Schleicher R L, Fallon M T, Austin G E, Zheng M, Zhang M, Dillehay D L, Collins D C
Medical Research Service, Veterans Affairs Medical Center (Atlanta), Decatur, GA 30033, USA.
Prostate. 1996 Jan;28(1):32-43. doi: 10.1002/(SICI)1097-0045(199601)28:1<32::AID-PROS5>3.0.CO;2-Q.
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), followed by 3 days of s.c. testosterone (100 mg/kg BW). There 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.
为建立改良的人类前列腺癌模型，16周龄的Wistar大鼠口服抗雄激素药物氟他胺（50毫克/千克体重/天），持续18天，随后皮下注射睾酮（100毫克/千克体重），持续3天。这是对照动物（第1组，n = 10）接受的唯一处理。在第三次注射睾酮后的第二天，通过尾静脉给予N-甲基-N-亚硝基脲（MNU），剂量为50毫克/千克体重（第2组，n = 40；第3组，n = 20）；在一些大鼠中，22周后通过相同途径给予第二剂（第3组）。向第四组大鼠前列腺内注射较小剂量的MNU（15毫克/千克体重）（第4组，n = 20）。在第2组（12/40，30%）、第3组（8/20，40%）和第4组（8/20，40%）接受MNU处理的大鼠中出现了附属性腺肿瘤；90%为肉眼可见肿瘤（25/28）。对照大鼠（第1组，0/10）的这些器官中未出现肿瘤。这些附属性腺肿瘤为腺癌或未分化癌，根据位置和组织学特征，似乎起源于前列腺，尽管一些肿瘤的大小和扩散情况使起源组织的精确定位难以确定。前列腺内注射单剂量MNU或静脉注射两剂量MNU的大鼠中，这些肿瘤的发生率相似，但前列腺内注射的动物体重维持较高水平，出现的无关肿瘤较少。与静脉注射单剂量（45 +/- 6周）或前列腺内剂量（56 +/- 7周）相比，静脉注射两剂量MNU后，大鼠临床或死后检测到前列腺肿瘤的平均（+/-标准差）潜伏期最短（39 +/- 3周）。在57%的病例（16/28）中，前列腺肿瘤转移至远处部位。在MNU诱导的原发性前列腺肿瘤（检查的10例中有8例）及其转移灶（3例中有2例）中检测到Ki-ras癌基因第12密码子的激活点突变，但在正常前列腺组织中未检测到（0/6）。本研究表明，与单剂量相比，两剂全身给药的MNU可增加前列腺肿瘤的发生率并缩短潜伏期，且前列腺内注射单剂量MNU可诱导前列腺腺癌，而不会出现静脉注射后通常出现的许多其他肿瘤和体重减轻情况。
