INTRAVENOUS VS INTRAPROSTATIC ADMINISTRATION OF N-METHYL-N-NITROSOUREA TO INDUCE PROSTATE-CANCER IN RATS

To develop an improved model of human prostate cancer, 16-wk-old Wista r rats were treated orally for 18 days with the antiandrogen, flutamid e (50 mg/kg body weight [BW]/day), followed by 3 days of s.c. testoste rone (100 mg/kg BW). These were the only treatments the control animal s received (Group 1, n = 10). On the day after the third testosterone injection, N-methyl-N-nitorsourea (MNU) was administered via the tail vein at a dose of 50 mg/kg BW (Groups 2, n = 40 and 3, n = 20); in som e rats, a second dose was delivered by the same route 22 wk later (Gro up 3). A smaller dose of MNU (15 mg/kg BW) was administered intraprost atically (Group 4, n = 20) to a fourth group. In Groups 2, 3, and 4, s ilastic capsules containing testosterone were implanted s.c. approxima tely every 6 wk beginning 1 wk post-MNU. Accessory sex gland tumors ar ose in MNU-treated rats in Group 2 (12/40, 30%), Group 3 (8/20, 40%), and Group 4 (8/20, 40%); 90% were macroscopic (25/28). There were no n eoplasms in these organs in the control rats (Group 1, 0/10). These ac cessory sex gland neoplasms were adenocarcinomas or undifferentiated c arcinomas which appeared to be derived from the prostate based on loca tion and histological characteristics, although the size and spread of some of the tumors Precluded definitive localization of the tissue of origin. The incidence of these neoplasms was similar in rats given a single dose of MNU intraprostatically or two doses of MNU i.v., but th e animals treated intraprostatically maintained higher body weights an d developed fewer extraneous tumors. The average (+/- SD) latent perio d for clinical or postmortem detection of prostate neoplasia after MNU was shortest in the rats given two i.v. doses (39 +/- 3 wk) compared with the single i.v. dose (45 +/- 6 wk) or an intraprostatic dose (56 +/- 7 wk). In 57% of the cases (16/28), the prostate tumors metastasiz ed to distant sites. An activating point mutation was detected in codo n 12 of the Ki-ras oncogene in the MNU-induced primary prostate tumors (8/10 examined), and metastases arising from these prostate tumors (2 /3) but was absent in normal prostate tissue (0/6). This study demonst rates that two systemic doses of MNU increase the incidence and decrea se the latency of prostate neoplasms compared with a single dose, and that a single dose of MNU injected intraprostatically induces prostate adenocarcinoma without many of the other tumors and weight loss typic ally found after i.v. administration. (C) 1996 Wiley-Liss, Inc.