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， 在美国，前吸烟者的数量继续增加。的 建立香烟烟雾介导的肺肿瘤发生的A/J小鼠模型， 其中肺肿瘤的增加发生在停止烟雾暴露之后， 为开发临床前化学预防方案提供了独特的机会 对于前吸烟者。这项研究的假设是， 致癌作用是多种协同、相加和 各种烟草烟雾成分之间的拮抗相互作用。然后它 因此，需要暴露于多种化学预防剂， 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肺癌小鼠模型， 确定疾病的中间终点或生物标志物并测试疗效 化学预防剂的混合物在抑制分子和细胞 与肺癌发生相关的事件。在目标1中， 发生，合成剂将在体外筛选其能力， 抑制香烟烟雾诱导的DNA氧化损伤。代理显示 这些实验中的承诺将在体内测试它们对 胁迫相关基因表达和DNA修复。根据得到的数据， 将选择三种化学预防剂的混合物，并在 A/J小鼠模型，用于其抑制肺肿瘤指数的功效 （多重性和发生率）。的 烟雾和/或化学预防剂混合物对基因表达的影响 DNA氧化损伤负荷、DNA修复和基因频率 还将评估突变。预计，这些综合 分析将为临床的未来发展提供基础。 化疗方案用于前吸烟者肺肿瘤的化学预防。

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.