Combined treatment of Dunning R3327 rat prostatic tumor with the 5α-reductase inhibitor PNU 157706 and the antiandrogen bicalutamide

PNU 157706 [N-(1,1,1,3,3,3-hexafluorophenylpropyl)-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide], a novel, potent and selective dual Sa-reductase inhibitor, was reported to be effective in inhibiting the growth of established tumors in the Dunning R3327 rat prostatic carcinoma model. Purpose: We investigated the efficacy of treatment with PNU 157706 in combination with the antiandrogen bicalutamide in this prostatic tumor model. Methods: Rats with tumor diameters of about 1 cm were treated orally 6 days a week for 9 weeks with PNU 157706 (10 mg/kg per day) alone or in combination with bicalutamide (0.2 and 1 mg/kg per day). Animals were killed 24 h after the last treatment, and ventral prostates were removed for testosterone (T) and dihydrotestosterone (DHT) determination. Results: PNU 157706 reduced the growth of established tumors by 39%; bicalutamide proved ineffective at 0.2 mg/kg per day, but reduced tumor growth by 45% at a dose of 1 mg/kg per day. The combination of PNU 157706 with both doses of bicalutamide caused an additive tumor growth inhibition (50% and 64%). Castration resulted in marked tumor growth inhibition (72%). Ventral prostate weight was markedly reduced by PNU 157706 (78%) treatment and by bicalutamide (59% and 77%); combined treatment was as effective as castration. Prostatic DHT content was markedly reduced by PNU 157706 (88%), whereas prostatic T increased slightly (60%). Concomitant treatment with bicalutamide antagonized the T increase induced by PNU 157706 and did not modify the already remarkable suppression of DHT. Conclusions: These data show that the inhibitory effect of PNU 157706 and bicalutamide on Dunning prostatic tumor growth is additive, thus suggesting a possible role of PNU 157706 in the therapy of advanced prostate cancer, in combination with antiandrogens, to provide an effective peripheral androgen ablation therapy with minimal side effects.