MOLECULAR BIOMARKERS OF EXPOSURE AND SUSCEPTIBILITY IN HUMAN COLON CANCER

人类结肠癌暴露和易感性的分子生物标志物

• 批准号: 6106355
• 负责人: PAUL T STRICKLAND
• 金额: $ 30.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6106355
• 关键词: DNA damage; biomarker; cancer risk; carbopolycyclic compound; clinical research; colon neoplasms; family genetics; heterocyclic compounds; human subject; meat; neoplasm /cancer epidemiology; neoplasm /cancer genetics; nutrition related neoplasm /cancer; toxin metabolism; urinalysis

A major route of exposure to environmental carcinogens is through the diet. Epidemiological studies indicate the 20 to 50 percent of all human cancers can be attributed to dietary causes. The frequent consumption of animal fat, red meats, or grilled/smoked meats has been associated with increased risk for cancers of the gastrointestinal tract and pancreas. In contrast to the strong association between aflatoxin and liver cancer described in other projects in this program, the specific etiologic agents responsible for causing many diet- associated human cancers have yet to be determined. Two classes of chemical carcinogens, polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (Has), have been indentified in grilled or fried meats. These chemicals produce a variety of cancers, including colon, stomach, breast, and liver cancers, in experimental animal models. The overall goals of this project are to investigate the role of these dietary carcinogens in colon carcinogenesis in humans, and to identify susceptibility factors (effect modifiers) that modulate the metabolism of these carcinogens and, ultimately, colon polyp/cancer risk. Our work hypothesis is that ingestion of dietary carcinogens formed in meat during cooking is a causative factor in the formation of colon polys, preneoplastic lesions that occur early in the process of human colon cancer development. This project (Aim 1 and 2) will examine inter- individual differences in urinary HA and PAH metabolite profiles in subjects ingesting fried or broiled meat during controlled feeding studies. Relevant metabolic phenotypes and potential confounders will be assessed to investigate their role in intra-and inter-individual differences. These studies should provide insight into the biological basis for inter-individual variation in response to ingestion of carcinogens found in cooked meats. This project ( Aim 3 and 4) will also evaluate the association of these biomarkers of exposure and metabolism with risk of colon polyp development in a case-control and a case-case study. The identification of critical metabolic and dietary determinants of colon polyp risk should lead to new approaches for prevention of colon polyps and cancer.

接触环境致癌物的一个主要途径是通过 饮食。 流行病学研究表明，20%至50%的人 人类癌症可归因于饮食原因。 频繁的 食用动物脂肪、红肉或烤/熏肉 与胃肠道癌症风险增加有关 道和胰腺。 与之间的强关联相反 本计划其他项目中描述的黄曲霉毒素和肝癌， 导致许多饮食- 相关的人类癌症尚未确定。 两类 化学致癌物、多环芳烃（PAH）和 杂环胺 (Has)，已在烧烤或油炸中被鉴定出 肉类。 这些化学物质会产生多种癌症，包括结肠癌、 实验动物模型中的胃癌、乳腺癌和肝癌。 该项目的总体目标是调查这些因素的作用 膳食致癌物在人类结肠癌发生中的作用，并确定 调节代谢的易感因素（效应调节剂） 这些致癌物以及最终的结肠息肉/癌症风险。 我们的工作 假设是摄入肉类中形成的膳食致癌物 烹饪过程中的食物是形成结肠多聚体的一个致病因素， 人类结肠早期发生的癌前病变 癌症的发展。 该项目（目标 1 和 2）将审查 尿 HA 和 PAH 代谢谱的个体差异 受试者在控制喂养期间摄入油炸或烤肉 研究。 相关的代谢表型和潜在的混杂因素将 进行评估以调查他们在个人内部和个人之间的作用 差异。 这些研究应该提供对生物学的深入了解 个体间对摄入的反应差异的基础 熟肉中发现致癌物质。 该项目（目标 3 和 4）将 还评估这些暴露和生物标志物的关联 在病例对照中代谢与结肠息肉发展的风险 案例研究。 关键代谢和饮食的识别 结肠息肉风险的决定因素应导致新的治疗方法 预防结肠息肉和癌症。