Additive in vivo growth-inhibitory effects of flutamide and finasteride on androgen-sensitive Shionogi 115 carcinoma

The antiandrogen flutamide and the 5 alpha-reductase inhibitor finasteride were administered twice daily at a dose of 1 mg alone or in combination in mice bearing androgen-sensitive Shionogi tumors, a model predictive of androgen-sensitive prostate cancer in men. Intact or orchiectomized animals were supplemented with an implant of androstenedione in order to mimic the contribution of androgens of adrenal origin in men. Treatment for 20 days with flutamide alone caused 28% and 36% decreases in tumor size and prostatic weight respectively, whereas finasteride alone caused 18% and 16% inhibitions of the same parameters. On the other hand, combination of the two compounds inhibited the value of the same parameters by 43% and 58%. In orchiectomized animals also implanted with androstenedione, flutamide alone caused 35% and 39% decreases in tumor growth and prostatic weight respectively, whereas finasteride alone caused respective 27% and 15% inhibitions, and combination treatment caused 53% and 61% inhibitions in tumor growth and prostatic weight respectively. The present data show that the inhibitory effects of flutamide and finasteride on Shionogi tumor and prostate growth are nearly additive or additive respectively, and suggest that such a combination of the two compounds could provide the basis for further improvement of the endocrine therapy of prostate cancer and induce the maximal degree of apoptosis or cancer cell death. The limited efficacy of the 5 alpha-reductase inhibitor alone resulting from the increased intratumoral testosterone concentrations can be regained by the antiandrogen, thus permitting complementary action of the two compounds. The present data also show that the maximal inhibitory effects are achieved with the triple combination of castration, a pure antiandrogen, and a 5 alpha-reductase inhibitor.