Can nicotinic antagonists prevent tobacco smoke-induced*

描述(由申请者提供)：长期目标：开发药物化学预防曾吸烟的人和暴露于二手烟的人的肺癌。理由：戒烟后的头几年，与现在吸烟者或从不吸烟者相比，曾经吸烟者患肺癌的风险更高。背景：尼古丁和致癌亚硝胺通过表达在非神经细胞质膜上的烟碱型乙酰胆碱受体(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，并改变细胞nAChR亚型。工作假设：nAChRs的药理拮抗作用应该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。具体目的：研究nAChR拮抗剂对ETS或4(甲基亚硝基)-1-(3-吡啶)-1-丁酮(NNK)诱导的A/J小鼠肺癌的抑制作用。方法：这项建议将利用已建立的动物模型来研究化学预防烟草烟雾在肺部致癌的作用。品系A/J小鼠在暴露于ETS 5个月后出现肺癌，然后在空气中恢复4个月。在没有或存在α7或非α7 nAChRs的药理拮抗剂的情况下，小鼠将接受ETS、NNK或纯尼古丁的治疗。肿瘤发病率和肿瘤多样性将在实验结束时进行分析。意义重大。这一建议的结果将为这一新方向的未来研究奠定基础，为开发通过药物阻断肺nAChRs来化学预防烟草相关癌症的有效方法奠定基础。 描述。这项拟议的研究源于一个得到充分证实的假设，即前吸烟者肺癌发生率的增加是由于尼古丁诱导的局部荷尔蒙乙酰胆碱与肺细胞结合并在肺细胞内传递信号的变化。拟议中的研究将确定特定的药物，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，是否可以减少A/J菌株小鼠的肺癌发展。A/J菌株是研究香烟烟雾和化学致癌物致癌作用的已建立的动物模型。

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.