Interaction Between Irinotecan and Dietary Flavonoids

伊立替康和膳食黄酮类化合物之间的相互作用

• 批准号: 6792642
• 负责人: LALITHA V IYER
• 金额: $ 33.56万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-18 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6792642
• 关键词: alternative medicine; antineoplastics; antioxidants; cell line; clinical research; colorectal neoplasms; dietary constituent; dietary supplements; enzyme induction /repression; flavones; flavonoids; genetic polymorphism; genistein; glucuronosyltransferase; human tissue; irinotecan; laboratory rat; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nutrient drug interaction; nutrition aspect of cancer; nutrition related tag; pharmacogenetics; phytoestrogens; quercetin; soybeans; tea; toxicology

DESCRIPTION (provided by applicant): Over 50% of cancer patients use alternative medicines regularly while undergoing chemotherapy. These products, though derived from natural sources, may contain active ingredients that may influence the disposition and/or therapeutic outcome of concomitantly administered chemotherapeutics. This application will address the issue of drug/botanical interaction between the anticancer agent irinotecan (used against colorectal cancer) and the popular dietary flavonoids from soy (genistein and daidzein) and fruits and vegetables (chrysin and quercetin). Irinotecan has complex dispositional characteristics, with sequential metabolic activation and inactivation steps, biliary and urinary excretion. The PI has studied some of these pathways extensively and has shown that the enzyme UGT1A1 glucuronidates its active metabolite, SN-38, and that the multidrug resistance transporter, p-glycoprotein (P-gp), plays a major role in irinotecan's biliary excretion. Flavonoids such as chrysin and quercetin are known inducers of UGT1A1. Our hypothesis are that (i) the selected dietary flavonoids will influence the disposition and toxicity of irinotecan via induction of the glucuronidation (by UGT1A1) of its active metabolite, SN-38; and (ii) induction of UGT1A1 by dietary flavonoids is influenced by genetic differences in the promoter region of the UGT1A1 gene. The specific aims are to (1) investigate the in vivo interaction of soy isoflavones, chrysin and quercetin with irinotecan in rats, (2) determine whether hepatic UGT1A1 induction by flavonoids is responsible for their interaction with irinotecan, and (3) investigate the influence of the TATA polymorphism in the promoter region of UGT1A1 on inducibility by these flavonoids. Aim 1 will involve in vivo pharmacokinetic, biliary, and urinary excretion studies with irinotecan after chronic pretreatment of rats with the selected dietary flavonoids. The potential induction of UGT1A1 will be studied in Aim 2 by measuring SN-38 glucuronidation in hepatocytes and liver microsomes from flavonoid treated rats, as well as by measuring UGT1A1 protein levels. In Aim 3, luciferase reporter assays will be performed to investigate UGT1A1 activity after pretreatment with flavonoids in Hep G2 cells transfected with known polymorphic forms (TA5,TA6,TA7,TA8) of the TATA sequence of UGT1A1. As irinotecan has a narrow therapeutic index, minor changes in its disposition can significantly modify the therapeutic outcome, so this investigation will have major potential benefits to cancer patients and oncologists. This pilot/developmental project will generate significant preliminary results to propose larger (R01) grants being planned by the PI and colleagues on the interaction between natural medications & dietary supplements and conventional chemotherapy, and its pharmacogenetic implications.

描述（由申请人提供）：超过50％的癌症患者在接受化学疗法的同时定期使用替代药物。这些产品虽然源自自然来源，但可能包含可能影响同时给药化学治疗剂的处置和/或治疗结果的活性成分。该应用将解决抗癌剂伊立替康（针对大豆（Genastein and daidzein））以及水果和蔬菜（Chrysin and槲皮素）之间的流行饮食类黄酮（用于结直肠癌）之间的药物/植物相互作用问题。伊立替康具有复杂的性格特征，具有顺序代谢激活和灭活步骤，胆道和尿液排泄。 PI已广泛研究了其中的一些途径，并表明酶UGT1A1葡萄糖醛酸糖可以使其活性代谢物SN-38，并且多药抗性转运蛋白P-糖蛋白（P-GP）在Irinotecan的胆汁胆汁卵中起主要作用。类黄酮（例如菊花和槲皮素）是UGT1A1的诱导剂。我们的假设是（i）选定的饮食类黄酮将通过诱导其活性代谢物SN-38的葡萄糖醛酸化（通过UGT1A1）来影响伊立替康的处置和毒性； （ii）饮食类黄酮诱导UGT1A1受到UGT1A1基因启动子区域的遗传差异的影响。具体目的是（1）研究大鼠中大豆异黄酮，二晶和槲皮素与大鼠中伊立替康的体内相互作用，（2）确定黄酮素是否负责肝ugt1a1诱导是否负责其与伊立替克的相互作用，以及（3）研究影响。这些类黄酮诱导性的UGT1A1启动子区域的TATA多态性。 AIM 1将涉及体内药代动力学，胆道和尿液排泄研究，并在患有选定饮食类黄酮的大鼠长期治疗后，通过虹膜肌肉进行研究。通过测量来自类黄酮治疗的大鼠的肝细胞和肝微粒体中的SN-38葡萄糖醛酸化，以及测量UGT1A1蛋白水平，将在AIM 2中研究UGT1A1的潜在诱导。在AIM 3中，将进行荧光素酶报道测定法测定在用UGT1A1 TATA序列的已知多态性形式（TA5，TA6，TA7，TA8）转染的Hep G2细胞中用类黄酮进行预处理后的UGT1A1活性。由于伊立替康具有狭窄的治疗指数，因此其处置的微小变化可以显着改变治疗结果，因此，这项研究将对癌症患者和肿瘤学家具有很大的潜在益处。该试点/发育项目将产生重要的初步结果，以提出PI及其同事计划对天然药物与饮食补充剂与常规化学疗法之间的相互作用及其药物遗传学意义计划的较大（R01）赠款。