Nicotine Derived Nitrosamines & Tobacco Related Cancers

尼古丁衍生的亚硝胺

• 批准号: 6515016
• 负责人: TIMOTHY R O'CONNOR
• 金额: $ 27.56万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6515016
• 关键词: DNA repair; adduct; carcinogen testing; chemical carcinogenesis; environmental toxicology; fibroblasts; gene mutation; guanine nucleotide binding protein; human tissue; methylguanine DNA methyltransferase; mutagen testing; mutagens; nicotine; nitrosamines; p53 gene /protein; passive smoking; plasmids; smoking; tobacco abuse

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.

描述（由申请人提供）：直接使用烟草产品增加 一个人对癌症的敏感性。尼罗宁衍生的亚硝胺是 在烟草，无烟烟草，烟草中发现的癌症嫌疑人 烟雾和侧词（环境或继发性）烟雾。普遍的性质 这些化合物中有对其作为因果因素的作用引起了人们的兴趣 与烟草有关的恶性肿瘤。尽管很多工作已经解决了致癌 尼罗宁衍生的亚硝基胺的性质，几乎没有出现的工作 这些化合物形成的加合物与肿瘤发生的文献 分子水平。暴露后有关DNA损伤和维修的知识 致癌物对于理解DNA中加合物的持久性至关重要， 因此，突变的形成导致肿瘤。这 化合物4-（甲基硝基氨基）-l-（3-吡啶基）-L-丁酮（NNK）被认为是 尼罗宁衍生的硝酸胺的大多数致癌性。我们将映射加合物 由NNK形成的，通过碱基切除修复，核苷酸切除来修复 修复，在核苷酸分辨率下的O6-甲基鸟嘌呤-DNA甲基转移酶 与肿瘤发生密切相关的两个基因的人类细胞：p53和ki-ras。 最终，我们将在实验中比较损坏和维修率 这些基因在烟草相关肿瘤中发现的突变。我们也会 确定不同DNA修复系统对根除的贡献 NNK形成的加合物。该项目的目的是确定 烟草相关，烟草烟有关的病因和次级 烟草相关的癌症。