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基本机制的新知识转化为临床有用的方案，以减少香烟烟雾引起的肺癌的发病率。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，肺泡上皮细胞的多次诱变事件被认为与癌变有关。如果是这样，那么减少这种突变的频率将减少诱变剂引起的肺癌的发病率。最近的数据表明，香烟烟雾中主要化学致癌物之一苯并[a]芘的活性代谢物诱导的几乎所有突变都依赖于一种新发现的由REV1基因编码的y家族DNA聚合酶。该应用建议通过靶向特定亚细胞区室的基因特异性核酶在细胞内表达来减少小鼠肺部的REV1 mRNA。然后，这些小鼠将暴露于一种既定的致癌物质诱导的肺癌方案中。这将在两个具体目标中实现：1)优化报告基因在体内的雾化递送到小鼠肺。2)使用这种方法递送表达针对REV1 mRNA的核酶的DNA。小鼠和适当的对照将暴露于已知会诱发肺癌的持续方案中。该假说预测，降低这种蛋白的水平会降低肺上皮细胞对香烟烟雾中化学致癌物质的致突变反应，从而大大降低肺癌的发病率。这项初步研究的目的是提供实验基础，以扩大吸烟在啮齿动物中诱发肺肿瘤的更大方案。原则上，在不改变细胞毒性反应的情况下减少诱变的想法提出了一种新颖而有吸引力的方法，可以在疾病症状出现之前降低烟雾暴露人群患肺癌的风险。

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.