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)

The pregnene derivative, 4-pregnene-3-one-20 beta-carboxaldehyde (22-A) was evaluated as an inhibitor of 17 alpha-hydroxylase/C17,20-lyase in rat testicular microsomes and of 5 alpha-reductase in human prostatic homogenates. The effect of the compound in vivo was studied in adult male rats. The 22-A demonstrated potent and competitive inhibition of 17 alpha-hydroxylase and C17,20-lyase with Ki values 8.48 and 0.41 microM, respectively, significantly below the Km values for these two enzymes (33.75 and 4.55 microM). This compound also showed potent inhibition of 5 alpha-reductase with a Ki value of 15.6 nM (Km for this enzyme is 50 nM). By comparison, ketoconazole, a currently studied 17 alpha-hydroxylase/C17,20-lyase inhibitor for the treatment of prostatic cancer, showed less potent inhibition of 17 alpha-hydroxylase (Ki 39.5 microM) and C17,20-lyase (Ki 3.6 microM) and did not inhibit 5 alpha-reductase. Progesterone which has been reported to inhibit the 17 alpha-hydroxylase/C17,20-lyase, did not significantly reduce the production of testosterone by rat testes in vitro in comparison to controls, while the same concentration of 22-A demonstrated a 42% reduction of testosterone biosynthesis. When the adult male rats were injected s.c. with 22-A at 50 mg/day/kg for a 2 week period, the testosterone concentrations in the rat sera were significantly lower than control values (P less than 0.05), whereas serum corticosterone levels did not change. These results suggest that 22-A is a selective potent inhibitor for 17 alpha-hydroxylase and C17,20-lyase, but is more potent for the C17,20-lyase. The compound also inhibits 5 alpha-reductase, and therefore may reduce biosynthesis of testosterone and dihydrotestosterone effectively. Thus, 22-A may be useful in the treatment of problems associated with the androgen excess and prostatic cancer.
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PMID:4-pregnene-3-one-20 beta-carboxaldehyde: a potent inhibitor of 17 alpha-hydroxylase/C17,20-lyase and of 5 alpha-reductase. 160 43

Human or rat microsomal 5 alpha-reductase activity, as measured by enzymic conversion of testosterone into 5 alpha-dihydrotestosterone or by binding of a competitive inhibitor, [3H]17 beta-NN-diethulcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one ([3H]4-MA) to the reductase, is inhibited by low concentrations (less than 10 microM) of certain polyunsaturated fatty acids. The relative inhibitory potencies of unsaturated fatty acids are, in decreasing order: gamma-linolenic acid greater than cis-4,7,10,13,16,19-docosahexaenoic acid = cis-6,9,12,15-octatetraenoic acid = arachidonic acid = alpha-linolenic acid greater than linoleic acid greater than palmitoleic acid greater than oleic acid greater than myristoleic acid. Other unsaturated fatty acids such as undecylenic acid, erucic acid and nervonic acid, are inactive. The methyl esters and alcohol analogues of these compounds, glycerols, phospholipids, saturated fatty acids, retinoids and carotenes were inactive even at 0.2 mM. The results of the binding assay and the enzymic assay correlated well except for elaidic acid and linolelaidic acid, the trans isomers of oleic acid and linoleic acid respectively, which were much less active than their cis isomers in the binding assay but were as potent in the enzymic assay. gamma-Linolenic acid had no effect on the activities of two other rat liver microsomal enzymes: NADH:menadione reductase and glucuronosyl transferase. gamma-Linolenic acid, the most potent inhibitor tested, decreased the Vmax. and increased Km values of substrates, NADPH and testosterone, and promoted dissociation of [3H]4-MA from the microsomal reductase. gamma-Linolenic acid, but not the corresponding saturated fatty acid (stearic acid), inhibited the 5 alpha-reductase activity, but not the 17 beta-dehydrogenase activity, of human prostate cancer cells in culture. These results suggest that unsaturated fatty acids may play an important role in regulating androgen action in target cells.
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PMID:Inhibition of steroid 5 alpha-reductase by specific aliphatic unsaturated fatty acids. 163 46

