NSAID and COX/PG Metabolism and Colorectal Cancer

描述（由申请人提供）：结肠直肠癌研究合作家庭登记处（Colon CFR）提议研究非甾体抗炎药/前列腺素合成酶（NSAIDs/PTGS）途径中遗传多态性在预防结直肠癌中的作用。结直肠癌是美国癌症相关死亡的第二大原因，定期使用阿司匹林和其他非甾体抗炎药可将结直肠癌的风险降低约50%，可能是通过抑制前列腺素的合成。腺瘤的复发率也可降低40%。化学预防对整个人群的好处是显而易见的，但在个人层面上，由于新陈代谢的遗传变异，会产生一些不必要的影响和不同的效果，这个等式就不太清楚了。我们之前的研究表明，非甾体抗炎药代谢（葡萄糖醛酸化和氧化）和前列腺素合成的多态性会影响腺瘤的风险或改变常规使用非甾体抗炎药的益处。因此，在结肠CFR中4310对不一致的兄弟姐妹（受影响的病例/未受影响的亲属）中，我们现在建议使用候选SNP和基于单倍型的方法来研究非甾体抗炎药代谢和前列腺素合成多态性对结直肠癌风险的影响。将在5个民族的300个个体中生成PTGS1、PTGS2、NF-KappaB和IkappaB的单倍型，并对4310对不一致的兄弟姐妹进行基因分型。此外，我们将建立体外研究，哪些ugt催化阿司匹林和其他非甾体抗炎药（包括布洛芬、舒林酸、舒林酸砜和吲哚美辛）的糖醛酸化，以及多态性对代谢能力的影响。最终，这些代谢变化的信息将有助于优化非甾体抗炎药和非甾体抗炎药方案，并将允许个性化的化学预防。

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.