Analysis of susceptibility of carcinogenesis using transgenic rats

利用大鼠模型的优势，其特征在于较大的器官大小，丰富的信息有关preneoplasias和无病毒的宪法，我们已经集中注意力在产生转基因大鼠轴承副本的人c-Ha-ras原癌基因，并显示Hras 128株是非常敏感的乳腺癌的诱导，并在较小程度上，在膀胱，食道和皮肤的病变。在大多数乳腺癌中，存在转基因而非内源性H-ras基因的突变，似乎发生在癌变过程的早期，其涉及癌发生之前的末端芽（TEB）中的细胞增殖和导管内增生。我们最近的一项研究表明，在注射N-甲基-N-亚硝基脲后5天内发生转基因突变，并在30天内观察到癌症发展。此外，虽然肿瘤的发展是独立的内源性卵巢激素，它是抑制大豆异黄酮和促进阿特拉津和壬基酚。虽然机制方面的进一步研究显然是必要的，该模型似乎有很大的潜力，用于筛选目的的修饰剂在乳腺中的活性。

Taking the advantages of rat models characterized by larger organ size, abundant information regarding preneoplasias and virus-free constitution, we have concentrated attention on generation of transgenic rats bearing copies of the human c-Ha-ras proto-oncogene and shown the Hras 128 strain to be extremely sensitive to induction of mammary carcinomas, and to a lesser extent, lesions in the urinary bladder, esophagus and skin. In most of the mammary cancers, mutations of the transgene but not the endogenous H-ras gene are present, appearing to occur early in the process of carcinogenesis, which involves proliferation of cells in terminal end buds (TEBs) and intraductal hyperplasia before carcinomas arise. One of our recent studies demonstrated that mutation in the transgene occurred within 5 days after injection of N-methyl-N-nitrosourea and cancer development was observed within 30 days. Furthermore, while tumor development was independent of endogenous ovarian hormones, it was inhibited by soy isoflavones and promoted by atrazine and nonylphenols. Although further studies of mechanistic aspect are clearly necessary, the model appears to have great potential for screening purposes for modifying agents active in the mammary gland.