Novel strategies to prevent lung cancer

预防肺癌的新策略

• 批准号: 7002476
• 负责人: WILLIAM G MCGREGOR
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7002476
• 关键词: DNA directed DNA polymerase; benzopyrenes; cancer prevention; carcinogenesis inhibitor; chemical carcinogenesis; gene delivery system; gene therapy; laboratory mouse; lung neoplasms; mutagens; nucleotidyltransferase; reporter genes; respiratory epithelium; ribozymes; tobacco abuse

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.

描述（由申请人提供）：本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，以降低香烟烟雾诱导的肺癌的发病率。DNA突变通常被认为在癌症的发展中具有病因学作用。在非小细胞肺癌的情况下，肺泡上皮细胞中的多种诱变事件被认为是致癌的原因。如果是这样的话，那么降低这种突变的频率将降低诱变剂诱发肺癌的发病率。最近的数据表明，几乎所有由香烟烟雾中的主要化学致癌物之一苯并[a]芘的活性代谢物诱导的突变都依赖于由REV 1基因编码的新描述的Y家族DNA聚合酶。本申请提出通过靶向特定亚细胞区室的基因特异性核酶的细胞内表达来减少小鼠肺中的REV1 mRNA。然后，将小鼠暴露于已建立的致癌物诱导的肺癌方案。这将在2个特定目的中实现：1）优化报告基因在体内向小鼠肺的雾化递送。2)使用这种方法来递送表达靶向REV 1 mRNA的核酶的DNA。小鼠和适当的对照将暴露于已知诱导肺癌的持续方案。该假说预测，降低这种蛋白质的水平将降低肺上皮细胞对香烟烟雾中化学致癌物的致突变反应，并将导致肺癌发病率大大降低。这项初步研究的目的是提供实验原理，以扩大该方法的更大的协议，其中肺肿瘤诱导啮齿动物吸烟。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且有吸引力的方法，以在疾病症状出现之前降低烟雾暴露人群中肺癌的风险。