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: 6467578
• 负责人: PAUL T STRICKLAND
• 金额: $ 19.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6467578
• 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.

接触环境致癌物的主要途径是通过 饮食。 流行病学研究表明所有的20％至50％ 人类癌症可以归因于饮食原因。 频繁 消费动物脂肪，红肉或烤/烟熏肉有 与胃肠道癌的风险增加有关 区域和胰腺。 与 黄曲霉毒素和肝癌在该计划的其他项目中描述了 负责引起许多饮食的特定病因学 相关的人类癌症尚未确定。 两类 化学致癌物，多环芳烃（PAHS）和 杂环胺（HAS）已在烤或油炸中被缩进 肉。 这些化学物质会产生各种癌症，包括结肠， 在实验性动物模型中，胃，乳房和肝癌。 该项目的总体目标是调查这些项目的作用 在人类结肠癌中的饮食致癌物，并鉴定 调节代谢的敏感性因素（效应修饰符） 这些致癌物，最终导致结肠息肉/癌症风险。 我们的工作 假设是摄入肉类形成的饮食致癌物 在烹饪过程中是结肠poly的形成的原因， 在人类结肠过程的早期发生的肿瘤性病变 癌症发展。 该项目（AIM 1和2）将检查 尿HA和PAH代谢物轮廓的个体差异 受试者在受控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 评估以调查其在个体间和个体中的作用 差异。 这些研究应洞悉生物学 响应摄入的个体差异的基础 在煮熟的肉中发现了致癌物。 这个项目（AIM 3和4）将 还评估这些暴露生物标志物的关联和 在病例对照中有结肠息肉发育风险的代谢和 病例研究。 鉴定关键的代谢和饮食 结肠息肉风险的决定因素应导致新方法 预防结肠息肉和癌症。