Response of Rat Ventral Prostate to a New and Novel 5αa-Reductase Inhibitor

Brooks, J. R.; Baptista, Elaine M.; Berman, Charles L.; Ham, Edward A.; Hichens, Martin; Johnston, David B.; Primka, R. L.; Rasmusson, Gary H.; Reynolds, G. F.; Schmitt, S. M.; Arth, Glen E.

doi:10.1210/endo-109-3-830

Cited by 143 publications

(32 citation statements)

References 28 publications

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“…These drugs include 4-azasteroid derivatives, such as 17p8-(N-t-butyl)carbamoyl-4-aza-5a-androst-1-en-3-one Finasteride) and 17/3-(N,N-diethyl)carbamoyl-4-methyl-4-aza-5a-androstan-3-one (4-MA) (8,9), that function as competitive inhibitors ofthe enzyme (10). The exact mechanism by which these compounds act in vivo has not been elucidated, and the development of additional inhibitors of the human steroid 5a-reductase has been hampered by the absence of knowledge of the structure of the protein and by the very low levels of expression of this enzyme, even in androgen-responsive tissues (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

“…The central role played by steroid 5a-reductase and its product dihydrotestosterone in these disorders has been underscored by the development of inhibitors of this enzyme (8) and their recent use as therapeutic agents (9). These drugs include 4-azasteroid derivatives, such as 17p8-(N-t-butyl)carbamoyl-4-aza-5a-androst-1-en-3-one (MK-906, Finasteride) and 17/3-(N,N-diethyl)carbamoyl-4-methyl-4-aza-5a-androstan-3-one (4-MA) (8,9), that function as competitive inhibitors ofthe enzyme (10).…”

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confidence: 99%

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Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases.

Andersson

Russell

1990

Proc. Natl. Acad. Sci. U.S.A.

431

209

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The microsomal enzyme steroid Sa-reductase is responsible for the conversion of testosterone into the more potent androgen dihydrotestosterone. In man, this steroid acts on a variety of androgen-responsive target tissues to mediate such diverse endocrine processes as male sexual differentiation in the fetus and prostatic growth in men. Here we describe the isolation, structure, and expression of a cDNA encoding the human steroid 5a-reductase. A rat cDNA was used as a hybridization probe to screen a human prostate cDNA library. A 2.1-kilobase cDNA was identified and DNA sequence analysis indicated that the human steroid 5a-reductase was a hydrophobic protein of 259 amino acids with a predicted molecular weight of 29,462. A comparison of the human and rat protein sequences revealed a 60% identity. Transfection of expression vectors containing the human and rat cDNAs into simian COS cells resulted in the synthesis of high levels of steroid 5a-reductase enzyme activity. Both enzymes expressed in COS cells showed similar substrate specificities for naturally occurring steroid hormones. However, synthetic 4-azasteroids demonstrated marked differences in their abilities to inhibit the human and rat steroid 5a-reductases.The enzyme steroid 5a-reductase (EC 1.3.99.5) is a microsomal protein that plays a central role in human sexual differentiation and androgen physiology. Interest in this protein arises from several distinguishing characteristics. First, steroid 5a-reductase catalyzes the conversion of testosterone to the more potent androgen dihydrotestosterone (1). This latter steroid induces a program of differentiation during fetal development that leads to the development of the male external genitalia (2). Second, mutations in the gene for steroid 5a-reductase give rise to a rare form of male pseudohermaphroditism in which affected males develop normal internal urogenital tracts but fail to develop external male structures (3). Third, the expression of the gene is regulated by androgens in tissues such as the prostate and liver (4). A fourth distinguishing feature of steroid 5a-reductase is its role in several endocrine abnormalities including benign prostate hyperplasia, male pattern baldness, acne, and hirsutism (5-7).The central role played by steroid 5a-reductase and its product dihydrotestosterone in these disorders has been underscored by the development of inhibitors of this enzyme (8) and their recent use as therapeutic agents (9). These drugs include 4-azasteroid derivatives, such as 17p8-(N-t-butyl)carbamoyl-4-aza-5a-androst-1-en-3-one Finasteride) and 17/3-(N,N-diethyl)carbamoyl-4-methyl-4-aza-5a-androstan-3-one (4-MA) (8,9), that function as competitive inhibitors ofthe enzyme (10). The exact mechanism by which these compounds act in vivo has not been elucidated, and the development of additional inhibitors of the human steroid 5a-reductase has been hampered by the absence of knowledge of the structure of the protein and by the very low levels of expression of this enzyme, even in androgen-r...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases.

Andersson

Russell

1990

Proc. Natl. Acad. Sci. U.S.A.

