Takaoka Masaya, Sehata Shinya, Maejima Takanori, Imai Toshio, Torii Mikinori, Satoh Hiroshi, Toyosawa Kaoru, Tanakamaru Zen-yo, Adachi Tamiko, Hisada Shigeru, Ueda Makoto, Ogasawara Hiroyuki, Matsumoto Masahiro, Kobayashi Kiyoshi, Mutai Mamoru, Usui Toshimi
Planning and Promotion Department, New Drug Development Division, Sankyo Co, Ltd, Tokyo, Japan.
Toxicol Pathol. 2003 Mar-Apr;31(2):191-9. doi: 10.1080/01926230390183670.
In order to evaluate a short-term carcinogenicity testing system using CB6F1 -Tg rasH2 (rasH2-Tg) mice carrying a human prototype c-Ha-ras gene, 26-week studies were conducted in 12 different facilities as a part of an International Life Science Institute Health and Environmental Science Institute (ILSI HESI) international collaborative project. In each study N-methyl-N-nitrosourea (MNU) was administered to a separate group of rasH2-Tg mice by single intraperitoneal injection (75 mg/kg) as a positive control. We herein have summarized the mortality, body weight change, and neoplastic and nonneoplastic lesions detected in these positive control groups as representative historical positive control data. Also, we performed an interlaboratory comparison of the response of rasH2-Tg mice to MNU based on the data of 11 positive control groups from these studies. Although the body weight of rasH2-Tg mice showed lower values than that of non-Tgmice during the experimental period, body weight gain in the rasH2-Tg mice was similar to that in non-Tg mice. The mortality of rasH2-Tg mice during the study period was very low, the same as for the non-Tg mice. Incidences of spontaneous alveolar/bronchiolar adenomas and splenic hemangiomas/hemangiosarcomas were also low in the rasH2-Tg mice. Nonneoplastic lesions detected in the rasH2-Tg mice were similar to those in non-Tg mice, excluding the incidence of myopathy. There were interlaboratory differences in mortality and incidence of some lesions in the MNU-treated groups. However, the causes of death were common among the 11 laboratories and almost all the MNU-treated rasH2-Tg mice developed forestomach squamous cell papillomas/carcinomas or malignant lymphomas. This suggests that there is no appreciable difference in the response of the rasH2-Tg mouse to MNU used as a positive control. Therefore, it is concluded that MNU would be an adequate positive control compound in this testing system.
为了评估使用携带人类原型c-Ha-ras基因的CB6F1-Tg rasH2（rasH2-Tg）小鼠的短期致癌性测试系统，作为国际生命科学研究所健康与环境科学研究所（ILSI HESI）国际合作项目的一部分，在12个不同的设施中进行了为期26周的研究。在每项研究中，通过单次腹腔注射（75 mg/kg）将N-甲基-N-亚硝基脲（MNU）给予单独一组rasH2-Tg小鼠作为阳性对照。我们在此总结了这些阳性对照组中检测到的死亡率、体重变化以及肿瘤性和非肿瘤性病变，作为具有代表性的历史阳性对照数据。此外，我们根据这些研究中11个阳性对照组的数据，对rasH2-Tg小鼠对MNU的反应进行了实验室间比较。尽管在实验期间rasH2-Tg小鼠的体重低于非Tg小鼠，但rasH2-Tg小鼠的体重增加与非Tg小鼠相似。研究期间rasH2-Tg小鼠的死亡率非常低，与非Tg小鼠相同。rasH2-Tg小鼠中自发性肺泡/细支气管腺瘤和脾血管瘤/血管肉瘤的发生率也很低。在rasH2-Tg小鼠中检测到的非肿瘤性病变与非Tg小鼠相似，但肌病的发生率除外。MNU处理组在死亡率和某些病变的发生率方面存在实验室间差异。然而，11个实验室的死亡原因是相同的，几乎所有接受MNU处理的rasH2-Tg小鼠都发生了前胃鳞状细胞乳头状瘤/癌或恶性淋巴瘤。这表明rasH2-Tg小鼠对用作阳性对照的MNU的反应没有明显差异。因此，得出结论，MNU在该测试系统中将是一种合适的阳性对照化合物。
