Carcinogenesis biomarkers in former smokers of the Multi Ethnic Cohort Study

多种族队列研究中前吸烟者的致癌生物​​标志物

• 批准号: 10705695
• 负责人: STEPHEN S HECHT
• 金额: $ 32.65万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705695
• 关键词: 4 hydroxynonenal; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; Acetylcysteine; Acrolein; Aromatic Polycyclic Hydrocarbons; Bay Region; Biochemical; Biological Markers; C-reactive protein; CYP1A1 gene; Cancer Etiology; Cells; Chemicals; Chronic; Clinic; Clinical Research; Cohort Studies; Cytochromes; DNA; DNA Adduction; DNA Adducts; DNA Damage; Data; Dose; Environmental Carcinogens; Epoxy Compounds; Exposure to; Glycols; IL8 gene; Inflammation; Inflammatory; Inhalation; Inhalation Drug Administration; Interleukin-6; Label; Leukocytes; Linoleic Acids; Lipid Peroxidation; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Metabolic; Metabolic Activation; Oral; Oxidative Stress; Participant; Pathway interactions; Peroxidases; Phenols; Plasma; Pleural; Predisposition; Process; Production; Progress Reports; Prostaglandins; Pulmonary Inflammation; Questionnaires; Relative Risks; Risk; Sampling; Serum; Smoker; Smoking; Testing; Toxic effect; Tumor Promotion; Urine; Volatilization; adduct; alpha Tocopherol; black lung; cancer risk; carbonyl compound; carcinogenesis; carcinogenicity; cigarette smoking; ethnic difference; former smoker; high risk; innovation; insight; lung cancer prevention; multi-ethnic; never smoker; non-smoker; oxidative damage; particle; phenanthrene; potential biomarker; racial difference; recruit; smoking cessation; theories; toxicant; urinary

ABSTRACT Former smokers remain at high risk for lung cancer for years after quitting smoking, with at least 3-fold relative risk compared to never smokers, even 25 years after quitting. More lung cancer cases in the U.S. (50.8%) now occur in former smokers than in current smokers (36.7%), yet we know little about the relevant biochemical mechanisms and related potential biomarkers that could ultimately be used to identify those at high risk. This project proposes to investigate chemical and metabolic biomarkers in former smokers. The Specific Aims are to: 1) Perform a clinical study of inhaled [D10]phenanthrene ([D10]Phe) to determine the ratio of urinary [D10]phenanthrene tetraol ([D10]PheT) to [D9]phenanthrene phenols ([D9]PhOH) as an indicator of increased metabolic activation of PAH in the lungs of former smokers compared to never smokers, possibly due to pleural anthracosis (the accumulation of black particles in the lungs of smokers which persist in former smokers; 2) Perform a clinical study of inhaled [13C18]linoleic acid to determine levels of [13C]mercapturic acids of acrolein, 4-hydroxynonenal and related α,β-unsaturated carbonyl compounds in the urine of former smokers compared to never smokers to investigate the hypothesis that pulmonary inflammation leads to production of these urinary metabolites; 3) Quantify the inflammation and oxidative damage-related adducts 1,N6-etheno-dA, 3,N4-etheno-dC, ɣ-OH- propano-dG, and 8-oxo-dG in DNA from oral cells and leukocytes of former smokers compared to never smokers; and 4) Working together with Core B, quantify biomarkers of potential harm - myeloperoxidase activity in plasma, IL-6, IL-8, and C-reactive protein levels in serum, and urinary levels of 8-epi-PGF2α and prostaglandin E metabolite (PGEM) in former and never smokers. Serum levels of α-tocopherol, protective against lung cancer, will also be quantified. Collaborative studies with Projects 1 and 3 are also proposed. These innovative studies are expected to provide important new insights on lung cancer mechanisms in former smokers and potentially identify new biomarkers of lung cancer susceptibility.

抽象的 吸烟后多年以前的吸烟者仍然患肺癌的风险很高，至少相对3倍 与永不吸烟者相比，即使在退出25年后，风险。美国更多的肺癌病例（50.8％） 以前的吸烟者比目前的吸烟者发生（36.7％），但我们对相关的生化知识一无所知 机制和相关的潜在生物标志物最终可用于识别高风险的机制。这 项目的建议，以研究以前吸烟者的化学和代谢生物标志物。 具体目的是： 1）对遗传[D10]菲（[D10] PHE）进行临床研究以确定尿的比率 [D10]菲四酚（[D10] PHET）至[D9]均酚酚（[D9] PHOH）作为指标 与从未吸烟者相比 由于胸膜炭疽病（吸烟者肺中黑色颗粒的积累，这些颗粒的积累 坚持前吸烟者； 2）对遗传[13C18]亚油酸进行临床研究，以确定[13C]胃酸的水平 丙烯醛，4-羟基亚烯酸和相关的α，β-β-不饱和羰基化合物形式的尿液中的化合物 吸烟者与从不吸烟者相比研究了肺注射导致的假设 产生这些泌尿代谢物； 3）量化炎症和氧化性损伤相关的加合物1，N6-乙诺-DA，3，N4-乙诺荷DC，ɣ-OH-- 从未从不 吸烟者；和 4）与核心B一起工作，量化潜在损害的生物标志物 - 髓过氧化物酶活性 血清中的血浆，IL-6，IL-8和C反应蛋白水平，以及8-EPI-PGF2α和 前前，从未吸烟的前列腺素E代谢物（PGEM）。血清α-生育酚的水平， 对肺癌的保护性也将被量化。 还提出了与项目1和3的协作研究。这些创新的研究有望 提供有关前吸烟者肺癌机制的重要新见解，并有可能识别新的新见解 肺癌易感性的生物标志物。