Chemoprevention of experimental tobacco tumorigenesis.

描述(由申请人提供)： 烟草相关癌症化学预防策略的发展 由于吸烟仍然是肺癌的主要危险因素，因此成为优先事项 在美国，前吸烟者的数量继续增加。这个 建立香烟烟雾介导的小鼠肺肿瘤形成模型 在停止吸烟后，肺癌的发病率会增加， 为开发临床前化学预防方案提供了独特的机会 为前吸烟者准备的。拟议研究的假设是烟草 致癌是多种因素共同作用、相加和共同作用的结果 不同烟草烟雾成分之间的拮抗作用。然后它 因此，暴露于多种化学预防药物将被要求 防止吸烟引起的DNA损伤和肿瘤的发展。我们建议 利用香烟烟雾介导的小鼠肺肿瘤模型 确定疾病的中间终点或生物标志物，并测试其疗效 化学预防药物混合物对分子和细胞的抑制作用 与肺癌发生有关的事件。在目标1中，自然众多 和合成剂将在体外筛选它们的能力 抑制香烟烟雾引起的DNA氧化损伤。坐席显示 这些实验中的承诺将在体内测试它们对 应激相关基因表达与DNA修复。基于所得到的数据， 将选择三种化学预防药物的混合物并在 A/J小鼠模型对肺肿瘤指数的抑制作用 (多发性和发病率)在戒烟后给药。这个 烟雾和/或化学防腐剂混合物对基因表达的影响 概况、DNA氧化损伤负担、DNA修复和基因频率 突变也将被评估。预计这些全面的 分析将为临床的未来发展提供基础 曾吸烟者肺癌的化学预防方案。

DESCRIPTION (provided by applicant): Development of chemopreventive strategies for tobacco-related cancers has become a priority since smoking remains the major risk factor for lung cancer and the number of former smokers continues to increase in the US. The established A/J mouse model of cigarette smoke-mediated lung tumorigenesis, in which an increase in lung tumors occurs after the cessation of smoke exposure, provides a unique opportunity to develop preclinical chemopreventive regimens for former smokers. The hypothesis of the proposed studies is that tobacco carcinogenesis is the result of multiple synergistic, additive and antagonistic interactions among various tobacco smoke constituents. It then follows that exposure to multiple chemopreventive agents will be required to protect against smoke-induced DNA damage and tumor development. We propose to utilize the cigarette smoke-mediated lung tumorigenesis mouse model to identify intermediate endpoints or biomarkers of disease and test the efficacy of mixtures of chemopreventive agents in inhibiting molecular and cellular events associated with lung carcinogenesis. In Aim 1, numerous naturally occurring, and synthetic agents will be screened in vitro for their ability to inhibit oxidative DNA damage induced by cigarette smoke. Agents showing promise in these experiments will be tested in vivo for their effect on stress-related gene expression and DNA repair. Based on the resulting data, three mixtures of chemopreventive agents will be selected and tested in the A/J mouse model for their efficacy in inhibiting lung tumor indices (multiplicity and incidence) when administered following smoke cessation. The impact of smoke and/or the chemopreventive agent mixture on gene expression profiles, oxidative DNA damage burden, DNA repair and the frequency of gene mutations will also be evaluated. It is anticipated that these comprehensive analyses will provide the basis for the future development of a clinical regimen for the chemoprevention of lung tumors in former smokers.