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: 7522178
• 负责人: SERGEI A GRANDO
• 金额: $ 1.81万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7522178
• 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）：长期目的：开发以前烟熏肺癌的药理学化学预防，并在暴露于二手烟雾的人中。 理由：与当前吸烟者相比，在戒烟后的头几年中，前吸烟者患肺癌的风险增加。 背景：已证明尼古丁和致癌亚硝胺可以通过非神经元细胞的质膜上表达的烟碱类乙酰胆碱受体（NACHR）改变肺细胞。在两种情况下，长期暴露于环境烟草烟雾（ETS）或纯尼古丁会改变细胞生长的调节，并改变细胞NACHR亚型的曲目。 工作假设：NACHRS的药理学拮抗作用应通过阻止尼古丁和致癌硝基胺使用的信号传导途径来降低烟草诱导的肺肿瘤的频率。 具体目的：确定NACHR拮抗剂预防ETS-或4（甲基硝基氨基氨基）-1-（3-吡啶基）-1-丁酮（NNK）诱导的A/J小鼠中肺肿瘤的增加。 方法论：该建议将利用既定的动物模型研究肺中烟草烟雾致癌的化学预防。菌株A/J小鼠在暴露于ETS 5个月后发生肺肿瘤，然后在空气中恢复4个月。在不存在或存在α7或非α7NACHR的药理学拮抗剂的情况下，将用ET，NNK或纯尼古丁治疗小鼠。在实验结束时，将分析肿瘤的发病率和肿瘤多样性。意义。该提案的结果将为将来的研究奠定基础，以通过肺NACHR的药理阻断来开发与烟草相关癌症化学预防的有效方法的发展。 描述。拟议的研究源于良好的实验性假设，即以前吸烟者中肺癌的频率增加是尼古丁诱导的与局部激素乙酰胆碱肺细胞内结合和信号传导改变的改变。拟议的研究将确定可以消除尼古丁及其致癌衍生物通过该途径影响肺细胞能力的特定药物是否可以减少染色A/J小鼠的肺部肿瘤的发展，染色A/J小鼠是研究烟雾烟雾和化学癌的肿瘤产生作用的已建立动物模型。