NSAID and COX/PG Metabolism and Colorectal Cancer

NSAID 和 COX/PG 代谢与结直肠癌

• 批准号: 6984029
• 负责人: JOHN D POTTER
• 金额: $ 64.86万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6984029
• 关键词: I kappa B beta; aspirin; biotechnology; cancer prevention; chemoprevention; clinical research; colorectal neoplasms; cyclooxygenase inhibitors; drug metabolism; enzyme activity; family genetics; genetic screening; genetic susceptibility; glucuronosyltransferase; human genetic material tag; human subject; inflammation; neoplasm /cancer genetics; neoplasm /cancer pharmacology; nonsteroidal antiinflammatory agent; nuclear factor kappa beta; prostaglandin E; prostaglandin endoperoxide synthase; single nucleotide polymorphism

DESCRIPTION (provided by applicant): The Cooperative Family Registry for Colorectal Cancer Studies (Colon CFR) proposes to investigate the role of genetic polymorphisms in the non-steroidal anti-inflammatory drugs/prostaglandin synthase (NSAIDs/PTGS) pathway in preventing colorectal cancer. Risk of colorectal cancer, the second leading cause of cancer-related deaths in the United States, can be reduced by the regular use of aspirin and other NSAIDs by approximately 50%, presumably through inhibition of prostaglandin synthesis. Recurrence of adenomas can also be reduced by up to 40%. The chemopreventive benefit across the population is clear but at the individual level, given some unwanted effects and varying efficacy due to genetic variation in metabolism, the equation is less clear. We showed previously that polymorphisms in NSAIDs metabolism - glucuronidation and oxidation - and prostaglandin synthesis can affect adenoma risk or modify the benefit derived from regular NSAIDs use. Accordingly, in 4310 discordant sib-pairs (affected case/unaffected relative) in the Colon CFR, we now propose to use candidate SNP and haplotype-based approaches to investigate effects of polymorphisms in NSAIDs metabolism and in prostaglandin synthesis on colorectal cancer risk. Haplotypes will be generated for PTGS1, PTGS2, NF-KappaB, and IkappaB in 300 individuals in 5 ethnic groups and genotyping will be undertaken across the 4310 discordant sibpairs. In addition, we will establish in vitro studies, which of the UGTs catalyze the glucuronidation of aspirin and other NSAIDs including ibuprofen, sulindac, sulindac sulfone, and indomethacin, and the effects of polymorphisms on metabolic capacities. Ultimately, such information on the metabolic variation will be useful in optimizing NSAIDs and NSAID regimens and will allow individual tailoring of chemoprevention.

描述（由申请人提供）：结直肠癌研究（COLON CFR）的合作家族登记处提议研究遗传多态性在非甾体类抗炎药/前列腺素蛋白合酶（NSAIDS/PTGS）途径中的作用。结直肠癌的风险是美国与癌症相关死亡的第二大主要原因，可以通过定期使用阿司匹林和其他NSAID降低约50％，大概是通过抑制前列腺素的合成。腺瘤的复发也可以减少多达40％。整个人群的化学预防益处很明显，但是在个人水平上，由于代谢的遗传变异导致了一些不必要的效果和疗效，方程不太明显。我们先前表明，NSAIDS代谢中的多态性 - 葡萄糖醛酸化和氧化 - 以及前列腺素合成会影响腺瘤的风险或改变常规NSAID使用所获得的益处。因此，在结肠CFR中的4310个不一致的SIB对（受影响的病例/未受影响的病例相对）中，我们现在建议使用候选SNP和基于单倍型的方法来研究NSAIDS代谢代谢中的多态性以及Prostaglandin合成对大肠癌风险的影响。将在300个族裔中的300个人中为PTGS1，PTGS2，NF-KAPPAB和IKAPPAB生成单倍型，并将在4310个不和谐的sibpairs中进行基因分型。此外，我们还将建立体外研究，哪种UGT会催化阿司匹林和其他NSAID的葡萄糖素化，包括布洛芬，苏莱达克，苏洛丹克磺胺和吲哚美辛，以及多态性对代谢能力的影响。最终，有关代谢变异的此类信息将有助于优化NSAID和NSAID方案，并允许对化学预防的个人量身定制。