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. Si nce a growth promoting role for androstenedione has been suggested, we investigated the effect of inhibition of 3 beta-hydroxy-steroid-dehyd rogenase (3 beta-HSD), a key enzyme involved in the biosynthesis of pr actically all steroids. In a previous study a reduced proliferation ra te 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 inv estigation 3 beta-HSD enzyme activity derived fr om human placenta tes tis and ovarian cancer cell line and fram rat testis was determined us ing 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 f rom all tissue sources. 4MA was administered ed to male Copenhagen rat s bearing R3327-H androgen dependent prostate tumors and levels of dif ferent androgens in serum and prostate tumor were measured using rever sed phase HPLC and radioimmunoassay. The decreased content of androste nedione in serum and tumor tissue with DHEA accumulation in prostate t umor tissue showed an effective 3 beta-HSD inhibition by 4MA occurring in vivo as well. These observations unequivocally demonstrate a 3 bet a-HSD inhibiting effect of 4MA in vitro as well as in vivo and point t o a role for androstenedione in the promotion of cell proliferation in androgen sensitive tumors. 3 beta-HSD dependent androstenedione produ ction could thus constitute a proper target - eventually combined with other endocrine treatment - for the treatment of hormone dependent pr ostate cancer.