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: 6675840
• 负责人: LALITHA V IYER
• 金额: $ 33.28万
• 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 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6675840
• 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(申请人提供)：超过50%的癌症患者在接受化疗时经常使用替代药物。这些产品虽然来自天然来源，但可能含有活性成分，可能会影响同时使用的化疗药物的处置和/或治疗结果。这项申请将解决抗癌药物伊立替康(用于治疗结直肠癌)与来自大豆(染料木素和大豆苷元)以及水果和蔬菜(白杨素和栎素)的广受欢迎的饮食类黄酮之间的药物/植物学相互作用的问题。伊立替康具有复杂的排泄特征，有顺序的代谢激活和失活步骤，胆汁和尿液排泄。PI已经对其中一些途径进行了广泛的研究，并表明UGT1A1酶使其活性代谢物SN-38葡萄糖醛酸化，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起主要作用。黄酮类化合物，如白杨素和栎素，是已知的UGT1A1的诱导剂。我们的假设是：(I)所选择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(由UGT1A1诱导)来影响伊立替康的处置和毒性；(Ii)饮食类黄酮对UGT1A1的诱导受到UGT1A1基因启动子区域遗传差异的影响。本研究的具体目的是：(1)研究大豆异黄酮类、白杨素和槲皮素与伊立替康的体内相互作用；(2)确定黄酮类化合物诱导肝脏UGT1A1与伊立替康相互作用的机制；(3)研究UGT1A1启动子区域的TATA多态对其诱导作用的影响。目的1将涉及伊立替康在大鼠体内药代动力学、胆汁和尿液排泄的研究。在目标2中，将通过测量黄酮类药物处理的大鼠肝细胞和肝微粒体中SN-38葡萄糖醛酸化反应以及通过测量UGT1A1蛋白水平来研究UGT1A1的潜在诱导。在目的3中，将采用荧光素酶报告基因分析方法，研究经黄酮类化合物预处理后的Hep G2细胞中UGT1A1的活性。由于伊立替康的治疗指标很窄，其处置的微小变化可以显著改变治疗结果，因此这项研究将对癌症患者和肿瘤学家产生重大的潜在好处。这一试验/开发项目将产生重要的初步结果，以提议由PI和其同事就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计划提供更大的(R01)赠款。