431

209

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“…However, the role of 5a-reductase in sexual differentiation of the brain is not clear. Recently 5a-reductase has been shown to be dramatically inhibited by 4-aza-steroids in vivo [6] and in vitro [22], Administration of these compounds to pregnant rats causes the development of male pseudohermaphroditic pups [16], We undertook a study to understand the role of 5a-reduced steroids in sex ual differentiation of coital behavior and the hypothalamo pituitary axis of the guinea pig by administering a 4-azasteroid to pregnant animals during the critical period of sex ual differentiation of the fetal guinea pig brain.…”

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confidence: 99%

Role of Steroid 5α-Reductase Activity in Sexual Differentiation of the Guinea Pig

Connolly

Resko²

1989

Neuroendocrinology

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The possible role of 5α-reduction of steroids in the sexual differentiation of guinea pigs was determined by treating pregnant guinea pigs with a 5α-reductase activity (5αRA) inhibitor (17β-N, N-diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one, 4MA, 10 mg/day) from day 30 to 55 of gestation. 5αRA in fetal diencephalon tissue obtained from 4MA-treated mothers on day 55 of gestation was suppressed compared to that of control tissue. Four litters receiving 4MA were carried to term along with an equal number of litters receiving the vehicle alone. Males that received 4MA in utero (n = 6) had altered external genitalia, i.e., hypospadias and reduced anogenital distances, but their adult copulatory behavior did not differ from that of controls (n = 7). In order to evaluate treatment effects on the hypothalamic-pituitary axis, all animals were challenged with estradiol benzoate (EB, 10 µg in oil, s.c.) 2 weeks after gonadectomy. Serial plasma samples were obtained and analyzed for luteinizing hormone (LH) using an heterologous radioimmunoassay. Control females (n= 13) and 4MA-treated females (n = 5) released LH in surge quantities about 42 h after EB treatment. Plasma from 4MA-treated females differed from controls in that it contained greater overall quantities of LH (p < 0.05) and greater amounts at the time of the LH surge (p < 0.05). Regardless of treatment males did not respond to EB. However, 4MA-treatment appeared to blunt the post-castration rise in LH since control plasma (n = 7) contained significantly more LH (p < 0.05) compared to plasma obtained from 4MA-treated animals (n = 6). These data suggest that 5α-reduction of testosterone is not required for androgenization of the male brain but is needed for normal development of external genitalia. The data also suggest that 5α-reduced steroids exert developmental effects on female fetuses since inhibition of 5αRA in fetal life renders them more responsive to the positive feedback action of EB.

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“…seminal vesicles and epididymis) rely primarily on T (Wilson, 1989). Brooks et al ( 1981 ) first demonstrated the attenuating effect of 5a-reductase inhibitors on ventral prostate growth. During such treatment, intaprostatic levels of DHT are decreased, whereas those of T are increased.…”

Section: Discussionmentioning

confidence: 99%

The effect of finasteride on the prostate gland in men with elevated serum prostate-specific antigen levels

Côté

Skinner²,

Salem³

et al. 1998

Br J Cancer

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Summary Prostate cancer is a disease associated with androgens. It has been hypothesized that reducing the conversion of testosterone (T) to dihydrotestosterone (DHT) in the prostate by the use of the drug finasteride. a 5a-reductase inhibitor, will reduce the incidence of prostate cancer. We investigated the chemopreventive potential of finasteride by evaluating its effect on the prostate gland of men with elevated serum prostate-specific antigen (PSA). Fifty-two men with elevated PSA and prostate sextant biopsies negative for cancer were randomized to receive finastende 5 mg day-, (27 patients) or no medication (25 patients) for 12 months and were rebiopsied at 12 months.The biopsies were evaluated for the presence of cancer, the proportion of glandular and hyperplastic tissue, and the presence of high-grade prostatic intraepithelial neoplasia (PIN). Epithelial proliferation was assessed in the prestudy and 12-month biopsies by immunohistochemistry using antibody to proliferating cell nuclear antigen (PCNA). Serum blood samples were drawn at baseline and after 1. 3, 6 and 12 months of study. In the control group, serum levels of PSA and T were unchanged throughout the 12 months. In the finastende group, PSA decreased 48°o (P < 0.001), DHT decreased 670o (P < 0.001) and T increased 21 0°(P < 0.001). Histological evaluation of prestudy and 12-month biopsy specimens revealed that the finasteride group had a 300% reduction in the percentage of hyperplastic epithelial tissue (P = 0.002). although this decrease was not statistically significantly different between the finasteride and control groups (P = 0.11). In patients with PIN on prestudy biopsy, no change occurred in the PIN lesions with finasterde treatment. Finasteride also had no effect on the proliferation index of prostatic epithelial cells. Of the 27 patients treated with finastende, eight (309O) had adenocarcinoma of the prostate detected on the 12-month biopsy. compared with one (40o) of the control patients (P = 0.025). In the treatment group, six cancers occurred in the eight patients with PIN on the prestudy biopsy: in the observation group no cancers were detected in the five patients with PIN on the prestudy biopsy (P= 0.021). Two cancers occurred in the 19 men in the treatment group with no evidence of PIN on the prestudy biopsy. compared with one cancer in the 20 men in the observation group with no evidence of PIN on the prestudy biopsy (P = 0.60). This study, using a novel model for evaluating short-term efficacy of chemopreventive or therapeutic agents in men at high nsk of prostate cancer. provides little evidence that finasteride is an effective chemopreventive agent for prostate cancer in men with elevated PSA. Keywords: finastende: prostate carcinoma: intraepithelial neoplasia: proliferation Carcinoma of the prostate is the most frequentl diagnosed cancer in the US. Although the most important risk factor for prostate cancer is age (Ross et al. 1979). there is also profound -ariation in incidence between different racial groups in the US....

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Response of Rat Ventral Prostate to a New and Novel 5αa-Reductase Inhibitor

Cited by 143 publications

References 28 publications

Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases.

Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases.

Role of Steroid 5α-Reductase Activity in Sexual Differentiation of the Guinea Pig

The effect of finasteride on the prostate gland in men with elevated serum prostate-specific antigen levels

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