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）：直接使用烟草制品的人数增加 个人对癌症的易感性。尼古丁衍生的亚硝胺是 烟草、无烟烟草、烟草中发现的致癌物质 烟雾和侧流（环境或二次）烟雾。无处不在的本质 这些化合物引起了人们对其作为致病因素的作用的兴趣 与烟草有关的恶性肿瘤。尽管许多工作已经解决了致癌问题 尼古丁衍生的亚硝胺的性质，目前几乎没有研究工作 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。有关暴露后 DNA 损伤和修复的知识 致癌物对于理解 DNA 加合物的持久性至关重要， 结果，形成导致肿瘤的突变。这 化合物 4-(甲基亚硝基氨基)-l-(3-吡啶基)-l-丁酮 (NNK) 被认为是 尼古丁衍生的亚硝胺中致癌性最强。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 修复和 O6-甲基鸟嘌呤-DNA 甲基转移酶的核苷酸分辨率 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，我们将比较实验中的损坏率和修复率 在烟草相关肿瘤的这些基因中发现了突变。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。该项目的目标是确立以下角色： NNK 在烟草相关、烟草烟雾相关和继发性病因学中的作用 与烟草烟雾相关的癌症。