the prostate, epididymis and testis of human being is also included. The properties of these receptors are similar, if not identical to those described in rats, and we have not been able to demonstrate differences in androgen receptors of non-neoplastic and neoplastic tissue. From studies on testosterone metabolism it is demonstrated that human prostate is metabolizing testosterone to DHT much faster than the seminal vesicles. Furthermore, there is a drastic reduction in DHT formation in tissue from prostatic cancer compared to normal and hyperplastic prostatic tissue.
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PMID:Androgen receptors in male sex tissues of rats and humans. 6 89

We have searched for tissue-specific binding of 5alpha-androstan-17beta-ol-3-one (5alpha-dihydrotestosterone; 5alpha-DHT) in cytosols prepared from 25 surgically obtained benign prostatic hypertrophy (BPH) samples and in 3 tissue specimens containing prostate cancer cells. The distinction between steroid-receptor complexes and ligand binding to serum sex hormone-binding globulin (SHBG) was facilitated by combination experiments involving both sucrose gradient ultracentrifugation and agar gel electrophoresis. Gradient analysis of a cytosol prepared from a cervical lymph node (CLN) containing metastatic prostate tissue, revealed both 8-S and 4-S forms of high affinity (charcoal stable) 5alpha-[3H]DHT binding. When electrophoresis was performed on gradient fractions from these zones, anodally migrating steroid-receptor complexes were found only in the 8-S peak, the 4-S region containing radioligand bound to cathodally directed SHBG. In similar experiments with two BPH samples heavily invaded with prostate cancer cells only a single 4-S peak of radioligand binding was detected. Its multicomponent nature was uncovered electrophoretically when, in addition to SHBG, saturable, androgen binding molecules appeared anodally. Their incomplete resolution from SHBG on a gradient might have prevented their identification had this been the only method used. In contrast to the cancer-containing tissues, no saturable 5alpha-[3H]-DHT binding, other than that to SHBG, was detected in any of the BPH samples analysed. It is considered that, of the methods currently available, agar gel electrophoresis may be particularly useful for further investigations into the possible multicomponent nature of androgen binding of tissue origin in the human prostate.
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PMID:Steroid receptors in the human prostate. Detection of tissue-specific androgen binding in prostate cancer. 84 8

Local hyperthermia for benign and malignant prostatic disease remains largely empirical. In an attempt to understand the biological action of hyperthermia, and its potentiation by antiandrogen seen in clinical practice, the interaction of the two has been studied in prostatic cancer cell lines. Human prostatic cancer cell lines LNCaP and DU 145 were studied to examine the effects of heat shock treatment (HST), androgen (5 alpha-dihydrotestosterone: 5 alpha DHT) and antiandrogen (hydroxyflutamide: OH-Flut) on cell growth and survival. Response (measured as increased DNA content) to 5 alpha DHT demonstrated that LNCaP was androgen sensitive, whereas DU 145 was androgen insensitive; OH-Flut stimulated LNCaP growth but had no effect on DU 145 growth. Thermotolerance was exhibited by DU 145 cells but not by LNCaP cells. The combination of HST followed by OH-Flut markedly reduced survival of LNCaP cells compared with HST alone. This effect was not observed in DU 145 cells. The enhanced cytotoxic effect of antiandrogen and hyperthermia could minimise the effect of thermotolerance in malignant cells surviving initial hyperthermia treatment and might suggest real clinical value for the combination or sequence.
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PMID:Local hyperthermia for prostatic disease: in vitro studies on human prostatic cancer cell lines. 146 61

