Can nicotinic antagonists prevent tobacco smoke-induced*

烟碱拮抗剂可以预防烟草烟雾诱发*

• 批准号: 7091527
• 负责人: SERGEI A GRANDO
• 金额: $ 5.6万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091527
• 关键词: acetylcholine; biological signal transduction; cancer prevention; cancer risk; chemical carcinogen; chemical carcinogenesis; chemical related neoplasm /cancer; chemoprevention; disease /disorder model; inhibitor /antagonist; laboratory mouse; lung neoplasms; neoplastic growth; neurotransmitter receptor; nicotine; nonhuman therapy evaluation; receptor binding; receptor expression; respiratory epithelium; smoking; smoking cessation; tissue /cell culture; tobacco abuse

DESCRIPTION (provided by applicant): Long-term Objective: To develop pharmacological chemoprevention of lung cancer in former smokes, and in people exposed to secondhand smoke. Rationale: During the first few years after smoking cessation, former smokers have an increased risk for lung cancer, compared to current or never smokers. Background: Nicotine and carcinogenic nitrosamines have been shown to alter pulmonary cells via the nicotinic class of acetylcholine receptors (nAChRs) expressed on the plasma membrane of non-neuronal cells. Chronic exposure to environmental tobacco smoke (ETS) or pure nicotine in both cases alter cell growth regulation, and also changes repertoire of cellular nAChR subtypes. Working Hypotheses: Pharmacological antagonism at nAChRs should decrease the frequency of tobacco-induced lung tumors by blocking the signaling pathways used by nicotine and carcinogenic nitrosamines. Specific Aims: To determine the ability of nAChR antagonists to prevent ETS- or 4(methylnitrosamino)-1- (3-pyridyl)-1-butanone (NNK)-induced increase of lung tumors in A/J mice. Methodology: This proposal will utilize an established animal model to study chemoprevention of tobacco smoke carcinogenesis in the lung. The strain A/J mice develop lung tumors after exposure to ETS for 5 months, followed by a 4-months recovery period in air. The mice will be treated with ETS, NNK or pure nicotine in the absence or presence of pharmacological antagonists of alpha7 or non-alpha7 nAChRs. Both tumor incidence and tumor multiplicity will be analyzed at the end of experiments. Significance. Results of this proposal will lay a groundwork for future studies in this novel direction for the development of efficacious methods of chemoprevention of tobacco-related cancers through pharmacological blockade of pulmonary nAChRs. DESCRIPTION. The proposed research stems from the well-substantiated hypothesis that an increased frequency of lung cancer in former smokers results from nicotine-induced alterations of binding to and signaling within the lung cells of the local hormone acetylcholine. The proposed studies will determine if specific drugs that can abolish an ability of nicotine and its carcinogenic derivatives to affect pulmonary cells through this pathway can decrease lung tumor development in the stain A/J mice, an established animal model for studying tumor-producing effects of cigarette smoke and chemical carcinogens.

描述（由申请人提供）：长期目标：开发前吸烟者和二手烟暴露者肺癌的药物化学预防。理由：在戒烟后的最初几年中，与目前或从未吸烟的人相比，曾经吸烟的人患肺癌的风险更高。背景：尼古丁和致癌性亚硝胺已被证明通过非神经元细胞质膜上表达的烟碱类乙酰胆碱受体（nAChRs）改变肺细胞。在这两种情况下，长期暴露于环境烟草烟雾（ETS）或纯尼古丁都会改变细胞生长调节，也会改变细胞nAChR亚型的全部功能。工作假设：nachr的药理拮抗作用通过阻断尼古丁和致癌性亚硝胺使用的信号通路来降低烟草诱导的肺肿瘤发生的频率。特异性目的：研究nAChR拮抗剂对ETS-或4（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）诱导的A/J小鼠肺肿瘤增加的抑制作用。方法：本方案将利用已建立的动物模型，研究烟草烟雾对肺部癌变的化学预防作用。A/J型小鼠暴露于ETS 5个月后出现肺肿瘤，随后在空气中恢复4个月。小鼠将在缺乏或存在alpha7或非alpha7 nachr药理拮抗剂的情况下接受ETS、NNK或纯尼古丁治疗。在实验结束时，将分析肿瘤发生率和肿瘤多样性。的意义。本研究结果将为今后在这一新方向上的研究奠定基础，通过药物阻断肺nachr开发有效的化学预防烟草相关癌症的方法。