Novel strategies to prevent lung cancer

描述(由申请人提供)：该项目的总体目标是将诱变的基本机制的新知识转化为临床上有用的治疗方案，以减少香烟烟雾引起的肺癌的发生率。DNA突变通常被认为在癌症的发展中具有病因学作用。在非小细胞肺癌的病例中，肺泡上皮细胞中的多个突变事件被认为与癌症的发生有关。如果是这样的话，减少这种突变的频率就会降低诱变剂诱发肺癌的发生率。最近的数据表明，几乎所有由香烟烟雾中主要化学致癌物苯并[a]芘的活性代谢物引起的突变都依赖于新描述的由Rev1基因编码的Y-家族DNA聚合酶。这项应用提出了通过在细胞内表达针对特定亚细胞间隔的基因特异性核酶来减少小鼠肺中Rev1的mRNA。然后，这些小鼠将暴露在已建立的致癌物诱发肺癌方案中。这将通过两个具体的目标来实现：1)优化体内将报告基因雾化输送到小鼠肺中的方法。2)用这种方法表达针对Rev1mRNA的核酶。小鼠和适当的对照组将暴露在已知会诱发肺癌的正在进行的方案中。该假说预测，降低这种蛋白质水平将降低肺上皮细胞对香烟烟雾中化学致癌物的诱变反应，并将导致肺癌发病率大幅降低。这项先导性研究的目的是提供实验依据，将方法扩展到更大的方案，在这些方案中，用香烟烟雾诱导啮齿动物的肺肿瘤。原则上，在不改变细胞毒性反应的情况下减少突变的想法提供了一种新的和有吸引力的方法，可以在吸烟人群出现疾病症状之前降低肺癌的风险。

DESCRIPTION (provided by applicant): The overall aim of this project is to translate new knowledge of fundamental mechanisms of mutagenesis into a clinically useful regimen to reduce the incidence of cigarette smoke-induced lung cancer. Mutations in DNA are generally considered to have an etiologic role in the development of cancer. In the case of non-small cell lung cancers, multiple mutagenic events in alveolar epithelial cells are thought to be causally involved in carcinogenesis. If so, it follows that reducing the frequency of such mutations will reduce the incidence of lung cancer induced by mutagens. Recent data indicates that virtually all mutations induced by the active metabolite of 1 of the principal chemical carcinogens in cigarette smoke, benzo[a]pyrene, are dependent on a newly-described Y-family DNA polymerase encoded by the REV1 gene. This application proposes to reduce the REV1 mRNA in the lungs of mice by intracellular expression of gene-specific ribozymes that are targeted to specific subcellular compartments. Then, the mice will be exposed to an established carcinogen-induced lung cancer protocol. This will be accomplished in 2 Specific Aims: 1) to optimize the aerosolized delivery of a reporter gene to mouse lungs in vivo. 2) to use this method to deliver DNA that expresses ribozymes targeted against REV1 mRNA . The mice and the appropriate controls will be exposed to ongoing protocols that are known to induce lung cancer. The hypothesis predicts that reducing the level of this protein will reduce the mutagenic response of lung epithelial cells to chemical carcinogens in cigarette smoke, and will result in a greatly reduced incidence of lung cancer. This pilot study is designed to provide the experimental rationale to expand the approach to larger protocols in which lung tumors are induced in rodents by cigarette smoke. In principle, the idea of reducing mutagenesis without altering cytotoxic responses presents a novel and attractive method to reduce the risk of lung cancer in smoke-exposed populations prior to the appearance of disease symptoms.