The response of two androgen-responsive rat prostatic cancers (i.e., Dunning R-3327 H and G sublines) and one androgen-responsive human prostatic cancer (i.e., PC-82) to the 5 alpha-reductase inhibitor, SK&F 105657, was tested in vivo. SK&F 105657 was administered orally twice a day at a dose of 25 or 50 mg/kg/dose. The rat R-3327 G tumor and the human PC-82 tumor have a low to undetectable level of tissue 5 alpha-reductase activity and both responded to SK&F 105657 treatment with a reproducible inhibition of tumor growth. Associated with this antitumor effect was a major decrease (i.e., greater than 70%) in tissue dihydrotestosterone (DHT) content in both tumors. By contrast, the rat R-3327 H prostatic cancer has a much higher level of tissue 5 alpha-reductase activity, and neither tumor DHT content nor growth of the tumor was inhibited by treatment with SK&F 105657. Drug treatment of rats bearing R-3227 H tumors resulted in a similar reduction in the DHT content, wet weight, and DNA content of the ventral prostate as that produced in R-3327 G tumor-bearing rats which experienced an antitumor response. These results suggest that SK&F 105657 can produce antitumor effects if a substantial reduction in tissue DHT is achieved. Such reduction in tissue DHT, secondary to inhibition of the tissue 5 alpha-reductase enzyme, appears to be more difficult to achieve in tumors than in the normal prostate. In order to achieve such a DHT reduction in tumor tissue, prostatic cancers with low 5 alpha-reductase activity could be treated with SK&F 105657 on a dose regimen that lowers serum DHT to surgical castration levels, while concomitantly inhibiting the already low tumor tissue 5 alpha-reductase activity.
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PMID:Response of rat and human prostatic cancers to the novel 5 alpha-reductase inhibitor, SK&F 105657. 164 69

Endocrine management is the best palliative management available for patients with carcinoma of the prostate. It is based on androgen withdrawal by castration or other means. Endocrine management was introduced into clinical medicine by Huggins and his associates in the early 1940s on the basis of careful clinical and experimental research establishing the biological effects of androgen withdrawal in animal systems and in humans. It was believed for a long time that endocrine treatment would prolong life. This, however, in spite of extensive clinical research, remains unproven. The possibility that the life span of prostate cancer patients is determined by the hormone independent cell populations within virtually all prostate cancers still remains a possibility. Endocrine treatment has, however, been shown to have a significant impact on symptoms related to prostate cancer, especially on bone pain, urethral and ureteral obstruction. It has also been shown to prolong time to progression and to death from prostate cancer. Although castration and the application of exogenous oestrogens with the purpose of interfering with pituitary testicular feedback have been standard treatment of prostate cancer for more than 30 years, new treatment methods have recently become available. Luteinizing hormone releasing hormone agonists allow suppression of plasma testosterone to castration levels without exerting the side effects associated with oestrogens (eg cardiovascular incidents, gynaecomastia). Also, the application of pure or steroidal anti-androgens allows direct counteraction of circulating androgens at the target cell. The possibility that initial suppression of adrenal androgen production, which contributes about 10% of circulating androgens in males, may be more beneficial than suppression of testicular androgens alone has been subject to intense clinical research recently. Simultaneous suppression of testicular and adrenal androgens in primary management of prostate cancer is called total androgen blockade or total androgen suppression. Up to now, however, no convincing advantages of total androgen suppression regimens above castration have been shown. Total androgen suppression seems to produce significantly better survival when compared with daily injections of LHRH alone. The use of pure anti-androgens or of 5 alpha-reductase inhibitors could potentially prevent the most significant side effect of all androgen withdrawal regimens, loss of libido and impotence. However, neither the use of pure anti-androgens as monotherapy nor the use of 5 alpha-reductase inhibitors as monotherapy has been shown to produce clinical results that are equal to castration.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Endocrine therapy: where do we stand and where are we going? 184 51

