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(Colon CFR)建议调查非类固醇抗炎药物/前列腺素合成酶(NSAIDs/PTGS)途径中的基因多态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类固醇抗炎药可以降低大约50%的风险，可能是通过抑制前列腺素合成。腺瘤的复发也可以减少高达40%。整个人群的化学预防益处是明确的，但在个人层面上，考虑到代谢中的遗传变异造成的一些不必要的影响和不同的疗效，等式不太清楚。我们以前已经证明，非类固醇抗炎药代谢的多态--葡萄糖糖醛酸化和氧化--以及前列腺素合成可以影响腺瘤的风险，或者改变常规使用非类固醇抗炎药的益处。因此，在结肠CFR中4310对不协调的同胞对(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NSAIDs代谢和前列腺素合成的多态对结直肠癌风险的影响。将在5个民族的300个个体中产生PTGS1、Ptgs2、NF-kappaB和IkappaB的单倍型，并对4310个不一致的同胞对进行基因分型。此外，我们还将建立体外研究，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、舒林酸和消炎痛)的葡萄糖醛酸化反应，以及多态对代谢能力的影响。最终，这些关于代谢变化的信息将有助于优化非类固醇抗炎药和非类固醇抗炎药方案，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.