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Efficacious Chemoprevention of Primary Prostate Cancer by Flutamide in an Autochthonous Transgenic Model

University of Tennessee Urologic Research Laboratories, Memphis, Tennessee 38163 [S. R., E. K., M. S., M. S. S.], and Department of Cell Biology and Scott Department of Urology, Baylor College of Medicine, Houston, Texas 77030 [N. G.]

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 progression. There is no cure for the advanced disease. Because prostate cancer initially 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) in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of prostate cancer. Three groups of mice received s.c. implantation of slow-release flutamide pellets: (a) low-dose flutamide group (6.6 mg/kg); (b) high-dose flutamide group (33 mg/kg); and (c) control placebo group. Efficacy was measured by the absence of palpable tumor formation. Prostate tissues/tumors were harvested for evaluation by molecular and histology techniques. The low-dose flutamide group did not differ significantly from the placebo group, in which palpable tumors initially presented at 17 weeks of age, and by 33 weeks, all of the animals developed palpable tumors. In the high-dose flutamide group, however, tumors did not appear until 24 weeks, a lag of 7 weeks, and by 34 weeks, 42% of the animals were still tumor free. The period of 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 weeks in the placebo group. The difference between the placebo and high-dose flutamide groups was statistically significant (log rank, P = 0.0036; Wilcoxon’s statistical analysis, P = 0.0060). Tumors from high-dose flutamide-treated animals were more differentiated and retained much of the normal glandular architecture compared with those of the placebo group, whose tumors consisted of sheets of poorly differentiated cells. The expression of T antigen in the prostate tissues of flutamide-treated animals (at 10 weeks age) was lower than that in the comparable placebo-treated group. Flutamide had the ability to suppress T antigen-driven carcinogenesis, resulting in a significant decrease in the incidence of prostate cancer and an increase in the latency period of prostate cancer in TRAMP mice.

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