Male rats bearing implants of the Dunning rat prostatic
carcinoma, R-3327, were used in a 42-day study to determine the effect of
castration or orally administered
flutamide (FL), DES (
diethylstilbestrol) or the
5 alpha-reductase inhibitor,
MK-906, on the growth of this
androgen-responsive
cancer. The rate of growth and final weights of the
tumor and the ventral prostate (VP) were all reduced (P less than 0.05) by
castration.
Flutamide (25 mg/kg/day) significantly decreased
tumor and VP weights in intact rats and castrates given 100 micrograms/day (SC) of
testosterone propionate (TP) or
dihydrotestosterone propionate (DHTP). It also significantly retarded
tumor growth rate in TP- or DHTP-treated castrates and was marginally effective in intact animals. DES (100 micrograms/kg/day) reduced (P less than 0.05)
tumor and VP weights of intact rats but did not significantly affect
tumor growth rate or weight in castrates given TP or DHTP. These results indicated that the effect of DES on
tumor growth is caused by its inhibition of the secretion or release of the
gonadotropins necessary for testicular
androgen production.
MK-906 (25 mg/kg/day) affected neither the gross nor the histomorphology of the
tumor in intact rats or castrates given TP or DHTP. Further, it caused no histological changes in the testes of intact rats. It did, however, significantly reduce VP weight in intact animals and TP-treated castrates but not in those given DHTP. This illustrates that the anti-androgenicity of
MK-906 stems from its inhibition of DHT formation. The failure of
MK-906 to influence
tumor growth in the TP-treated castrates strongly suggests that the R-3327
tumor can respond to
testosterone directly. If that is true, then its growth is unlikely to be affected by a pure
5 alpha-reductase inhibitor such as
MK-906. In ancillary experiments,
tumors from MK-906-treated animals were found to have reduced levels of DHT and, when assayed in vitro, to have a reduced capacity to convert [3H]-T to [3H]-DHT.