Efficacious chemoprevention of primary prostate cancer by flutamide in an autochthonous transgenic model

Although the etiology of prostate cancer is still not clear, family history , hormones, and age are thought to play a role in its initiation and progre ssion. There is no cure for the advanced disease. Because prostate cancer i nitially develops as an androgen-dependent tumor, agents with antiandrogen activity have become the focus for chemoprevention of this disease. A pilot study was undertaken to test the efficacy of flutamide (an antiandrogen) i n the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of pros tate cancer. Three groups of mice received s.c. implantation of slow-releas e flutamide pellets: (a) tow-dose flutamide group (6.6 mg/kg); (b) high-dos e flutamide group (33 mg/kg); and (c) control placebo group. Efficacy was m easured by the absence of palpable tumor formation. Prostate tissues/tumors were harvested for evaluation by molecular and histology techniques. The l ow-dose flutamide group did not differ significantly from the placebo group , in which palpable tumors initially presented at 17 weeks of age, and by 3 3 weeks, all of the animals developed palpable tumors. In the high-dose flu tamide group, however, tumors did not appear until 24 weeks, a lag of 7 wee ks, and by 34 weeks, 42% of the animals were still tumor free. The period o f time at which 50% of the animals had tumors was 33 weeks in the high-dose flutamide group, 24.5 weeks in the low-dose flutamide group, and 24.5 week s in the placebo group. The difference between the placebo and high-dose fl utamide groups was statistically significant (log rank, P = 0.0036; Wilcoxo n's statistical analysis, P = 0.0060). Tumors from high-dose flutamide-trea ted animals were more differentiated and retained much of the normal glandu lar architecture compared with those of the placebo group, whose tumors con sisted of sheets of poorly differentiated cells. The expression of T antige n in the prostate tissues of flutamide-treated animals (at 10 weeks age) wa s lower than that in the comparable placebo-treated group. Flutamide had th e ability to suppress T antigen-driven carcinogenesis, resulting in a signi ficant decrease in the incidence of prostate cancer and an increase in the latency period of prostate cancer in TRAMP mice.