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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The endocrine treatment of metastatic prostate cancer includes castration which reliably lowers the serum testosterone (T); however, the effect on intratumor levels of T and dihydrotestosterone (DHT) is less predictable. In vitro work demonstrated that the human prostate cancer cell line PC-3 had significant 5-a-reductase activity that could be inhibited with 17b-N,N-diethylcarbamoyl-4-aza-5a-androstan-3-one (4MA). In this study, we examined the effect of 5-a-reductase inhibition with 4MA and androgen suppression with dexamethasone on the growth characteristics and intratumor androgen levels in the PC-3 cell line in male athymic nude mice (Balb/c). The mice were randomized into six treatment groups: 1) noncastrate vehicle control, 2) 4MA, 0.25 mg/day, 3) 4MA, 1 mg/day, 4) dexamethasone, 25 micrograms/day, 5) 4MA, 1 mg/day, and dexamethasone, 25 micrograms/day, and 6) castrate control group. After 21 days of treatment the animals were sacrificed, serum collected, and tumors harvested. Each treatment produced intratumor DHT levels equivalent to the castrate group. Only the low dose 4MA caused a reduction in intratumor DHT without producing castrate levels of circulating T. The combination of dexamethasone and 4MA was less effective in lowering the intratumor DHT/T ratio than 4MA alone. No significant differences in tumor growth parameters were noted between intact control animals and any of the treatment arms. Serum T levels correlated poorly with intratumor androgen levels. Five-a-reductase inhibition produced castrate levels of intratumor DHT in the nonandrogen-dependent prostate cancer cell line PC-3. The combination of dexamethasone and 5-a-reductase inhibition with 4MA appears to be less effective in lowering intratumor androgen levels than either therapy alone.
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PMID:Effect of 5-alpha-reductase inhibition and dexamethasone administration on the growth characteristics and intratumor androgen levels of the human prostate cancer cell line PC-3. 817 Aug 35

For advanced prostate cancer, hormonal suppression has long played an important role in patient management. Furthermore, the concept of combined androgen blockade using a luteinizing hormone-releasing hormone agonist in combination with an antiandrogen such as flutamide is gaining increasing acceptance. The novel regimen of finasteride (a 5-alpha-reductase inhibitor) plus flutamide may also have a role to play in the future. In the neoadjuvant setting, androgen suppression prior to radical prostatectomy is a novel approach. This strategy aims to reduce the size of the tumor as much as possible, hopefully downstaging the disease, and thus increasing the chances of a successful outcome at operation. Data from studies presented at this symposium revealed a clear reduction in tumor size by this method but the effects on both staging of disease and long-term outcome were not so definitive. Questions were put to the audience and the expert panel to assess their opinion of hormonal therapy and staging techniques, both in the neoadjuvant and advanced disease settings.
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PMID:Workshop summary: hormonal suppression in the neoadjuvant setting and advanced disease. 826 27

Adrenal androgens contribute 40% of total androgens in adult men. The inactive precursor steroids dehydroepiandrosterone (DHEA) and DHEA-sulfate are secreted in large amounts by the adrenals and reach the prostate and other peripheral target tissues, where they are transformed into the potent androgen dihydrotestosterone (DHT). We have cloned and sequenced the cDNAs and/or genes which encode the enzymes responsible for the transformation of DHEA into DHT, namely 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase, 17 beta-hydroxysteroid dehydrogenase and 5 alpha-reductase. Blockade of DHT synthesized by these enzymes, with a pure antiandrogen of the class of flutamide, prolongs life in advanced prostate cancer, the effect being much more important when a small number of metastases is present. Most importantly, 3-month combination therapy reduces cancer-positive margins at radical prostatectomy, from 38.5% in control patients to only 13% in those who received combination therapy. Combined with an efficient strategy for detection of early-stage prostate cancer, the present approach could offer the possibility of a cure to more than 80% of prostate cancer patients, compared with the present situation where a cure can be offered to less than 20% of patients, since the first diagnosis of prostate cancer is usually made at a late stage of the disease.
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PMID:Intracrinology: the basis for the rational design of endocrine therapy at all stages of prostate cancer. 826 32

In view of the well established clinical results of the deprivation of androgens through orchiectomy in prostatic cancer and the structural similarities of 4-androsten-3,17-dione and atamestane (1-methyl-ADD), we studied the influence of 1-methyl-ADD on the conversion of 4-androsten-3,17-dione to testosterone by the 17 beta-hydroxysteroid reductase enzyme in human testicular tissue. Our studies, presented in this manuscript, demonstrate that 1-methyl-ADD is a competitive inhibitor of 4-androsten-3,17-dione in its reduction to testosterone by the 17 beta-hydroxysteroid reductase enzyme in the human testis.
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PMID:In vitro studies on the inhibition of testosterone synthesis in the human testis by atamestane. 838 73

