Testosterone-induced DNA synthesis in cultured rat ventral prostate: effects of estracyt and its derivatives

Abstract

Summary Testosterone-induced DNA synthesis in cultured rat ventral prostate was used to compare the direct effects of EstracytR and EmcytR with that of their metabolite, estramustine, and their carrier-hormone, oestradiol-17/ on prostatic growth. In serum-supplemented medium (5-20% FCS), all the compounds were equally effective in suppressing testosterone stimulated DNA synthesis which was reduced by between 40-50%, whereas in serum-free medium the estramustine compounds were consistently less effective than oestradiol-17,B. In the presence of 4 x 10 -9M testosterone in serum-free medium, stimulated DNA synthesis was reduced by 15-30% following incubation with 4 x 10-7 M of EstracytR, EmcytR and estramustine and by 60% with 4 x 10-7 M oestradiol-17f3. Thus, none of the estramustine compounds appear to offer any selective advantage over that of oestradiol-17/1 in suppressing prostatic DNA synthesis at the target tissue level.Prostatic cancer is the most common malignancy of the male urogenital tract and a leading cause of death due to cancer in aging men (Chisholm, 1981;Flanders, 1984 (Tew, 1983;Hoisaeter, 1984).In both the rat (Plym-Forshell & Nilsson, 1974;Hoisaeter, 1976aHoisaeter, , 1977 Hoisaeter & Bakke, 1983) and man (PlymForshell et al., 1976;Sandberg, 1983), Estracyt is rapidly dephosphorylated to yield estramustine and its dehydrogenated counterpart, estromustine. These metabolites are selectively retained in the prostate by interactions with estramustine binding protein (Forsgren et al., 1979(Forsgren et al., , 1981Bjork et al., 1982) and subsequent intracellular hydrolysis of these compounds slowly liberates free nitrogen mustard and oestrogen moieties. However, the question remains whether the antiprostatic actions of Estracyt are mediated by the oestrogen moiety, the nitrogen mustard moiety or the intact drug complex itself.While in vivo studies have shown that Estracyt is a more potent inhibitor of rat prostatic DNA synthesis than either its hormone or cytostatic parts (Hoisaeter, 1976b(Hoisaeter, , 1977, such comparisons are limited by the extensive metabolism of Estracyt in vivo. Thus, in the present study, an in vitro model of induced DNA synthesis in cultured rat ventral prostate (Mistry et al., 1982;Buchanan & Riches, 1985, 1986

Anti‐androgenic effects of Win 49,596 on development of the neonatal mouse bulbourethral gland in culture

“…The inhibition of androgen-induced BUG growth by Win 49,596 is comparable to previous reports of the effects of anti-androgens in organ culture. For example, Buchanan and Riches [21] showed that a 100-fold excess of cyproterone acetate decreased iododeoxyuridine uptake by 50% in cultured prostate. A 100-fold excess of cyproterone acetate or flutamide decreased prostatic acid phosphatase activity to one third of normal T-stimulated levels in vitro [22], while a 50-fold excess of cyproterone acetate decreased the growth of developing prostatic ducts in cultured urogenital sinus by 50% [12].…”