Nicotine Derived Nitrosamines & Tobacco Related Cancers

描述（由申请人提供）：烟草产品的直接使用增加 个体对癌症的易感性。尼古丁衍生的亚硝胺是 烟草、无烟烟草、烟草中发现的疑似癌症物质 烟雾和侧流（环境或二次）烟雾。无处不在的性质 这些化合物引起了人们对它们作为致病因素的作用的兴趣， 烟草相关的恶性肿瘤虽然许多工作已经解决了致癌性 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 对理解DNA中加合物的持久性至关重要， 结果，形成导致肿瘤形成的突变。的 化合物4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）被认为是 尼古丁衍生的亚硝胺中最致癌的。我们将绘制加合物 由NNK形成，通过碱基切除修复、核苷酸切除修复 修复，和O6-甲基鸟嘌呤-DNA甲基转移酶在核苷酸分辨率， 人细胞中与肿瘤发生密切相关的两个基因：P53和Ki-Ras。 最终，我们将比较我们实验中的损坏和修复率， 在烟草相关肿瘤中发现的基因突变。我们还将 确定不同的DNA修复系统对根除的贡献 由NNK形成的加合物。该项目的目标是建立 NNK在病因学上与烟草有关，与烟草烟雾有关，与继发 与吸烟有关的癌症。

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.