Chemoprevention of Carcinogen-Induced Lung Cancer

描述(由申请人提供) 在超过50%的人类癌症中发现了p53突变，包括肺癌。这些突变强烈地选择了不能以序列特异性方式与DNA结合的p53蛋白。P53蛋白是一种四聚体，需要锌离子才能发挥其活性，因为DNA结合转录肺癌是美国癌症死亡的主要原因，而较低的肺癌存活率强烈表明需要新的方法来控制这种毁灭性的疾病。化学预防是逆转、抑制或预防肺癌发生的一种方法。超过80%的肺癌归因于烟草和香烟烟雾中的致癌物质。即使在戒烟后，曾经吸烟的人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，对肺癌发生的深入了解将导致制定有针对性的干预措施，并对新的化学预防方法持乐观态度，以预防与烟草有关的肺癌，特别是在前吸烟者中。我们已经建立了一种烟草致癌物暴露的吸烟相关肺癌的转基因小鼠模型。显性-负性突变型p53转基因基因在Clara细胞特异性蛋白(CCSP)启动子作用下特异性地表达于支气管上皮，导致对自发性肺癌和BaP诱发肺癌的易感性增加，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)建立模拟高风险既往吸烟者的小鼠模型，并确定肺癌的替代生物标志物；(2)确定化学预防药物的有效性，并验证替代生物标志物作为化学预防终点的使用；(3)评价磁共振成像(MRI)在评估肿瘤生长和化学预防药物有效性方面的应用。

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.