CHEMOPREVENTION OF LUNG CANCER IN MICE

小鼠肺癌的化学预防

• 批准号: 6652148
• 负责人: MING YOU
• 金额: $ 37.41万
• 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 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6652148
• 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呢基转移酶抑制剂（FTI）是啮齿动物化学致癌的有效抑制剂。 FTI 被开发为针对 ras 癌基因的抗癌剂，通过阻断 ras 癌基因转化活性所需的翻译后法尼基化。尽管已发现FTI可抑制ras和RhoB蛋白的法尼基化，并具有调节细胞周期和凋亡的作用，但其化疗和化学预防活性的机制目前尚不清楚。该提案的总体目标是在临床前将 FT 描述为一种有效的肺癌化学预防剂，并确定 FTI 预防小鼠肺癌功效的分子机制。此前，我们曾报道，在使用 FTI-276 治疗后，A./J 小鼠中已形成的肺部肿瘤减少了 60%。最近，我们发现 FTI-276 作为一种化学预防剂，可以通过完整的化学预防方案有效抑制肺部肿瘤的发生。具体目标包括：（1）在具有人类肺癌常见遗传变化的转基因小鼠肺癌模型中评估FTI对肺腺癌癌变的影响； (2) 在转基因小鼠肺癌模型中确定FTI对烟草烟雾肺癌发生的化学预防功效； (3) 通过在化学诱导和烟雾肺癌实验方案中将小鼠暴露于雾化 FTI 来评估 FTI 对肺癌的化学预防作用； (4)探讨FTI对小鼠肺癌化学预防作用的机制。由于以下原因，该建议是及时且重要的。首先，几项悬而未决的 FTI 针对肺癌的化学预防临床试验需要对其功效和机制进行强有力的临床前表征。其次，我们将使用新开发的小鼠肺肿瘤模型，该模型具有在人类肺腺癌发生过程中观察到的组织病理学特征和遗传改变（激活的癌基因和灭活的肿瘤抑制基因）。第三，我们将使用“前吸烟者”方案和通过气雾剂提供 FTI 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。