Studies on in vivo evaluation system of treatment for cancer prevention and progression using cancer prone gene-engineered mice

使用易患癌症的基因工程小鼠研究癌症预防和进展治疗的体内评价系统

• 批准号: 12558097
• 负责人: OHNISHI Yasuyuki
• 金额: $ 8.45万
• 依托单位: Central Institute for Experimental Animals
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12558097/
• 关键词: H-ras; IL-6; transgenic; knockout; bigenic; cancer prevention; mouse; urethane; トランスジェニツク; 肺がん; ビニルカーバメート; 変異; ビニールカーバメート; p53; メチルニトロソウレア

We studied to establish in vivo evaluation system of treatment for cancer prevention and progression using cancer prone gene-engineered mice. We have been studying carcinogenicity testing model using rasH2 transgenic mice harboring human prototype H-ras oncogene. In this study, we established urethane-induced lung cancer model with very rapid tumorigenicity. We applied this cancer prone mice system for evaluation of drug or treatment protocol for cancer protection or prevention of cancer progression such as chemoprevention.The rasH2 mice were injected urethane to induce lung tumor. After or before urethane injection, IL-6 related gene complex (IL-6, IL-6 receptor and gp130) was challenged into the mice. The incidence of lung tumor formation in the urethane injected rasH2 mice was clearly reduced, meaning the IL-6 related gene complex has chemoprevention effects.The mutational analyses of introducing human H-ras were performed in the lung tumor which induced by urethane and vinylcarbamate (VC, proximal carcinogen of urethane). The results showed almost all tumors had mutation at the 61st codon of H-ras. These results suggested that point mutations at codon 61 of the transgene play an important role in the carcinogenesis of VC- and urethane- induced lung tumors in rasH2 mice.

我们研究了使用癌症易感基因工程小鼠建立用于癌症预防和进展的治疗的体内评价系统。我们一直在研究致癌性试验模型，使用rasH 2转基因小鼠携带人类原型H-ras癌基因。本研究建立了一种快速致瘤的小鼠肺癌模型。我们将这种癌症易感小鼠系统应用于评估癌症保护或预防癌症进展的药物或治疗方案，如化学预防。在乌拉坦注射前或注射后，将IL-6相关基因复合物（IL-6、IL-6受体和gp 130）激发入小鼠体内。在乌拉坦和乙烯基氨基甲酸酯（VC，乌拉坦的近端致癌物）诱发的小鼠肺肿瘤中进行了导入人H-ras基因的突变分析。结果表明，几乎所有的肿瘤都存在H-ras基因第61位密码子的突变。这些结果表明，转基因的61密码子的点突变在rasH 2小鼠中VC和氨基甲酸乙酯诱导的肺肿瘤的发生中起重要作用。

项目成果

Maruyama, C: "Overexpression of human H-ras transgene is responsible for tumors induced by chemical carcinogens in mice"Oncol.Rep.. 8. 233-237 (2001)

Maruyama, C：“人类 H-ras 转基因的过度表达是导致小鼠化学致癌物诱发肿瘤的原因”Oncol.Rep.. 8. 233-237 (2001)

Birumachi, J.: "Diesel exhaust-induced airway hyperresponsiveness in c-Ha-ras transgenic mice"Toxicology. 163. 145-152 (2001)

Birumachi, J.：“柴油机尾气引起 c-Ha-ras 转基因小鼠气道高反应性”毒理学。

Zembutsu H.: "Genome-wide cDNA microarray screening to correlate gene expression profiles with sensitivity of 85 human cancer xenografts to anticancer drugs."Cancer Res.. 62. 518-527 (2002)

Zembutsu H.：“全基因组 cDNA 微阵列筛选，将基因表达谱与 85 个人类癌症异种移植物对抗癌药物的敏感性相关联。”Cancer Res.. 62. 518-527 (2002)

Chulan, S.a: "Characterization of the mutations of the K-ras, p53, p16, and SMAD4 genes in 15 human pancreatic cancer cell lines"Oncol. Rep.. 58. 89-92 (2001)

Chulan, S.a：“15 种人类胰腺癌细胞系中 K-ras、p53、p16 和 SMAD4 基因突变的特征”Oncol。

Ohnishi, Y.: "Induction of drug metabolism-related enzymes by methylcholanthrene and phenobarbital in transgenic mice carrieng human prototype c-Ha-ras gene and their wild type littermates"Exp.Anim.. 50. 33-39 (2001)

Ohnishi, Y.：“在携带人类原型 c-Ha-ras 基因的转基因小鼠及其野生型同窝小鼠中通过甲基胆蒽和苯巴比妥诱导药物代谢相关酶”Exp.Anim.. 50. 33-39 (2001)