Repair of tobacco carcinogens in the susceptibility of lung cancer

描述(申请人提供)：吸烟是美国癌症死亡的唯一主要原因，也是许多癌症的危险因素，包括肺癌、上消化道、膀胱癌和胰腺癌。目前旨在控制肺癌的战略在很大程度上仍然不成功。早期发现仍然是提高存活率的关键。通过将筛查重点放在最易患烟草诱发肺癌的有限吸烟者群体中，识别出烟草引发癌症的风险增加的个人将有助于公众健康。DNA修复效率低下是一个增加个人患烟草诱发肺癌风险的特征。目前的范例是使用特定的致癌物通过一般的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质，它们会产生各种DNA损伤，具有一系列的致突变性，可以通过多种机制修复。该项目的长期目标是开发高度特异的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高效液相-MS/MS分析方法，该方法可以测量个体对两种最有效的烟草烟雾致癌物质苯并[a]芘和4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.形成的十种dna加合物的修复能力我们将测试的假设是，腺或鳞状细胞癌的风险取决于特定DNA加合物的修复，而不是其他加合物。这一假设将在两个目标上得到检验。首先，将建立并验证一种可以测量10种DNA加合物的高度特异的高效液相色谱-质谱仪/质谱仪。其次，这一假设将在一项以医院为基础的病例对照研究中得到验证。这个项目可以改变进行DNA修复分析的范例，在这种范例中，被选择进行修复分析的加合物将基于对癌症病因的理解。

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.