The presence of androgen receptor (AR) in prostate cancer has been linked to the androgen-dependent nature of the tumor and has also been shown to have prognostic significance; it also appears to be a positive prognostic indicator in breast cancer. However, due to the relatively low AR concentrations in most tumors and the inherently low specific activity of tritium, the assay of AR based on available 3H-ligands is not sensitive enough to measure accurately the amount of receptor in small specimens. A 125I-ligand like those available for the estrogen and progesterone receptors would be helpful, but development of such a ligand for AR has not been very successful. Although several androgen analogues containing iodine, bromine, or selenium have been synthesized specifically as potential probes for AR, none have shown any significant affinity or specificity for the receptor. We therefore undertook the synthesis of new potential AR ligands which could be radioiodinated, and determined their affinities for AR (from rat uterus and MCF-7 human breast cancer cells) by using a competition assay. We have examined both 5 alpha-dihydrotestosterone (5 alpha-DHT) and 19-nortestosterone analogues and have identified two such compounds which showed high AR affinity: (17 alpha,20E)-17 beta-hydroxy-21-iodo-5 alpha-pregn-20-en-3-one (17 alpha-[E)-iodovinyl)-5 alpha-DHT, 9) and 17 beta-hydroxy-7 alpha-methyl-(17 alpha,20E)-21-iodo-19-norpregna-4,20-dien-3- one (7 alpha-methyl-17 alpha-[E)-iodovinyl)-19-nortestosterone, 11). In fact, the affinity of the latter for human AR was found to be superior to that of 5 alpha-DHT itself. These iodovinyl analogues could be easily prepared in the radioiodinated form, and should prove to be extremely useful in assaying low levels of AR in small specimens.
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PMID:A potential radioiodinated ligand for androgen receptor: 7 alpha-methyl-17 alpha-(2'-(E)-iodovinyl)-19-nortestosterone. 200 46

To understand better the mechanism by which 5-alpha-dihydrotestosterone (5-alpha-DHT) influences prostate epithelial cell function, we examined the effects of 5-alpha-DHT on phosphoinositide metabolism in human prostate cancer cell lines. Androgen receptor-positive LN-CaP cells showed dose-responsive, steady-state elevations in phosphoinositide metabolism when treated with 5-alpha-DHT. The intracellular pool of 3H-myoinositol decreased and the incorporation of 3H-myoinositol into cellular lipids increased with increasing concentrations of 5-alpha-DHT. 5-alpha-DHT increased the release of 3H-inositol phosphates into the media. The inactive stereoisomer, 5-beta-DHT, did not increase phosphoinositide metabolism. In androgen receptor-negative cells, phosphoinositide metabolism was not altered by 5-alpha-DHT. The slow induction of phosphoinositide metabolism by 5-alpha-DHT suggests that the effects may be mediated through other factors that serve as intermediates in 5-alpha-DHT modulation of intracellular signalling. We conclude that this modulation involves increased turnover of phosphatidylinositol, incorporation of myoinositol into cellular lipids, and alterations in the aqueous intracellular myoinositol pool size, possibly as a result of altered transport mechanisms.
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PMID:Phosphoinositide metabolism in human prostate cancer cells in vitro. 215 36

The effect of steroidal and nonsteroidal "anti-androgens" on the proliferative capacity of androgen-sensitive LNCaP-FGC human prostate tumor cells in culture was studied using charcoal-dextran stripped human serum-supplemented media. Cyproterone and medroxyprogesterone acetates, flutamide, hydroxyflutamide, and anandron (R23908) were administered alone at concentrations between 3 X 10(-12) and 3 X 10(-6) M. Results indicated that although medroxyprogesterone induced maximal proliferation at 3 X 10(-9) M, the other "anti-androgens" (with the exception of flutamide that was ineffective) were effective at 3 X 10(-8) M and higher concentrations; the amplitude of the proliferative response by these compounds was comparable to that elicited by estradiol-17 beta (3 to 5-fold over control). None of the anti-androgens tested triggered the shutoff effect characteristic of androgen action. When 3 X 10(-10) M DHT and the above mentioned anti-androgens were administered simultaneously, a synergistic pattern was seen; on the contrary, 3 X 10(-8) M DHT cancelled the proliferative effect of each of the anti-androgens when administered simultaneously. The relative binding affinity of these anti-androgens to androgen receptors present in LNCaP-FGC cells did not correlate well with their proliferative efficiency. The data collected were interpreted within the premises of the negative control hypotheses for the regulation of cell proliferation in metazoans. Within those premises, results became compatible with the notion that first, "anti-androgens" elicited the proliferation of androgen-sensitive cells by neutralizing the effect of a serum-borne inhibitor (androcolyone-I); this event seems not to be mediated by androgens receptors. Second, anti-androgens did not trigger a proliferative shutoff response like androgens do, i.e. the proliferative pattern induced by anti-androgens was comparable to that elicited by estrogens and progestins. Third, when administered simultaneously with 3 X 10(-10) M DHT, anti-androgens behaved synergistically. Fourth, the DHT-induced shutoff effect consistently overrode the proliferative effect generated by anti-androgens and estrogens when added alone. Finally, taken together these results raise important questions regarding the therapeutic role of anti-androgens in prostate cancer.
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PMID:The proliferative effect of "anti-androgens" on the androgen-sensitive human prostate tumor cell line LNCaP. 230 13

