Estracyt (Estradiol-3N-Bis- (2-chloroethyl) -Carbamate-17β-phosphate), a conjugate of estradiol-17β and nitrogen mustard, has been reported to be used successfully in the treatment of advanced prostatic cancer. In this paper we investigated the mechanism of this compound and the following results were obtained.
1. Estracyt had strong antiprostatic effect in male rats (reduction of prostatic weights and nucleic acid contents). Equivalent amounts of the two main components of Estracyt, nitrogen mustard and estradio1-17β-phosphate, were not able to mimic this antiprostatic effect of Estracyt.
2. A dose of 100 mg of Estracyt per kg of body weight injected intraperitoneally daily for 4 days revealed antiandrogenic effect. On the other hand, equivalent amounts of the two main components of Estracyt were not able to show any antiandrogenic effect at all.
3. Administration of Estracyt to intact rats for 7 days significantly reduced serum gonadotropins levels.
4. In order to clarify the mechanism of direct effect of Estracyt, we performed some experiments, using
3H-Estramustine of high specific activity. The following results were obtained.
a)
3H-radioactivity was accumulated selectively in the ventral prostate of castrated male rat after the administration of
3H-Estramustine. Estramustine and its metabolites were retained in the ventral prostate for longer time.
b) The uptake of
3H-radioactivity was found almost in the cytosol fraction and not in the purified nuclei fraction at all. These results strongly suggested that there existed the mechanism of retention of Estramustine and its metabolites in the cytosol of rat ventral prostate.
c) The sucrose density gradient analysis showed that Estramustine binding protein in the cytosol of ventral prostate have sedimentation coefficient of 3 to 4 S.
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