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)

Cyproterone acetate (CPA) has been discovered more than 25 years ago and it was the first antiandrogen suitable for clinical use. CPA inhibits the action of endogenous and exogenous androgens at all androgen target organs; these include the prostate, seminal vesicles, testes, and the vas deferens. However, this antiandrogen also antagonizes less sex-specific effects of androgens, for example ossification of the epiphyseal cartilage, sebaceous gland function and skin thickness. Indications for CPA: Prostate cancer, androgen induced disorders of the skin (acne, seborrhoea, hirsutism, alopecia), precocious puberty and sexual disorders in men. Concerning sexual deviations clinical trials started in 1966. CPA leads to loss of libido and the ability to achieve erection, followed by the inability to achieve orgasm, after about 14 days of treatment (100-200 mg daily orally or 300 mg weekly i.m.). These effects are reversed in the same order as the onset. About 75 to 80% of patients respond to this therapy. CPA is generally well tolerated. Tiredness, lack of drive, listlessness and depressive moods have been reported as non-specific side-effects. Slight gynecomastia occurs in about 20% of patients. There are no good alternatives in this indication. Pure antiandrogens are unsuitable, because these are unable to inhibit libido sufficiently. Tranquilizers are not very effective, high doses of estrogens are associated with severe (cardiovascular) side effects. Orchidectomy is an irreversible intervention, LHRH analogues are associated with hot flushes and the initial increase in testosterone (flare phenomenon).
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PMID:Cyproterone acetate in the treatment of sexual disorders: pharmacological base and clinical experience. 183 80

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

Antiandrogens, substances that prevent androgens from expressing their activity at target cells, play an important role in the treatment of prostate cancer. The most frequently used substances have either a steroidal structure (cyproterone acetate) or a non-steroidal structure (Flutamide or Anandron). Antiandrogens have been tested both alone and in combination with treatments aimed at inhibiting testicular secretion (castration, LH-RH analogs), thereby producing complete blockade of androgen secretion and action. Patients treated by such combination protocols have often shown an improvement in the percentage of remissions and, less often, improvement in survival. Administration of antiandrogens improves the clinical symptoms of patients with benign prostatic hypertrophy, but the exact mechanism of their action requires further investigation. Cutaneous manifestations due to hyperandrogenicity (hirsutism, alopecia, acne) have also been improved by cyproterone acetate, which is often given together with estrogens (reversed sequential regime), by spironolactone or topically applied products. Finally, antiandrogens have been successfully used to treat breast cancer in men, early puberty, hypersexuality and sexual deviations.
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PMID:Clinical applications of antiandrogens. 246 32

Antiandrogens can be used in various androgen-dependent diseases. Depending upon the therapeutic indication, they can be administered systemically or topically. Systemic treatment with an antiandrogen will inhibit androgen action not only in the desired target site but also in all other target tissues; thus, it will block the androgen-dependent feedback regulating the secretion (hypothalamo-pituitary-testis axis) or the action (protein factors) of androgens. In contrast, topical treatment (acting through cutaneous receptors or local metabolism) should not produce systemic side effects especially in man. Pharmacological assays which can select antiandrogens irrespective of the mechanism measure changes in the final androgenic response, but they consume a great deal of time and test compound and bear little relation to therapeutic activity. Therefore, the biological strategy that we report here and which, at Roussel-Uclaf, has led to the selection of a systemic and a topical antiandrogen (RU 23908 and RU 38882) has consisted in successively performing: (1) in vitro assays which measure an effect at a specific level in the mechanism of antiandrogen action, e.g. interaction with the androgen receptor. Assessing interactions with other classes of steroid hormone receptor can be used to predict possible hormonal side-effects, (2) in vitro determinations of agonist or antagonist activity, e.g. in pituitary cells (LH response to LHRH) or mammary tumor cells (induction of androgen-dependent proteins), (3) in vivo antiandrogen assays after a single treatment (induction of mouse kidney proteins, rat prostatic binding protein) or after repeated treatment (inhibition of the growth of rat accessory glands or of hamster sebaceous glands), to determine the active dose of the compound and possibly the absence of systemic effects by the topical route, (4) assays in animal models designed to mimic a therapeutic context e.g. for prostate cancer: inhibition of the "flare-up" effect of LHRH-A or of the trophic effect of perfused adrenal androgens on rat prostate, antitumoral activity in experimental cancer models. For hyperseborrhoea and acne: histological and stereological analysis of rat skin biopsies to measure the volume density of the smooth endoplasmic reticulum vesicles of the differentiating cells of the sebaceous gland.
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PMID:How the study of the biological activities of antiandrogens can be oriented towards the clinic. 305 62

A 65-year-old man who had had acne conglabata since early adult life was treated with buserelin for advanced prostatic cancer. Within 1 month of starting therapy, the inflammatory acne had completely resolved and this coincided with remission of the carcinoma. Gonadotrophin-releasing hormone analogues may be useful in the treatment of resistant acne.
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PMID:Acne conglobata responding to buserelin, a gonadotrophin-releasing hormone analogue. 622 45

Superactive GnRH agonists represent a new class of pharmacologic agents that inhibit reproductive function in both men and women when administered chronically. These hormonal drugs are being tested extensively as both male and female contraceptive agents, as a treatment for prostate cancer, and as a new treatment for idiopathic precocious puberty. Other potential uses include treatment for endometriosis, hirsutism, polycystic ovarian disease, and severe intractable androgen-related acne. This chapter reviews the effects of GnRH agonists on gonadotropin and steroid hormone secretion in both men and women, and assesses the potential of these agents in the varied clinical uses delineated above.
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PMID:Superactive gonadotropin-releasing hormone agonists. 634 74