To evaluate the role of small amounts of DHT in prostate tissue as a stimulus to epithelial cell growth (protein synthesis) we studied tissue from patients given various androgen-blocking drugs prior to transurethral resection of the prostate (TURP) and measured epithelial protein synthesis and DHT in the tissue specimens. We also studied the effects on stromal cell protein synthesis of an antiestrogen, tamoxifen. Test drugs prior to TURP included Megace 160 mg per day, Megace 160 mg per day plus Tamoxifen 40 mg per day, Megace 160 mg a day plus ketoconazole 1200 mg per day and tamoxifen 40 mg/day. The tissue was processed immediately and epithelial and stromal cells separated by digestion of tissue with 0.5% collagenase. After separation, epithelial cells were labeled with either [3H]leucine or L-[35S]methionine. Stromal cells were labelled with [3H]proline. DHT was measured in whole prostate tissue. Megace alone and Megace plus tamoxifen significantly decreased both [3H]leucine incorporation into protein and tissue concentration of DHT; Megace plus ketoconazole significantly decreased L-[35S]methionine incorporation into protein and DHT. Tamoxifen significantly decreased stromal protein synthesis. When the data correlating DHT with epithelial protein synthesis using both labeling techniques were combined, the curves were parallel and a strong correlation was noted between DHT and protein synthesis over a wide range of values (P less than 0.001). These results suggest that in hormone-dependent prostate cancer even small amounts of prostate DHT such as may occur from adrenal androgens following castration may significantly stimulate growth of the tumor epithelial cells. Since tamoxifen decreased stromal protein synthesis, estrogen is likely a significant growth stimulus to the increased stromal mass characteristic of benign prostatic hypertrophy.
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PMID:Effect of antiandrogen and/or antiestrogen blockade on human prostate epithelial and stromal cell protein synthesis. 243 6

We measured the concentrations of testosterone and its metabolites in serum and prostate glands of Nigerians, a low risk population for prostatic tumours, by means of radioimmunoassay after solvent and chromatographic extractions. Our results show that the values of serum testosterone in normal, elderly Nigerian men (447.0 +/- 112 ng./dl.) and those with benign prostatic hypertrophy (BPH) (430 +/- 112 ng./dl.) were similar (p greater than 0.05) and compare with values reported for Caucasians. In the Nigerian patients with advanced prostatic cancer, the serum testosterone concentrations (314 +/- 202 ng./dl.) were significantly lower (p less than 0.001) than those of Nigerians with normal prostate and BPH. This again is similar to reports in Caucasians with metastatic prostatic cancer. The serum concentrations of testosterone metabolites in our patients were the same in normal BPH and cancer subjects. The ratios of testosterone to its metabolites were similar in our normal and BPH subjects but lower in cancer patients. Also the testosterone concentrations in BPH glands of Nigerians (0.5 +/- 0.03 SEM ng./gm.) compared favourably with those reported from the western world. The testosterone concentrations in malignant prostate gland (7.9 +/- .06 SEM ng./gm.) were significantly higher than those in hypertrophic glands. This again agrees with the pattern in Caucasians. The DHT concentrations (4.9 +/- 0.3 SEM ng./gm.) were considerably higher in BPH than in cancerous glands (1.7 +/- 0.2 SEM ng./gm.). This pattern has been documented elsewhere. Because the concentrations and pattern of distribution of androgens in serum and prostate gland of our patients are comparable to published Caucasian and black American values, any difference in incidence rates of BPH and carcinoma of the prostate between whites, Afro-Americans and indigenous Africans may not be related to androgens.
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PMID:Androgen concentration in blacks with benign and malignant prostatic disease. 245 27

