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）是一种有效的抑制化学致癌作用的啮齿动物。FTI通过阻断ras癌基因转化活性所需的翻译后法尼基化而被开发为针对ras癌基因的抗癌剂。虽然FTI能抑制ras和RhoB蛋白的法尼基化，并对细胞周期和凋亡有调节作用，但其化疗和化学预防作用的机制目前尚不清楚。本提案的总体目标是在临床前将FT表征为有效的肺癌化学预防剂，并确定FTI预防小鼠肺癌疗效的分子机制。以前，我们已经报道了在A./用FTI-276处理后的J小鼠。最近，我们发现，FTI-276是有效的化学预防剂在抑制肺肿瘤发生使用一个完整的化学预防协议。具体目标包括：（1）观察FTI对转基因小鼠肺腺癌发生的影响，（2）观察FTI对烟草烟雾诱导的转基因小鼠肺腺癌发生的化学预防作用;（3）采用化学诱癌和烟雾诱癌两种方法，观察FTI对肺癌的化学预防作用;探讨FTI对小鼠肺癌化学预防作用的机制。这项建议是及时和重要的，原因如下。首先，FTI针对肺癌的几个待进行的化学预防临床试验需要对其功效和机制进行有力的临床前表征。其次，我们将使用一种新开发的小鼠肺肿瘤模型，该模型具有在人肺腺癌发生中观察到的组织病理学特征和遗传改变（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定，以测试使用“前吸烟者”方案和通过气雾剂递送FTI的功效。本研究结果将为FTI作为肺癌化学预防剂的临床试验提供坚实的基础。

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.