Morton Daniel, Alden Carl L, Roth Arthur J, Usui Toshimi
Pharmacia Corporation, Skokie, IL 60077, USA.
Toxicol Pathol. 2002 Jan-Feb;30(1):139-46. doi: 10.1080/01926230252824851.
The Tg rasH2 transgenic mouse has been developed as an altemative to the lifetime mouse bioassay to predict the carcinogenic potential of chemicals. Unlike the p53+/- mouse, the Tg rasH2 mouse is sensitive to both genotoxic and nongenotoxic carcinogens. The Tg rasH2 mouse, officially designated CB6F1-TgN (RasH2), contains multiple copies of the human c-Ha-ras oncogene and promoter within its genome. These mice develop spontaneous andchemically inducedneoplasms earlierin life and in greaternumbersthan wild-type mice, reflectingtheirenhanced sensitivity to neoplasia. The most common spontaneous neoplasms in control Tg rasH2 mice 8 to 9 months of age are lung adenomas and carcinomas (7.4% incidence), splenic hemangiomas and hemangiosarcomas (5.4%), forestomach squamous cell papillomas and carcinomas (2.4%), and skin neoplasms (1.2%). Simulations have demonstrated that 20 to 25 mice/sex/treatment group are required to provide the assay with adequate statistical power. Four of 6 known or suspected human carcinogens tested in Tg rasH2 mice were positive in this assay. For 19 nonmutagenic agents testing positive in conventional rodent bioassays, 7 chemicals were positive, 10 chemicals were negative, and 2 were equivocal. None of the 10 nonmutagenic rodent carcinogens that were negative in the Tg rasH2 mouse model are considered to be human carcinogens. All nonmutagenic chemicals that were negative in the conventional rodent bioassays were also negative in the Tg rasH2 model. Results for 15 of 18 mutagenic chemicals tested in Tg rasH2 mice agreed with the results of conventional rodent bioassays, and 3 results were equivocal. The Tg rasH2 mouse model appears to predict known or suspected human carcinogens as well as the traditional mouse bioassay, but with fewer positive results for nongenotoxic compounds that are not considered human carcinogens. The Tg rasH2 mouse model is the most thoroughly tested in vivo altemative to the lifetime mouse bioassay for nongenotoxic compounds administered by oral or parenteral routes. The U.S. FDA Carcinogenicity Assessment Committee has determined that the Tg rasH2 model has been adequately evaluated for consideration for carcinogenicity testing of pharmaceutical candidates and its use could contribute to the weight of evidence for carcinogenicity assessment. The FDA will consider proposals to replace lifetime mouse carcinogenicity studies with 6-month Tg rasH2 mouse studies to support pharmaceutical registration on a case-by-case basis.
Tg rasH2转基因小鼠已被开发出来，作为预测化学物质致癌潜力的终生小鼠生物测定法的替代方法。与p53+/-小鼠不同，Tg rasH2小鼠对基因毒性和非基因毒性致癌物均敏感。Tg rasH2小鼠，官方命名为CB6F1-TgN (RasH2)，其基因组中含有多个拷贝的人类c-Ha-ras癌基因和启动子。这些小鼠在生命早期比野生型小鼠更容易发生自发和化学诱导的肿瘤，数量也更多，这反映了它们对肿瘤形成的敏感性增强。8至9个月大的对照Tg rasH2小鼠中最常见的自发肿瘤是肺腺瘤和癌（发病率7.4%）、脾血管瘤和血管肉瘤（5.4%）、前胃鳞状细胞乳头瘤和癌（2.4%）以及皮肤肿瘤（1.2%）。模拟结果表明，每个性别/处理组需要20至25只小鼠才能为该测定提供足够的统计效力。在Tg rasH2小鼠中测试的6种已知或疑似人类致癌物中有4种在此测定中呈阳性。对于在传统啮齿动物生物测定中呈阳性的19种非诱变剂，7种化学物质呈阳性，10种化学物质呈阴性，2种结果不明确。在Tg rasH2小鼠模型中呈阴性的10种非诱变啮齿动物致癌物均不被认为是人类致癌物。在传统啮齿动物生物测定中呈阴性的所有非诱变化学物质在Tg rasH2模型中也呈阴性。在Tg rasH2小鼠中测试的18种诱变化学物质中有15种的结果与传统啮齿动物生物测定的结果一致，3种结果不明确。Tg rasH2小鼠模型似乎与传统小鼠生物测定一样能够预测已知或疑似人类致癌物，但对于不被认为是人类致癌物的非基因毒性化合物，阳性结果较少。对于通过口服或肠胃外途径给药的非基因毒性化合物，Tg rasH2小鼠模型是对终生小鼠生物测定进行最全面测试的体内替代方法。美国食品药品监督管理局（FDA）致癌性评估委员会已确定，Tg rasH2模型已得到充分评估，可用于药物候选物的致癌性测试，其使用有助于为致癌性评估提供证据权重。FDA将逐案考虑用6个月的Tg rasH2小鼠研究取代终生小鼠致癌性研究以支持药物注册的提议。
