Nicotine Derived Nitrosamines & Tobacco Related Cancers

说明(申请人提供)：直接使用烟草产品增加 一个人对癌症的易感性。尼古丁衍生的亚硝胺 烟草、无烟烟草、烟草中发现的致癌可疑物质 烟雾和侧流(环境或二次)烟雾。无处不在的自然 这些化合物作为致病因素引起了人们的兴趣。 与烟草相关的恶性肿瘤。尽管许多工作已经解决了致癌物质 关于尼古丁衍生的亚硝胺的性质，很少有工作出现在 将这些化合物形成的加合物与肿瘤发生联系起来的文献 分子水平。关于暴露后DNA损伤和修复的知识 致癌物对了解加合物在DNA中的持久性至关重要， 因此，突变的形成会导致肿瘤的形成。这个 复合4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone(NNK)被认为是 尼古丁衍生的亚硝胺中致癌作用最强的。我们将绘制加合物图 由NNK形成，通过碱基切除修复，核苷酸切除 修复和核苷酸分解时的O6-甲基鸟嘌呤-DNA甲基转移酶 人类细胞中有两个与肿瘤发生密切相关的基因：P53和Ki-RAS。 最终，我们将比较我们实验中的损坏和修复率与 在与烟草相关的肿瘤中发现了这些基因的突变。我们还将 确定不同的DNA修复系统对根除疾病的贡献 由NNK形成的加合物。该项目的目标是确立 NNK在烟草相关病因学中的作用，与烟草烟雾相关，以及继发性 与吸烟相关的癌症。

DESCRIPTION (Provided by Applicant): Direct use of tobacco products increases an individual's susceptibility to cancer. Nicotine-derived nitrosamines are cancer suspect agents that are found in tobacco, smokeless tobacco, tobacco smoke, and sidestream (environmental or secondary) smoke. The pervasive nature of these compounds has generated interest in their role as causative factors in tobacco-related malignancies. Although much work has addressed the carcinogenic nature of the nicotine-derived nitrosamines, little work has appeared in the literature connecting adducts formed by these compounds to tumorigenesis at the molecular level. Knowledge concerning DNA damage and repair following exposure to carcinogens is critical to understanding the persistence of adducts in DNA, and as a consequence, the formation of mutations leading to neoplasia. The compound 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK) is considered the most carcinogenic of the nicotine-derived nitrosamines. We will map the adducts formed by NNK that are repaired by base excision repair, nucleotide excision repair, and O6-methyguanine-DNA methyltransferase at nucleotide resolution in human cells in two genes closely associated with tumorigenesis: P53 and Ki-Ras. Ultimately, we will compare damage and repair rates in our experiments to the mutations found in those genes in tobacco-related tumors. We will also determine the contribution of different DNA repair systems to the eradication of adducts formed by NNK. The goal of this project is to establish the role of NNK in the etiology of tobacco-related, tobacco smoke-related, and secondary tobacco smoke-related cancers.