To aid in the design of new inhibitors of steroidal 5 alpha-reductase for treatment of prostate cancer, we have studied the topography of the 5 alpha-reductase active site (5 alpha-R) and of the related androgen (RA) and progesterone (RP) receptors in the region complementary to C.6 of progesterone. To this end we have determined the total structures of 17 alpha-acetoxy-6-methylene-4-pregnene-3,20-dione (VII; R = H) and of 17 beta-hydroxy-6,6-ethylene-4-androsten-3-one (VIa) by X-ray crystal structure analysis and, using these data, have developed Newman projections of the 6 alpha-Me, 6 beta-Me, 6-methylene and 6,6-ethylene derivatives of progesterone. From them we have developed a Newman projection of a composite model formed from steroids (V), (VI), (VIIIa) and (VIIIb). This is shown in Fig. 4 and illustrates the relative conformations of these substituents around C.6. From there we proceeded to receptor-binding studies. Our results led to the conclusion that androgen receptor, (RA), takes up preferred but different conformations when bound to testosterone (T) and to 17 beta-hydroxy-5 alpha-androstan-3-one (5 alpha-dihydrotestosterone, DHT), respectively, and that the resulting steroid-receptor complexes bind preferentially to different chromatin acceptor sites. We have therefore used the convention RT and RDHT in place of RA as appropriate. Working on the assumption that binding affinities reflect spatial contours, we have developed comparative silhouettes for the 5 alpha-R, RP and RDHT protein binding sites complementary to C.6 of the steroidal ligand. These data show that the 5 alpha-reductase active site is characterized by a hydrophobic pocket which specifically accommodates a 6-methylenic moiety and partially accommodates a 6 beta-methyl group. RDHT, in contrast, shows much less specificity and largely accommodates all the above substituents. Progesterone receptor differs in failing to accommodate 6,6-ethylene and 6 beta-methyl, with minimal accommodation of 6-methylene. It possesses a hydrophobic pocket skewed towards the alpha-face of the steroid, thereby allowing optimal binding of the 6 alpha-methyl substituent to the receptor. 6-Methylene-4-pregnene-3,20-dione (V) fails to bind significantly to androgen and progesterone receptors thereby supporting the postulate that its antiprostatic activity stems primarily from 5 alpha-reductase inhibition.
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PMID:Prostate. III--A structural feature characteristic of the rat prostate 5 alpha-reductase active site. 270 37

Activities of several steroid metabolizing enzymes (steroid sulfate-sulfatase, 17 beta-hydroxysteroid dehydrogenase, 5 alpha-reductase, and 3 alpha beta-hydroxysteroid dehydrogenase) as well as total tissue content and subcellular distribution (nuclear-extranuclear) of several androgen precursors, active androgens, and androgen deactivation products (DHEA sulfate, DHEA, 5-androstenediol, 4-androstenedione, testosterone, DHT, and 3 alpha-androstanediol) were quantified in primary tumors and lymph node metastases of human prostatic cancer obtained from patients without previous endocrine manipulation. Primary tumors were compared to benign parts of the same prostates, and the metastases were compared to their primary tumors. All enzymes and steroids found in benign prostatic tissues could also be detected in the malignant tissues. Even the capacity to accumulate active androgens in the nuclei was found to be unchanged in nearly all of the samples. Lower activities of hormone-dependent enzymes were observed in the cancers, suggesting a less efficient utilization of hormonal stimuli. Most striking changes found in the malignant tissues were a subtotal loss of 5 alpha-reductase activity and a metabolic shift to testosterone, which was more pronounced in samples from metastatic disease as compared to samples from non-metastatic disease. In conclusion, primary tumors and metastases of prostatic cancers not treated by endocrine manipulations retain their androgen receptor system and possess the same capacity to metabolize adrenal androgen precursors along the pathway to DHT as benign prostatic tissue. Consequently, they should be able to use at least androstenedione for production of active androgens directly in the target tissue.
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PMID:Androgens, adrenal androgen precursors, and their metabolism in untreated primary tumors and lymph node metastases of human prostatic cancer. 285 35


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