This updated literature review on heterosteroids and drug research has information on chemical structure, pharmacology, and effects. It first discusses the anti-inflammatory heterosteroids, such as mometasone furoate and cortivazol. It also covers heterosteroidal antimineralocorticoids and anabolic hetero derivatives. The review discusses at length the 19-norsteroid, mifepristone (RU-486), which exhibits antiprogestational activity and is being used for fertility control in women. It also has antiglucocorticoid activity and shows promise as a treatment of diseases characterized by muscle atrophy. In vitro studies indicate that mifepristone inhibits growth of breast cancer cell lines and of endometrial cancer cell lines. It has already exhibited growth inhibitory effects in some breast cancer patients. Discussions of mifepristone's pharmacokinetics and structural modifications of mifepristone follow. Danazol is an antigonadotropin and is used to treat endometriosis, benign breast disease, precocious puberty, hereditary angioneurotic edema, menorrhagia, some types of infertility, and gynecomastia. Danazol effects considerable changes in lipid metabolism. Other hormonal, antihormonal, and/or antifertility heterosteroids and/or aspects include androgen antagonists (e.g., cyproterone acetate), estrogen activity, antiestrogens, STS-557, and oximinosteroids. Heterosteroidal inhibitors of steroid hormone biosynthesis discussed are aromatase inhibitors, 5 alpha-reductase inhibitors, and 3 beta-hydroxysteroid dehydrogenase inhibitors (trilostane, epostane, and azastene). Heterosteroids affect the cardiovascular system, including the cardiac glycosides, antiarrhythmic agents, and antilipemic agents. Some heterosteroids affect central nervous system activity (e.g., RU-5135 causes convulsions in rodents). Pancuronium analogues and chandonium and analogues are neuromuscular blocking azasteroids. In addition to danazol and RU-486, several other antineoplastic heterosteroids exist (e.g., estramustine phosphate sodium, a prostate cancer drug).
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PMID:Heterosteroids and drug research. 184 48

While the elimination of androgens of testicular origin can be easily achieved by orchiectomy or medical castration with LHRH agonists, the action of adrenal androgen precursors which are converted into the active androgen 5 alpha-dihydrotestosterone (DHT) in the prostatic tissue itself can be partially neutralized by antiandrogens which compete with DHT for binding to the androgen receptor. In order to increase the efficiency of androgen blockade, we have used 4-MA, an inhibitor of 5 alpha-reductase, the enzyme which converts testosterone into DHT, to reduce intracellular DHT concentrations and thus facilitate the action of the antiandrogen Flutamide. The present data show that the inhibitory effects of 4-MA (17 beta, N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one) and of the antiandrogen Flutamide are additive on prostatic growth and on androgen-sensitive prostatic binding protein mRNA levels in the rat, thus clearly suggesting that such a combination could provide the basis for a further improvement in the therapy of prostate cancer.
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PMID:Combination of an antiandrogen and a 5 alpha-reductase inhibitor: a further step towards total androgen blockade? 205 5

The effect of nonsteroid antiandrogen flutamide on 3H-testosterone (3H-T) metabolism in vitro was studied in Wistar male rat prostatic and hepatic homogenates. Flutamide was administered per os in a dose of 25 mg/kg daily for 3, 10 or 30 consecutive days. Following 30 days 5 alpha-dihydrotestosterone (DHT) formation in the prostate was reduced by 50%. In castrated animals antiandrogen abolished the recovering action of testosterone propionate (TP) on 5 alpha-reductase activity. When added to incubation medium flutamide proved ineffective, while hydroxyflutamide appeared to decrease DHT formation. The metabolic utilization of 3H-T in the liver of rats receiving flutamide for 30 days was found to be 3 times lower. The formation of DHT, androsterone, ethiocholanolone and androstenedione was substantially suppressed. In castrated rats, both treated and nontreated with TP, flutamide also inhibited the formation of steroid metabolites of 3H-T. Synergism to flutamide and TP action on androgen metabolism in the liver is suggested to be related to antiandrogen ability of interaction with an unusual estrogen-binding protein of rat liver. The decrease in DHT formation induced by flutamide may play a role in the mechanism of its therapeutic action in prostatic cancer patients.
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PMID:Nonsteroid antiandrogen inhibiting effect on testosterone metabolism in rat prostate and liver. 209 78

