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.