The effects of the steroidal androgen receptor antagonist zanoterone (WIN 49596) and the steroidal 5 alpha-reductase inhibitor finasteride (MK-906) either alone or in combination on prostatic size, histomorphology, and biochemistry were determined in the intact male dog. Additionally, the effects of treatment with zanoterone and/or finasteride on testicular size, serum testosterone and LH levels, and spermatogenesis were determined in the same dogs. Daily oral treatment for 16 weeks with either zanoterone alone at 10 mg/kg.day or finasteride alone at 1.0 mg/kg.day reduced (P < 0.05) the size of the prostate, resulted in mild to moderate diffuse glandular atrophy of the prostate, and decreased prostatic DNA and prostatic arginine esterase (the primary canine prostatic protein) levels compared to those in intact controls. These changes occurred with no effect on testicular weight, testicular histomorphology, daily sperm production, or serum LH levels. Serum testosterone concentrations were increased (P < 0.05) approximately 3-fold in the 10 mg/kg.day zanoterone treatment group compared to those in intact controls. Combination treatment of male dogs for 16 weeks with zanoterone (10 mg/kg.day) plus finasteride (1.0 mg/kg.day) orally also reduced (P < 0.05) prostate size, resulted in moderate to marked diffuse prostatic glandular atrophy, and decreased prostatic DNA and arginine esterase levels more than either drug alone, without affecting testicular size, testicular histomorphology, serum LH concentrations, or serum testosterone concentrations compared to those in intact controls. The effects of combination treatment with zanoterone and finasteride on prostatic size; histomorphology; and DNA, arginine esterase protein, and arginine esterase mRNA levels were similar to those observed in castrate controls. In addition, in situ estimates of prostatic size using transrectal ultrasonography indicated that the median time to 70% prostatic regression in dogs administered combination zanoterone plus finasteride was similar to that in castrate controls (9.6 and 9.3 weeks, respectively), indicating that the combination was more effective in causing prostatic regression than either drug alone. Finally, at the dosages used, no adverse effects of combination treatment with zanoterone plus finasteride on testicular or other major body organ weights were observed. Based on these results, combination therapy using zanoterone and finasteride for the treatment of human androgen-dependent disorders such as benign prostatic hyperplasia and prostate cancer has potential utility.
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PMID:Effect of combination treatment with zanoterone (WIN 49596), a steroidal androgen receptor antagonist, and finasteride (MK-906), a steroidal 5 alpha-reductase inhibitor, on the prostate and testes of beagle dogs. 839 78

We compare testosterone (T) metabolism in primary cultures of epithelial cells and fibroblasts separated from benign prostate hypertrophy (BPH) and prostate cancer tissues. In all cultures, androstenedione (delta 4) formed by oxidation of T by 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) represented 80% of the metabolites recovered. The amounts of 5 alpha-dihydrotestosterone (DHT), formed by reduction of T by 5 alpha-reductase (5 alpha-R), were small: 5 and 2% (BPH) and 8 and 15% (adenocarcinoma) for epithelial cells and fibroblasts, respectively. Northern blot analysis of total RNA from epithelial cells (BPH or adenocarcinoma) attributed the reductive activity to the 5 alpha-reductase type 1 isozyme and oxidative activity to the 17 beta-HSD type 2. In cancer fibroblasts, only little 17 beta-HSD type 2 mRNA was detected. The 5 alpha-reductase inhibitors, 4-MA (17 beta-(N,N-diethyl)carbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one) and finasteride, inhibited DHT formation with a preferential action of 4-MA on epithelial cells (BPH or adenocarcinoma) and of finasteride on fibroblasts from adenocarcinoma. Neither inhibitor acted on delta 4 formation. On the other hand, the lipido-sterol extract of Serenoa repens (LSESr, Permixon) inhibited the formation of all the T metabolites studied [IC50 S = 40 and 200 micrograms/ml (BPH) and 90 and 70 micrograms/ml (adenocarcinoma) in epithelial cells and fibroblasts, respectively]. These results have important therapeutic implications when selecting appropriate treatment options for BPH.
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PMID:Testosterone metabolism in primary cultures of human prostate epithelial cells and fibroblasts. 854 Dec 34

Finasteride is the first of a new class of 5 alpha-reductase inhibitors which allows selective androgen deprivation affecting dihydrotestosterone (DHT) levels in target organs such as the prostate and scalp hair without effecting circulating levels of testosterone thus preserving the desired androgen mediated effects on muscle strength, bone density and sexual function. Finasteride has been demonstrated to produce significant effects in men with an enlarged prostate gland. The long-term data now emerging suggests that progression of benign prostatic hyperplasia (BPH) may be arrested providing additional long term benefits. Experimental uses in prostate cancer prevention and male pattern baldness offer new and exciting possibilities for this class of compounds.
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PMID:Finasteride: a clinical review. 856 56