Prostatic cancer is often locally advanced or metastatic when diagnosed, making surgical removal and radiotherapy ineffective treatments. Alternative therapy involves androgen deprivation because prostatic cancer is known to be androgen-dependent. Orchidectomy has proved effective but other methods of reducing androgen concentrations have also been developed. Oestrogens have proved effective, as have progestogens, and both steriodal and non-steroidal anti-androgens have been extensively studied. Another possible treatment is the use of inhibitors of androgen metabolism (aromatase and 5 alpha-reductase). Luteinizing hormone releasing hormone analogues, which act as antagonists or agonists, have been shown to have efficacies comparable to those of other therapies. Adrenal suppression has provided a useful alternative to adrenalectomy, particularly because of the high morbidity rate of surgery in elderly patients. Complete androgen withdrawal using an anti-androgen in association with surgical or chemical castration may be a more superior treatment. Another possible approach is the use of somatostatin analogues, which have been shown to inhibit the growth of animal prostatic cancer cells.
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PMID:Prostatic cancer--survey of hormonal treatment in Europe. 218 53

Human sera were tested for their ability to inhibit 5 alpha-reductase binding of a potent inhibitor of the enzyme. Thirty one of 227 serum samples from patients diagnosed or suspected of prostatic cancer had a significant inhibitory activity, whereas 128 serum samples from other patients were inactive. The majority of the inhibitory activity was in the IgG fraction purified by chromatography on a protein A-Sepharose affinity column and an anti-human IgG-agarose column. IgG fractions from non-inhibitory sera were inactive. Inhibitory IgG also inhibited the enzymatic activity of microsomal 5 alpha-reductase from liver, ventral prostate and preputial gland of rat, and liver, prostate, and facial skin of human. The inhibitory IgG had no effect on NADH-menadione reductase or 17 beta-hydroxysteroid dehydrogenase. These results suggest that 5 alpha-reductase autoantibodies are present in the blood of some prostatic cancer patients.
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PMID:Anti-5 alpha-reductase autoantibodies in the serum of patients with prostatic cancer. 222 23

Human placental 3 beta-hydroxysteroid dehydrogenase/5----4-ene isomerase (3 beta-HSD) purified from human placenta transforms C-21 (pregnenolone and 17 alpha-hydroxy pregnenolone) as well as C-19 (dehydroepiandrosterone and androst-5-ene-3 beta, 17 beta-diol) steroids into the corresponding 3-keto-4-ene-steroids and is thus involved in the biosynthesis of all classes of hormonal steroids. Trilostane, epostane and cyanoketone are potent inhibitors of 3 beta-HSD with Ki values of approximately 50 nM. 4-MA, a well known 5 alpha-reductase inhibitor, is also a potent inhibitor of 3 beta-HSD with a Ki value of 56 nM. Synthetic progestin compounds such as promegestone and RU2323 show relatively strong inhibitory effects with Ki values of 110 and 190 nM, respectively. Cyproterone acetate, a progestin used in the treatment of hirsutism, acne and prostate cancer as well as norgestrel and norethindrone that are widely used as oral contraceptives also inhibit 3 beta-HSD activity at Ki values of 1.5, 1.7 and 2.5 microM, respectively.
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PMID:Inhibitory effect of synthetic progestins, 4-MA and cyanoketone on human placental 3 beta-hydroxysteroid dehydrogenase/5----4-ene-isomerase activity. 226 54


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