Repair of tobacco carcinogens in the susceptibility of lung cancer

修复烟草致癌物质对肺癌的易感性

• 批准号: 8286292
• 负责人: Thomas E Spratt
• 金额: $ 16.48万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8286292
• 关键词: Address; Appearance; Aromatic Polycyclic Hydrocarbons; Benzo(a)pyrene; Biological Assay; Bladder; Butanones; Cancer Etiology; Carcinogen exposure; Carcinogens; Case-Control Studies; Cause of Death; Cessation of life; Characteristics; Chemistry; Chemopreventive Agent; Cigarette; DNA Adducts; DNA Damage; DNA Modification Process; DNA Repair; DNA Repair Gene; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Drug Metabolic Detoxication; Early Diagnosis; Environmental Exposure; Epidemiology; Gastrointestinal tract structure; Genetic; Genotype; Goals; High Pressure Liquid Chromatography; Histologic; Hospitals; Human; Incentives; Individual; Intervention; Knowledge; Life Style; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Modeling; Monitor; Muscat; Mutagenesis; Nitrosamines; Outcome; Outcomes Research; Pancreas; Pathology; Patients; Phenotype; Predisposition; Public Health; Research; Risk; Risk Factors; Route; Screening procedure; Sensitivity and Specificity; Site; Smoker; Smoking; Spottings; Squamous cell carcinoma; Staging; Survival Rate; Testing; Tobacco; Tobacco smoke; Tobacco-Associated Carcinogen; Work; adduct; base; cancer risk; innovation; lung cancer screening; mortality; novel; repaired; smoking cessation; tobacco carcinogenesis; tool; trait; treatment strategy

DESCRIPTION (provided by applicant): Tobacco-smoking is the single major cause of cancer mortality in the US, and is a risk factor for a number of cancers including lung, upper aero-digestive tract, bladder and pancreas. Current strategies aimed at the control of lung cancer remain largely unsuccessful. Early detection remains the key to increased survival. Identification of individuals who are at increased risk to tobacco-induced cancers would aid public health by focusing the screening to a limited set of smokers who are most susceptible to tobacco-induced lung cancer. Inefficient DNA repair is a characteristic that increases the risk for an individual to get tobacco-induced lung cancer. The current paradigm is to evaluate DNA repair capacities using specific carcinogens with a generalized DNA repair test. The problem is that tobacco contains multiple carcinogens that produce a variety of DNA damage with a range of mutagenicities that are repaired by multiple mechanisms. The long-term goal of this project is to develop highly specific DNA repair tests that can measure the repair capacity of multiple DNA adducts simultaneously. The current goal is to develop and validate an HPLC-MS/MS assay that can measure the repair capacity of individual to ten DNA adducts that form from two of the most potent tobacco smoke carcinogens, benzo[a]pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. The hypothesis that we will test is that the risk of adeno- or squamous cell carcinoma is dependent of the repair of specific DNA adducts but not others. This hypothesis will be tested in two aims. First, a highly specific HPLC-MS/MS assay that can measure ten DNA adducts will be developed and validated. Second, the hypothesis will be tested in a hospital-based case-control study. This project can change the paradigm by which DNA repair assays are conducted in which the adduct chosen to be analyzed for repair will be based upon an understanding of the etiology of the cancer.

描述（由申请人提供）：吸烟是美国癌症死亡率的单一主要原因，并且是许多癌症（包括肺癌、上呼吸消化道癌、膀胱癌和胰腺癌）的风险因素。目前针对肺癌控制的策略在很大程度上仍然不成功。早期发现仍然是提高生存率的关键。识别烟草诱发癌症风险增加的个人将有助于公共卫生，因为筛查的重点是最容易患烟草诱发肺癌的有限吸烟者。DNA修复效率低下是增加个体患烟草诱发肺癌风险的一个特征。目前的范例是使用特定的致癌物与广义的DNA修复测试来评估DNA修复能力。问题是烟草含有多种致癌物，这些致癌物会产生各种DNA损伤，并具有一系列致突变性，这些致突变性可通过多种机制修复。该项目的长期目标是开发高度特异性的DNA修复测试，可以同时测量多个DNA加合物的修复能力。目前的目标是开发和验证一种HPLC-MS/MS测定法，该测定法可以测量由两种最有效的烟草烟雾致癌物苯并[a]芘和4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮形成的单个至10个DNA加合物的修复能力。我们将检验的假设是，腺或鳞状细胞癌的风险取决于特定DNA加合物的修复，而不是其他。这一假设将在两个目标中得到检验。首先，将开发和验证一种可测量10种DNA加合物的高度特异性HPLC-MS/MS测定法。其次，将在一项以医院为基础的病例对照研究中检验这一假设。该项目可以改变DNA修复试验的模式，其中选择用于修复分析的加合物将基于对癌症病因学的理解。