5 alpha-reductase (5 alpha R) activity in two human prostate cancer cell lines was compared to that in benign prostatic hyperplasia (BPH) tissue and COS cells transfected with and expressing the human genes for 5 alpha-reductase type 1 (5 alpha R1) and type 2 (5 alpha R2). Comparisons were based on pH profiles and sensitivities to selective inhibitors of 5 alpha-reductase In the cancer lines, activity was greatest over the pH range 7-8, compared to a sharp peak of activity between pH 5-5.5 in BPH tissue and COS cells expressing 5 alpha R2. Finasteride and SKF105,657 were potent inhibitors of 5 alpha-reductase activity in BPH tissue and COS cells expressing 5 alpha R2, but weak inhibitors in the cancer lines and in COS cells expressing 5 alpha R1. In contrast, UK117,026 was a more potent inhibitor of 5 alpha-reductase activity in the prostate cancer cell lines and in COS cells expressing 5 alpha R1. These data indicate that human prostate cancer cell lines express 5 alpha-reductase activity similar to that in COS cells transfected with 5 alpha R1, but different from that in BPH tissue. This may be a consequence of in vitro culture. Alternatively, it may reflect a change occurring as a result of neoplastic transformation in which case it will be important to select appropriate inhibitors in the clinic.
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PMID:5 alpha-reductase expression by prostate cancer cell lines and benign prostatic hyperplasia in vitro. 863 34

The effects of various means of interfering with androgen action on rat coagulating gland, ventral prostate, lateral type 1 prostate, lateral type 2 prostate, and dorsal prostate were examined morphologically and quantitatively by assessing DNA content, wet weight, protein content, and zinc concentrations. Adult male Sprague-Dawley rats were subjected to 2 weeks of interfering with androgen action by treatment with Leuprolelin (a luteinizing hormone-releasing hormone analog), Finasteride (a 5 alpha-reductase inhibitor), or diethylstilbestrol (DES), or by physical castration. For all prostatic lobes, inhibition of 5 alpha-reductase elicited the smallest reduction in prostatic wet weight, DNA and protein contents, and zinc concentration. The most profound reductions in all parameters were elicited by castration. Treatments with DES and Leuprolelin gave intermediate effects with DES being the more effective in reducing all parameters in all prostatic lobes. Morphological changes elicited by all forms of androgen blockade were reduction of epithelial height, relative increase of connective tissue, reduction in ductal diameter, length, and number. The order of effectiveness of the various treatments on morphological features was as described above. While all forms of androgen blockade elicited similar effects throughout the prostate, differences in response to all forms of interference with androgen action were observed in different lobes of the prostate with regard to wet weight, DNA and protein contents, and zinc concentration as well as morphological effects. Regressive changes at the morphological level were particularly striking in the coagulating gland and ventral prostate, and indistinct in the lateral type 2 prostate. Prostatic zinc concentration in both normal and androgen-deprived rats was the highest in the lateral type 2 prostate and was reduced by interfering with androgen action to the greatest extent in the dorsolateral prostate (lateral type 1 and type 2, and dorsal prostate). The distribution of zinc correlated with the expression of metallothionein, which was detected by immunocytochemistry only in the lateral type 2 prostate of both normal and androgen deprived rats. Intraprostatic heterogeneity of zinc and metallothionein expression emphasizes interlobar differences in biological function within the rat prostate. The mechanism of development of regional heterogeneity within the prostate may shed light on the pathogenesis of prostatic proliferative diseases (prostatic hyperplasia and prostatic cancer) that initially owe their development to focal changes within large cell populations.
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PMID:Influence of diethylstilbestrol, Leuprolelin (a luteinizing hormone-releasing hormone analog), Finasteride (a 5 alpha-reductase inhibitor), and castration on the lobar subdivisions of the rat prostate. 868 49

Although early detection and treatment of prostate cancer is widely advocated, this so-called secondary prevention approach has a number of drawbacks. First, it is not yet certain that active treatment of localized prostate cancer offers any advantage over surveillance. Second, screening may detect indolent tumors while missing some virulent ones. Third, treatment is not uniformly successful, even in patients with early disease. Fourth, radical prostatectomy and radiotherapy are associated with considerable side effects. And finally, the economic and psychological costs of large-scale screening cannot be overlooked. Although attention has been focused on the possibility of primary prevention, neither large-scale dietary manipulation nor long-term prophylactic use of retinoids is considered feasible. With the recent approval of the 5-alpha-reductase inhibitor finasteride for the treatment of benign prostatic hyperplasia, the opportunity for primary chemoprevention has moved closer to reality. The Prostate Cancer Prevention Trial (PCPT), a randomized, placebo-controlled study expected to enroll 18,000 healthy men over the age of 55, is currently addressing the question of whether finasteride prophylaxis can reduce the incidence of prostate cancer over a 7-year period. This is a US government work. There are no restrictions on its use.
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PMID:Screening for prostate cancer: opportunities for prevention. 872 86


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