CHEMOPREVENTION OF LUNG CANCER IN MICE

小鼠肺癌的化学预防

• 批准号: 6780906
• 负责人: MING YOU
• 金额: $ 38.53万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6780906
• 关键词: SDS polyacrylamide gel electrophoresis; adenocarcinoma; aerosols; alkyltransferase; antineoplastics; biological models; cancer prevention; cell line; chemical carcinogenesis; chemoprevention; enzyme inhibitors; genetically modified animals; guanine nucleotide binding protein; histopathology; immunocytochemistry; immunoprecipitation; laboratory mouse; lung neoplasms; mass spectrometry; metastasis; molecular oncology; posttranslational modifications; smoking; smoking cessation

Increasing evidence suggest that farnesyltransferase inhibitor (FTI) is a potent inhibitor of chemical carcinogenesis in rodents. FTI was developed as an anti-cancer agent against ras oncogenes by blocking post-translational farnesylation required for the transforming activity of ras oncogene. Although FTI has been found to inhibit farnesylation of ras and RhoB proteins as well as having effect on the regulation of cell cycle and apoptosis, the mechanism(s) for its chemotherapeutic and chemopreventive activities are not clear at present. The overall objective of this proposal is to characterize FT pre-clinically as a potent lung cancer chemopreventive agent and to determine the molecular mechanism that underlie the efficacy of FTI in preventing lung cancer in mice. Previously, we have reported a 60% reduction in established lung tumors in A./J mice after treatment with FTI-276. Recently, we found that FTI-276 is effective as a chemopreventive agent in inhibiting lung tumorigenesis using a complete chemoprevention protocol. Specific aims include: (1) To evaluate the effect of FTI on lung adenocarcinoma carcinogenesis in a transgenic mouse lung carcinoma model with genetic changes commonly seen in human lung cancers; (2) To determine chemopreventive efficacy of FTI in tobacco-smoke lung carcinogenesis in transgenic mouse lung carcinoma model; (3) To evaluate chemopreventive effect of FTI against lung cancer by exposing mice to arosolized FTI in both chemically induced and smoke lung carcinogenesis protocols; And (4) to investigate the mechanism of FTI's chemopreventive efficacy against lung cancer in mice. This proposal is timely and significant for the following reasons. Firstly, several pending chemoprevention clinical trials of FTI against lung cancer require vigorous preclinical characterization of its efficacy and mechanism(s). Secondly, we will use a newly developed mouse lung tumor model, which shares both histopathological features and genetic alterations (activated oncogenes and inactivated tumor suppressors) observed in human lung adenocarcinogenesis. And thirdly, we will conduct comprehensive animal bioassays to test the efficacy of FTI using both "former smoker" protocol and delivering FTI via aerosol. The results from this proposal will provide a solid foundation for clinical trials of FTI as a lung cancer chemopreventive agent.

越来越多的证据表明，法尼基转移酶抑制剂（FTI）是啮齿动物中化学癌发生的有效抑制剂。 FTI是通过阻断RAS癌基因转化活性所需的翻译后法尼化而作为对Ras Oncogenes的抗癌剂开发的。尽管发现FTI抑制了RAS和RHOB蛋白的法尼化，并且对细胞周期和凋亡的调节作用，但目前尚不清楚其化学治疗和化学预防活性的机制。该提案的总体目的是在链式链接链球前的FT表征有效的肺癌化学预防剂，并确定FTI在预防小鼠肺癌方面有效性的分子机制。以前，我们报道了用FTI-276治疗后，A./j小鼠已建立的肺肿瘤降低了60％。最近，我们发现使用完整的化学预防方案抑制肺部肿瘤发生时，FTI-276是化学预防剂有效的。具体目的包括：（1）评估FTI对转基因小鼠肺癌模型中肺癌癌的影响，其遗传变化在人类肺癌中常见； （2）确定FTI在转基因小鼠肺癌模型中FTI在烟草肺癌发生中的化学效能； （3）通过将小鼠暴露于化学诱导和烟雾肺癌发生方案中的芳香化FTI，以评估FTI对肺癌的化学预防作用； （4）研究FTI对小鼠肺癌的化学预防疗效的机制。由于以下原因，该提案及时且重要。首先，FTI针对肺癌的几项进行化学预防的临床试验需要对其功效和机制进行剧烈的临床前表征。其次，我们将使用新开发的小鼠肺肿瘤模型，该模型既具有组织病理学特征和遗传改变（激活的肿瘤基因和灭活肿瘤抑制剂））。第三，我们将使用“以前的吸烟者”方案并通过气溶胶运送FTI来进行全面的动物生物测定，以测试FTI的功效。该提案的结果将为FTI作为肺癌化学预防剂的临床试验提供坚实的基础。

项目成果

Efficacy of the farnesyltransferase inhibitor R115777 in a rat mammary tumor model: role of Ha-ras mutations and use of microarray analysis in identifying potential targets.

法尼基转移酶抑制剂 R115777 在大鼠乳腺肿瘤模型中的功效：Ha-ras 突变的作用以及使用微阵列分析识别潜在靶点。

• DOI: 10.1093/carcin/bgi341
• 发表时间: 2006
• 期刊: Carcinogenesis
• 影响因子: 4.7
• 作者: Yao,Ruisheng;Wang,Yian;Lu,Yan;Lemon,WilliamJ;End,DavidW;Grubbs,ClintonJ;Lubet,RonaldA;You,Ming
• 通讯作者: You,Ming