NSAID and COX/PG Metabolism and Colorectal Cancer

描述（由申请人提供）：结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（NSAID/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NSAID可以降低约50%的结直肠癌风险，可能是通过抑制前列腺素合成。腺瘤的复发率也可降低高达40%。整个人群的化学预防益处是明确的，但在个体水平上，由于代谢的遗传变异，考虑到一些不必要的影响和不同的功效，等式不太清楚。我们以前发现，非甾体类抗炎药代谢-葡萄糖醛酸化和氧化-和前列腺素合成的多态性可以影响腺瘤的风险或修改从定期使用非甾体类抗炎药的好处。因此，在4310个不一致的同胞对（受影响的情况下/未受影响的相对）在结肠CFR，我们现在建议使用候选SNP和单体型为基础的方法来调查的影响，在非甾体抗炎药代谢和前列腺素合成的多态性对结直肠癌的风险。将在5个种族组的300名个体中生成PTGS 1、PTGS 2、NF-κ B和IkappaB的单倍型，并在4310个不一致同胞对中进行基因分型。此外，我们将建立体外研究，其中UGT催化阿司匹林和其他NSAID（包括布洛芬、舒林酸、舒林酸砜和吲哚美辛）的葡萄糖醛酸化，以及多态性对代谢能力的影响。最终，这些信息的代谢变化将是有用的优化NSAID和NSAID方案，并允许个体定制的化学预防。

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.