Inhibition of 3 beta-hydroxysteroid-dehydrogenase: an approach for prostate cancer treatment?
Over 80% of clinically manifested prostate cancers respond to androgen withdrawal. Several alternatives to castration have been explored. Since a growth promoting role for androstenedione has been suggested, we investigated the effect of inhibition of 3 beta-hydroxy-steroid-dehydrogenase (3 beta-HSD), a key enzyme involved in the biosynthesis of practically all steroids. In a previous study a reduced proliferation rate of androgen responsive R3327-H tumor was demonstrated after in vivo treatment with 17 beta-N,N-diethylcarbamoyl-4-aza-5 alpha-androstan-3-one (4MA) - a putative 5 alpha-reductase inhibitor. In the present investigation 3 beta-HSD enzyme activity derived from human placenta, testis and ovarian cancer cell line and from rat testis was determined using radiolabeled dehydroepiandrosterone (DHEA) or pregnenolone. Among different synthetic compounds known to interfere with steroidogenesis, only 4MA was shown to potently inhibit in vitro 3 beta-HSD activity from all tissue sources. 4MA was administered to male Copenhagen rats bearing R3327-H androgen dependent prostate tumors and levels of different androgens in serum and prostate tumor were measured using reversed phase HPLC and radioimmunoassay. The decreased content of androstenedione in serum and tumor tissue with DHEA accumulation in prostate tumor tissue showed an effective 3 beta-HSD inhibition by 4MA occurring in vivo as well. These observations unequivocally demonstrate a 3 beta-HSD inhibiting effect of 4MA in vitro as well as in vivo and point to a role for androstenedione in the promotion of cell proliferation in androgen sensitive tumors. 3 beta-HSD dependent androstenedione production could thus constitute a proper target -eventually combined with other endocrine treatment - for the treatment of hormone dependent prostate cancer.
Geldof
A A
AA
Department of Endocrinology, Academisch Ziekenhuis Vrije Universiteit, Amsterdam, The Netherlands.
Dijkstra
I
I
Newling
D W
DW
Rao
B R
BR
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology; D003687:Dehydroepiandrosterone / Q000097:blood; D013196:Dihydrotestosterone / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D008297:Male; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy*; D051381:Rats; D013739:Testosterone / Q000097:blood
D001378:Azasteroids; D004791:Enzyme Inhibitors; D013196:Dihydrotestosterone; D013739:Testosterone; D003687:Dehydroepiandrosterone; C031563:17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one; D015096:3-Hydroxysteroid Dehydrogenases