CHEMOPREVENTION OF LUNG CANCER IN MICE

越来越多的证据表明，法尼基转移酶抑制剂(FTI)是一种有效的啮齿动物化学致癌抑制物。FTI是通过阻断ras癌基因转化活性所需的翻译后法尼化作用，作为一种针对ras癌基因的抗癌药物而发展起来的。尽管FTI已被发现抑制ras和RhoB蛋白的法尼化，并对细胞周期和细胞凋亡有调节作用，但其化疗和化学预防作用的机制(S)目前尚不清楚。这项建议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药物，并确定FTI预防小鼠肺癌的有效性的分子机制。在此之前，我们曾报道，在使用FTI-276治疗后，A/J小鼠已建立的肺部肿瘤减少了60%。最近，我们发现FTI-276是一种有效的化学预防药物，使用完整的化学预防方案可以抑制肺癌的发生。其具体目的包括：(1)在转基因小鼠肺癌模型上评价FTI对肺腺癌发生的影响；(2)在转基因小鼠肺癌模型中，确定FTI对烟草烟雾致肺癌的化学预防作用；(3)通过化学诱导和吸烟两种致癌方法，评价FTI对小鼠肺癌的化学预防作用；(4)研究FTI对小鼠肺癌的化学预防作用的机制。由于以下原因，这项提议是及时和重要的。首先，几项正在进行的FTI治疗肺癌的化学预防临床试验需要对其有效性和机制进行积极的临床前表征(S)。其次，我们将使用一个新开发的小鼠肺肿瘤模型，该模型既有组织病理学特征，也有人类肺腺癌发生过程中观察到的遗传变化(激活的癌基因和失活的肿瘤抑制因子)。第三，我们将进行全面的动物生物测试，以测试使用“前吸烟者”方案和通过气雾剂传递FTI的效果。这一建议的结果将为FTI作为肺癌化学预防药物的临床试验提供坚实的基础。

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.