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：开发对以前吸烟者和暴露于二手烟的人的肺癌的药物化学预防。 理由：在戒烟后的最初几年，与目前或从不吸烟的人相比，前吸烟者患肺癌的风险增加。 背景：尼古丁和致癌亚硝胺已被证明可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。长期暴露于环境烟草烟雾 (ETS) 或纯尼古丁在这两种情况下都会改变细胞生长调节，并且还会改变细胞 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发的肺肿瘤的发生率。 具体目的：确定 nAChR 拮抗剂预防 A/J 小鼠中 ETS-或 4(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 诱导的肺部肿瘤增加的能力。 方法：该提案将利用已建立的动物模型来研究烟草烟雾致癌的化学预防。 A/J 品系小鼠在接触 ETS 5 个月后出现肺部肿瘤，随后在空气中进行 4 个月的恢复期。在不存在或存在α7或非α7 nAChR的药理学拮抗剂的情况下，用ETS、NNK或纯尼古丁治疗小鼠。实验结束时将分析肿瘤发生率和肿瘤多样性。意义。该提案的结果将为未来在这一新方向上的研究奠定基础，通过药物阻断肺部 nAChR 来开发有效的化学预防烟草相关癌症的方法。 描述。拟议的研究源于一个已得到充分证实的假设，即前吸烟者患肺癌的频率增加是由于尼古丁引起的局部激素乙酰胆碱与肺细胞内的结合和信号传导的改变所致。拟议的研究将确定能够消除尼古丁及其致癌衍生物通过该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 小鼠的肺肿瘤发展，染色 A/J 小鼠是一种已建立的动物模型，用于研究尼古丁及其致癌衍生物的肿瘤产生作用。香烟烟雾和化学致癌物质。