Combined treatment with the 5 alpha-reductase inhibitor PNU 157706 and theantiandrogen flutamide on the Dunning R3327 prostatic carcinoma in rats

The steroid 5 alpha-reductase enzyme catalyzes the conversion of testostero ne to the potent androgen 5 alpha-dihydrotestosterone (DHT). PNU 157706, a novel, potent and selective dual 5 alpha-reductase inhibitor, was reported to be effective in inhibiting the growth of established tumors in the Dunni ng R3327 rat prostatic carcinoma model, We have studied the efficacy of com bined treatment with PNU 157706 and the antiandrogen flutamide in this pros tatic tumor in rats. Rats with tumor diameters of about 1 cm were treated orally 6 days a week f or 9 weeks with PNU 157706 (10 mg/kg per day) alone or in combination with flutamide (1 and 5 mg/kg per day). Animals were kilted 24 h after the last treatment and ventral prostates were removed for testosterone and DHT deter mination. PNU 157706 reduced the growth of established tumors by 36%; flutamide showe d a slight effect at 1 mg/kg per day (24% inhibition), while at the dose of 5 mg/kg per day it reduced tumor growth by 48%, The combination of PNU 157 706 with the lower dose of flutamide caused an additive tumor growth inhibi tion (60%) and the combination with the higher dose of flutamide resulted i n a better inhibition of tumor growth (68%) than did either treatment alone . Castration resulted in marked tumor growth inhibition (76%), Ventral pros tate weight was more markedly reduced by PNU 157706 treatment than by fluta mide; combined treatment was as effective as castration. Prostatic DHT cont ent was markedly reduced by PNU 157706 (93%), whereas prostatic testosteron e increased (137%). Concomitant treatment with flutamide partially antagoni zed the testosterone increase induced by PNU 157706 and did not modify the already considerable suppression of DHT. These data show that the inhibitory effects of PNU 157706 and flutamide on Dunning prostatic tumor growth are additive, thus supporting the rationale of this combination therapy in advanced prostate cancer, in order to achiev e adequate androgen blockade with minimal side-effects.