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: 7001068
• 负责人: SERGEI A GRANDO
• 金额: $ 7.58万
• 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 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7001068
• 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：开发前吸烟者和暴露于二手烟的人群中肺癌的药理学化学预防。 基本原理：在戒烟后的最初几年，与目前或从未吸烟者相比，前吸烟者患肺癌的风险增加。 背景资料：尼古丁和致癌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（nAChR）改变肺细胞。在这两种情况下，长期暴露于环境烟草烟雾（ETS）或纯尼古丁会改变细胞生长调节，也会改变细胞nAChR亚型的库。 工作假设：nAChRs的药理学拮抗作用应通过阻断尼古丁和致癌亚硝胺使用的信号通路来降低烟草诱导的肺肿瘤的发生率。 具体目标：确定nAChR拮抗剂预防ETS或4（甲基亚硝基）-1-（3-吡啶基）-1-丁酮（NNK）诱导的A/J小鼠肺肿瘤增加的能力。 方法：本研究将利用已建立的动物模型来研究烟草烟雾致癌作用的化学预防。A/J系小鼠在暴露于ETS 5个月后发生肺肿瘤，随后在空气中恢复4个月。在不存在或存在α 7或非α 7 nAChR的药理学拮抗剂的情况下，用ETS、NNK或纯尼古丁处理小鼠。将在实验结束时分析肿瘤发生率和肿瘤多样性。意义这一建议的结果将为未来的研究奠定基础，在这个新的方向，通过药理学阻断肺nAChRs的烟草相关癌症的化学预防的有效方法的发展。 说明.这项拟议的研究源于一个得到充分证实的假设，即前吸烟者肺癌发病率的增加是由于尼古丁诱导的与肺细胞内局部激素乙酰胆碱结合和信号传导的改变。拟议的研究将确定可以消除尼古丁及其致癌衍生物通过这一途径影响肺细胞的能力的特定药物是否可以减少染色A/J小鼠中的肺肿瘤发展，这是一种用于研究香烟烟雾和化学致癌物产生肿瘤影响的动物模型。