Thirty-five patients with advanced cancers were treated with estramustine phosphate tablets (Estracyt). Doses ranged between 420 mg and 700 mg daily. One partial response was documented in a hormone resistant prostatic cancer patient. Four minor responses (less than 50% responses, or less than one month more than 50% response) were obtained; one in a hormone resistant prostatic cancer, two in metastatic colorectal cancers; and another in a malignant melanoma. Toxicity phenomena included nausea (9/35 - 25%), water retention (4/35 - 11.5%) and mild elevation of alkaline phosphatase (2/35 - 6%). Other toxicity effects were vaginal bleeding in two women, acne in one woman and mild pruritus in another patient. Myelosuppression and immune suppression were not significantly detected.
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PMID:Oral estramustine phosphate (Estracyt): a broad phase II study. 659 4

5 alpha-Reductase inhibitors are a new class of substances with very specific effects on type I and type II 5 alpha R which may be of use in the treatment of skin disease, such as male pattern baldness, male acne and hirsutism, as well as prostatic hyperplasia and prostate cancer. At least two types of 5 alpha R inhibitors with a different pH optimum have been described. cDNA encoding for both the type I and the type II enzyme has been cloned. Most of the orally effective 5 alpha R inhibitors belong to the class of 4-azasteroids. The radical substituted in the 17 position of the steroid ring seems to be related to species specific variations and to the types of 5 alpha R enzymes in different species and organ systems. 5 alpha R inhibitors lead to a decrease of plasma DHT by about 65% while there is a slight rise in plasma testosterone. The decrease of tissue DHT in the ventral prostate of the intact rat, the dog and in humans is more pronounced and amounts to about 85%. There is a reciprocal rise of tissue T in these systems. The application of an inhibitor of 5 alpha R type II leads to a shrinkage of BPH in men by about 30%. In the rat a similar shrinkage accompanied by a significant decrease of total organ DNA occurs. This decrease, however, is not as pronounced as can be achieved with castration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5 alpha-reductase inhibitors and prostatic disease. 752 99

Cyproterone acetate (CPA) is a synthetic steroid hormone used in the therapy of prostate cancer in men and different forms of acne and hirsutism in women. CPA has been shown by 32P-postlabeling analysis to bind covalently to hepatic DNA of rats in vivo and in vitro. A prerequisite for DNA adduct formation of CPA is metabolic activation of the drug to a reactive intermediate. In the present study bile was collected from [3H]CPA-treated female rats and, following chromatographic separation of bile extracts, fractions of the eluate were examined for the presence of reactive metabolites which were able to form adducts with calf thymus DNA in vitro. The formation of adducts was detected by 32P-postlabeling analysis. One major metabolite of CPA present in the bile extracts was isolated and, following a thorough structural elucidation by mass spectrometry and 1H-NMR, this metabolite was identified as 3 alpha-hydroxy-cyproterone acetate (3 alpha-OH-CPA). This metabolite was able to form the same major adduct in vitro which has been observed before in CPA-treated rats in vivo and in rat hepatocytes in vitro. A number of already known or putative metabolites of CPA were available as authentic standards and these were also examined for their propensity to form adducts in vitro. A positive result was obtained for 3-O-acetyl-cyproterone acetate, which formed the same major adduct as 3 alpha-OH-CPA. However, the presence of this putative metabolite in rat bile could not be demonstrated. Besides 3 alpha-OH-CPA, additional reactive metabolites of CPA were present in the bile extracts, however, since these were only minor components, their chemical structures could not be elucidated.
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PMID:Identification of 3 alpha-hydroxy-cyproterone acetate as a metabolite of cyproterone acetate in the bile of female rats and the potential of this and other already known or putative metabolites to form DNA adducts in vitro. 763 11

Since evidence of 5 alpha-reductase activity in rabbit liver homogenate was discovered in 1954, the presence of this enzyme has been demonstrated in many other organs and tissues of mammalian species. 5 alpha-Reductase selectively transforms a 4-ene-3-oxosteroid (e.g., testosterone) irreversibly to the corresponding 5 alpha-3-oxosteroid (e.g., 5 alpha-dihydrotestosterone) in the presence of NADPH as an essential coenzyme at an optimal pH. However, excessive production of 5 alpha-dihydrotestosterone is the major cause of many androgen-related disorders, such as prostate cancer, benign prostatic hyperplasia, acne, female hirsutism, and male pattern baldness; therefore, inhibition of androgenic action by 5 alpha-reductase inhibitors is a logical treatment. During the past two decades, research has focused on understanding the biological functions and effects of 5 alpha-reductase and its 5 alpha-reduced metabolites: purification of the enzyme, substrates, and metabolites; characterization of their physical, chemical, and biochemical properties; analysis of the amino acid sequence of the enzyme; synthesis of various classes of molecules as potential inhibitors; and examination of the biological activity of the inhibitors in vitro and/or in vivo. This review summarizes the biochemical studies on this enzyme, suggests the mechanisms of action of the enzyme or inhibitors, and discusses the chemistry necessary for the preparation, structure-activity relationships, and in vitro and/or in vivo data obtained from the evaluation of nonsteroidal and steroidal compounds that have been tested as inhibitors of 5 alpha-reductase. In particular, IC50 and Ki values for relevant compounds will be compared according to molecular class. This review could function as a comprehensive working reference of what research has been accomplished so far and what problems remain to be solved in the future for those engaged in this interesting field.
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PMID:The enzyme and inhibitors of 4-ene-3-oxosteroid 5 alpha-oxidoreductase. 767 75


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