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）是一种有效的化学致癌物。FTI通过阻断ras癌基因转化活性所需的翻译后法尼化而被开发为ras癌基因的抗癌剂。虽然FTI已被发现抑制ras和RhoB蛋白的法尼化，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FTI描述为一种有效的肺癌化学预防剂，并确定FTI在小鼠中预防肺癌功效的分子机制。在此之前，我们报道了FTI-276治疗a /J小鼠后，已建立的肺肿瘤减少了60%。最近，我们发现FTI-276是一种有效的化学预防剂，使用完整的化学预防方案来抑制肺肿瘤的发生。具体目的包括：(1)在具有人类肺癌常见基因改变的转基因小鼠肺癌模型中，评价FTI对肺腺癌癌变的影响；(2)在转基因小鼠肺癌模型中检测FTI对烟草烟雾性肺癌的化学预防作用；(3)在化学诱导和烟雾肺癌实验中，通过将小鼠暴露于雾化的FTI中，评估FTI对肺癌的化学预防作用；(4)探讨FTI对小鼠肺癌的化学预防作用机制。这一建议是及时和重要的，原因如下。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疗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，我们将进行全面的动物生物试验，以测试FTI的效果，采用“前吸烟者”方案和通过气溶胶输送FTI。本研究结果将为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.