Effect of castration, DES, flutamide, and the 5 alpha-reductase inhibitor, MK-906, on the growth of the Dunning rat prostatic carcinoma, R-3327.
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.
Brooks
J R
JR
Merck Sharp & Dohme Research Laboratories, Rahway, NJ 07065.
Berman
C
C
Nguyen
H
H
Prahalada
S
S
Primka
R L
RL
Rasmusson
G H
GH
Slater
E E
EE
D058891:5-alpha Reductase Inhibitors; D000728:Androgens / Q000032:analysis; D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D001378:Azasteroids / Q000494:pharmacology*; D004054:Diethylstilbestrol / Q000494:pharmacology*; D018120:Finasteride; D005485:Flutamide / Q000494:pharmacology*; D008297:Male; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000473:pathology*; D051381:Rats; D011916:Rats, Inbred F344
D058891:5-alpha Reductase Inhibitors; D000728:Androgens; D000736:Androstenes; D001378:Azasteroids; D018120:Finasteride; D004054:Diethylstilbestrol; D005485:Flutamide