Analysis of susceptibility of carcinogenesis using transgenic rats

转基因大鼠致癌易感性分析

• 批准号: 12213152
• 负责人: TSUDA Hiroyuki
• 金额: $ 27.84万
• 依托单位: Nagoya City University (2003-2004)National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East (2000-2002)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12213152/
• 关键词: Ras; transgenic rat; conditional; mammary gland; carcinogenesis; TEB; ras; 膵管発がん; 乳腺発がん; 組織発生; 乳線発がん; 腺房; 筋上皮; 乳頭; ヒトプロト型c-Ha-ras遺伝子; 高発がん感受性; 膀胱; 食道; Terminal endbud; 発がん物質中期検索法; 皮膚

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.

利用大鼠模型的器官体积较大、关于癌前病变的信息丰富和无病毒构成的特点，我们将注意力集中在携带人c-Ha-ras原癌基因拷贝的转基因大鼠的产生上，结果表明，HRAS 128株对诱发乳腺癌非常敏感，对膀胱、食道和皮肤的病变也不太敏感。在大多数乳腺癌中，存在转基因而不是内源性H-ras基因的突变，似乎发生在癌变过程的早期，这涉及到末端芽(TEB)细胞的增殖和癌变前的导管内增生。我们最近的一项研究表明，注射N-甲基-N-亚硝脲后5天内发生转基因突变，并在30天内观察到癌症的发生。此外，虽然肿瘤的发展不依赖于内源性卵巢激素，但大豆异黄酮会抑制肿瘤的发展，而阿特拉津和壬基酚则会促进肿瘤的发展。虽然机制方面的进一步研究显然是必要的，但该模型似乎在筛选活跃在乳腺中的修饰剂方面具有巨大的潜力。

项目成果

Possible enhancing effects of atrazine and nonylphenol on 7,12-dimethylbenz[a]anthracene-induced mammary tumor development in human c-Ha-ras proto-oncogene transgenic rats

• DOI: 10.1111/j.1349-7006.2004.tb03223.x
• 发表时间: 2004-05-01
• 期刊: CANCER SCIENCE
• 影响因子: 5.7
• 作者: Fukamachi, K;Han, BS;Tsuda, H
• 通讯作者: Tsuda, H

Tsuda, H. et al.: "Cancer prevention by bovine lactoferrin and underlying mechanisms-a review of experimental and clinical studies"Biochem. Cell. Biol.. 80. 131-136 (2002)

Tsuda, H. 等人：“牛乳铁蛋白预防癌症及其潜在机制 - 实验和临床研究综述”Biochem。

Tokuzen,R.,Tsuda,H., et al.: "Establishment and characterization of three new rat renal cell carcinoma cell lines from N-ethyl-N-hydroxyethylnitrosamine-induced basophilic cell tumors."Pathol.Int.. 51. 65-71 (2000)

Tokuzen,R.、Tsuda,H. 等人：“N-乙基-N-羟乙基亚硝胺诱导的嗜碱性细胞肿瘤中三种新的大鼠肾细胞癌细胞系的建立和表征。”Pathol.Int.. 51. 65

Transgenic rats carrying copies of the human c-Ha-ras proto-oncogene exhibit enhanced susceptibility to N-butyl-N-(4-hydroxybutyl)nitrosamine bladder carcinogenesis

• DOI: 10.1093/carcin/21.7.1391
• 发表时间: 2000-07-01
• 期刊: CARCINOGENESIS
• 影响因子: 4.7
• 作者: Ota, T;Asamoto, M;Tsuda, H
• 通讯作者: Tsuda, H

Rapid emergence of mammary preneoplastic and malignant lesions in human c-Ha-ras proto-oncogene transgenic rats : possible application for screening of chemopreventive agents.

人c-Ha-ras原癌基因转基因大鼠中乳腺癌前病变和恶性病变的快速出现：筛选化学预防剂的可能应用。

• 发表时间: 2003
• 期刊: Toxicol Pathol 31
• 作者: Matsuoka;Y.;Tsuda;H.;et al.
• 通讯作者: et al.