Intravenous vs. intraprostatic administration of N-methyl-N-nitrosourea to induce prostate cancer in rats

Abstract

To develop an improved model of human prostate cancer, 16‐wk‐old Wistar rats were treated orally for 18 days with the antiandrogen, flutamide (50 mg/kg body weight[BW]/day), weight followed by 3 days of s.c. testosterone (100 mg/kg BW). These were the only treatments the control animals 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 some rats, a second dose was delivered by the same route 22 wk later (Group 3). A smaller dose of MNU (15 mg/kg BW) was administered intraprostatically Group 4, n = 20) to a fourth group. In Groups 2, 3, and 4, silastic capsules containing testosterone were implanted s.c. approximately every 6 wk beginning 1 wk post‐MNU. Accessory sex gland tumors arose 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 neoplasms in these organs in the control rats (Group 1, 0/10). These accessory sex gland neoplasms were adenocarcinomas or undifferentiated carcinomas which appeared to be derived from the prostate based on location 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 the animals treated intraprostatically maintained higher body weights and developed fewer extraneous tumors. The average (± SD) latent period 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 metastasized to distant sites. An activating point mutation was detected in codon 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 demonstrates that two systemic doses of MNU increase the incidence and decrease 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 typically found after i.v. administration. © 1995 Wiley‐Liss, Inc.

Quantitative and immunohistochemical evaluation of PCNA, androgen receptors, apoptosis, and Glutathione-S-Transferase P1 on preneoplastic changes induced by cadmium and zinc chloride in the rat ventral prostate

“…wiley.com.] other carcinogenic agents [8,30,31]. The lesions observed were histologically similar to those described as atypical hyperplasia induced in rats by treatment with phenylephrine [32].…”

Multiple pathways of prostate carcinogenesis analyzed by using cultured cells isolated from rats treated withN-methyl-N-nitrosourea and testosterone

“…This study con®rmed that a high proportion of prostate carcinomas induced in rats by the direct-acting methylating carcinogen MNU and subsequent chronic testosterone treatment carried the activating G 35 3 A mutation in the Ki-ras proto-oncogene observed in previous studies, but no mutations were detected in codon 12 of the Ha-ras gene [17,19]. This study further demonstrated that frequency of the Ki-ras mutation was similar in tumors induced in different rat strains, regardless of the substantial differences in sensitivity among these strains to the induction of prostate cancer by MNU and testosterone.…”

“…We previously reported that approximately 75% of prostate carcinomas induced in Wistar rats by MNU and subsequent chronic testosterone treatment carry an activating G 35 3 A mutation at the second position of codon 12 of the Ki-ras proto-oncogene [17], which was con®rmed by Schleicher et al [19]. We hypothesized that there are at least two molecular pathways of tumor induction by MNU in the rat prostate, the predominant one of which involves activation of the Ki-ras protooncogene [17].…”

Human prostate cancer risk factors

“…Cancer developed commonly in Wistar rats that were treated by sequential chemical castration, stimulation, and MNU exposure. MNU‐induced prostate/accessory sex gland adenocarcinoma or poorly differentiated carcinoma contained activating mutations in codon 12 of the Ki‐ras oncogene in 80% of primary tumors and in 66% of metastases 633…”