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疗时定期使用替代药物。这些产品虽然源自天然来源，但可能含有可能影响同时施用的化疗药物的处置和/或治疗结果的活性成分。该申请将解决抗癌剂伊立替康（用于治疗结直肠癌）与来自大豆（染料木黄酮和大豆黄酮）以及水果和蔬菜（白杨素和槲皮素）的流行膳食黄酮类化合物之间的药物/植物相互作用问题。伊立替康具有复杂的处置特征，具有连续的代谢激活和失活步骤、胆汁和尿液排泄。 PI 对其中一些途径进行了广泛研究，并表明酶 UGT1A1 葡萄糖醛酸化其活性代谢物 SN-38，并且多药耐药转运蛋白 p-糖蛋白 (P-gp) 在伊立替康的胆汁排泄中发挥着主要作用。白杨素和槲皮素等黄酮类化合物是已知的 UGT1A1 诱导剂。我们的假设是 (i) 所选膳食黄酮类化合物将通过诱导其活性代谢物 SN-38 的葡萄糖醛酸化（通过 UGT1A1）影响伊立替康的处置和毒性； (ii) 膳食类黄酮对 UGT1A1 的诱导受到 UGT1A1 基因启动子区域遗传差异的影响。具体目的是（1）研究大豆异黄酮、白杨素和槲皮素与伊立替康在大鼠体内的相互作用，（2）确定黄酮类化合物对肝脏 UGT1A1 的诱导是否是其与伊立替康相互作用的原因，以及（3）研究 UGT1A1 启动子区 TATA 多态性对这些药物诱导性的影响 黄酮类化合物。目标 1 将涉及用选定的膳食黄酮类化合物对大鼠进行长期预处理后，对伊立替康进行体内药代动力学、胆汁和尿液排泄研究。目标 2 将通过测量黄酮类处理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 蛋白水平来研究 UGT1A1 的潜在诱导。在目标 3 中，将进行荧光素酶报告基因测定，以研究用 UGT1A1 TATA 序列的已知多态性形式（TA5、TA6、TA7、TA8）转染的 Hep G2 细胞中用黄酮类化合物预处理后的 UGT1A1 活性。由于伊立替康的治疗指数较窄，其处置的微小变化可以显着改变治疗结果，因此这项研究将为癌症患者和肿瘤学家带来重大的潜在益处。该试点/开发项目将产生重要的初步结果，以提议 PI 及其同事计划提供更大的 (R01) 拨款，研究天然药物和膳食补充剂与传统化疗之间的相互作用及其药物遗传学影响。