Aspirin, UGT1A6 Genotype, and Colon Gene Expression

阿司匹林、UGT1A6 基因型和结肠基因表达

• 批准号: 6878599
• 负责人: JOHN D POTTER
• 金额: $ 85.94万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-13 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6878599
• 关键词: BCL2 gene /protein; Bax gene /protein; apoptosis; aspirin; biomarker; biopsy; cancer prevention; clinical research; colon; colon neoplasms; complementary DNA; drug metabolism; epithelium; gastrointestinal epithelium; gene expression; genotype; glucuronides; glucuronosyltransferase; human subject; immunocytochemistry; microarray technology; patient oriented research; polymerase chain reaction; rectum /anus; uridine diphosphate

DESCRIPTION (provided by applicant): Colorectal cancers are thought to arise as the result of a series of molecular changes that transform normal epithelial cells into a colorectal carcinoma, with an adenomatous polyp as an intermediate step in this process. One way to reduce mortality from this cancer involves the use of oral agents that prevent neoplasms from developing in the large bowel. Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) reduces the incidence of colon adenomas as well as carcinomas by approximately 50 percent. Enzymes prominently involved in metabolizing aspirin are UDP-glucuronosyltransferases (UGT). UGT1A6 is a polymorphic UGT and its variant alleles metabolize aspirin less efficiently. We showed that in NSAIDs users, and aspirin users in particular, the risk for colon neoplasia is reduced only in individuals who are UGT1A6 heterozygous and homozygous variant, but not homozygous wild-type. Aspirin and its metabolite, salicylic acid, can inhibit growth through the inhibition of cyclooxygenases (catalysts of prostaglandin synthesis), the promotion of apoptosis, and other as yet unidentified pathways. The goal of this project is to determine the effect of UGT1A6 genotype on aspirin metabolism and on aspirin-induced changes in colonic gene expression and protein markers of apoptosis (Bax and Bcl-2). We propose to study: 1) urinary excretion of aspirin metabolites in 380 healthy individuals with different UGT1A6 genotypes in a cross-sectional study and 2) changes in colon gene expression induced by aspirin supplementation in a randomized, placebo-controlled trial of 40 individuals who are either homozygous wild-type or homozygous variant for UGT1A6. We hypothesize that in slow metabolizers the proportion of glucuronidated metabolites is smaller and that a smaller proportion of the aspirin dose is excreted within a specific time. Alterations in colonic gene expression will be determined using cDNA microarray analysis of biopsy RNA from the sigmoid colon and rectum and Bax and Bcl-2 expression in the colonic crypts will be measured by immunohistochemistry. We hypothesize that expression of e.g. growth-promoting genes will be reduced and apoptotic genes increased during aspirin use and that this reduction may be stronger in slow metabolizers than fast metabolizers. This project will also allow the identification of other genes whose expression is affected by aspirin supplementation. Ultimately, information obtained from this project will be useful in developing chemopreventive drugs that specifically target pathways involved in colon neoplasia. By targeting relevant pathways, side effects caused by the use of NSAIDs or specific Cox-2 inhibitors may be avoided.

描述（由申请人提供）：结直肠癌被认为是 一系列分子变化的结果会改变正常上皮 细胞进入结直肠癌，并具有腺瘤息肉为中间 踏上此过程。从这种癌症中降低死亡率的一种方法涉及 使用可防止肿瘤在大肠中发育的口服剂。 定期使用阿司匹林和其他非甾体类抗炎药（NSAIDS） 将结肠腺瘤和癌的发生率降低 50％。参与代谢阿司匹林的酶是 UDP-葡萄糖基转移酶（UGT）。 UGT1A6是多态性UGT及其变体 等位基因对阿司匹林的代谢效率降低。我们表明，在NSAIDS用户中， 特别是阿司匹林使用者，仅降低结肠肿瘤的风险 在ugt1a6杂合和纯合的个体中，但不是 纯合野生型。阿司匹林及其代谢物水杨酸可以抑制 通过抑制环氧酶（前列腺素催化剂的抑制作用）生长 合成），促进凋亡以及其他尚未确定的途径。 该项目的目的是确定UGT1A6基因型对 阿司匹林代谢和阿司匹林诱导的结肠基因表达变化 和凋亡的蛋白质标志物（BAX和BCL-2）。我们建议研究：1） 380个健康个体中阿司匹林代谢产物的尿排泄 横断面研究中的不同UGT1A6基因型和2）结肠的变化 在随机的， 40个纯合野生型的人的安慰剂对照试验 或用于UGT1A6的纯合变量。我们假设在缓慢代谢器中 葡萄糖醛酸苷代谢物的比例较小，并且较小 阿司匹林剂量的比例在特定时间内排出。改变 在结肠基因表达中，将使用cDNA微阵列分析确定 来自Sigmoid结肠和直肠和Bax和Bcl-2表达的活检RNA 结肠隐窝将通过免疫组织化学测量。我们假设 例如促进生长基因将减少并凋亡 基因在使用期间增加了基因，这种降低可能会更强 缓慢的代谢剂比快速代谢器。该项目还将允许 鉴定其表达受阿司匹林影响的其他基因 补充。最终，从该项目获得的信息将是 对于开发专门针对途径的化学预防药物有用 参与结肠肿瘤。通过针对相关途径，副作用 可以避免使用NSAID或特定COX-2抑制剂引起的。