Chemoprevention of Carcinogen-Induced Lung Cancer

描述（由申请人提供） p53突变在超过50%的人类癌症中发现，包括肺癌。这些突变强烈选择不能以序列特异性方式结合DNA的p53蛋白。p53蛋白是一种四聚体，其DNA结合转录活性需要锌离子。在美国，肺癌是癌症死亡的主要原因，肺癌的低生存率强烈要求采用新的方法来控制这种毁灭性的疾病。化学预防是一种逆转、抑制或预防肺癌发生的方法。超过80%的肺癌归因于烟草和香烟烟雾中的致癌物质。即使戒烟后，前吸烟者仍然处于高风险状态，占目前肺癌病例的50%以上。随着微阵列技术的最新发展，对肺癌发生机制的深入了解将导致靶向干预的发展，并对新的化学预防方法持乐观态度，以预防烟草相关的肺癌，特别是在前吸烟者中。我们通过暴露于烟草致癌物建立了吸烟相关肺癌的转基因小鼠模型。显性负突变型p53转基因在Clara细胞特异性蛋白（CCSP）启动子下特异性表达于支气管上皮细胞中，这导致对自发性和BaP诱导的肺癌的易感性增加，从而为研究烟草相关肺癌的化学预防提供了临床前模型。具体目的如下：（1）建立模拟高风险前吸烟者的小鼠模型并鉴定肺癌的替代生物标志物;（2）确定化学预防剂的功效并验证替代生物标志物作为化学预防终点的用途;（3）评价磁共振成像（MRI）用于评估肿瘤生长和化学预防剂的功效的用途。

DESCRIPTION (provided by applicant) p53 mutations are found in more than 50% of all human cancers, including lung cancer. These mutations strongly select for p53 proteins that fail to bind to DNA in a sequence-specific fashion. The p53 protein is a tetramer and requires zinc ions for its activity as DNA-binding transcription Lung cancer is the leading cause of cancer death in the United States and the poor lung cancer survival rates argue strongly for new approaches to control this devastating disease. Chemoprevention represents an approach to reverse, suppress, or prevent lung carcinogenesis. Over 80% of lung cancers are attributed to tobacco and carcinogens from cigarette smoke. Even after quitting smoking, former smokers remain at high risk and account for over 50% of current lung cancer cases. With the recent developments in microarray technology, increased insights in lung carcinogenesis will led to the development of targeted intervention and optimism for new chemopreventive approaches to prevent tobacco-related lung cancer, especially in former smokers. We have developed a transgenic mouse model for smoking-related lung cancer by exposure to tobacco carcinogen. The dominant-negative mutant p53 transgene is specifically expressed in the bronchial epithelium under the Clara Cell Specific Protein (CCSP) promoter which results in increased susceptibility to both spontaneous and BaP-induced lung cancer, hence offering a preclinical model for studying chemoprevention of tobacco-related lung cancer. The specific aims are as follows: (1) To establish a mouse model to mimic high risk former smokers and to identify surrogate biomarkers for lung cancer; (2) To determine the efficacy of chemopreventive agents and to validate the use of surrogate biomarkers as endpoints for chemoprevention; (3) To evaluate the use of magnetic resonance imaging (MRI) for assessing tumor growth and and efficacy of chemopreventive agents.