Interaction Between Irinotecan and Dietary Flavonoids

说明（申请人提供）：超过50%的癌症患者在化疗期间定期使用替代药物。这些产品虽然来源于天然来源，但可能含有可能影响同时施用化疗药物的处置和/或治疗结果的活性成分。该应用程序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）和水果和蔬菜（菊花素和槲皮素）的常见膳食类黄酮之间的药物/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对其中的一些途径进行了广泛的研究，并表明UGT1A1葡萄糖醛酸酶使其活性代谢物SN-38和多药耐药转运体p-糖蛋白（P-gp）在伊立替康的胆道排泄中起主要作用。黄酮类化合物如菊花素和槲皮素是已知的UGT1A1的诱导剂。我们的假设是：(i)选定的膳食类黄酮将通过诱导其活性代谢物SN-38的糖醛酸化（由UGT1A1）来影响伊立替康的处置和毒性；（ii）膳食黄酮类化合物对UGT1A1的诱导受UGT1A1基因启动子区域遗传差异的影响。具体目的是：(1)研究大鼠体内大豆异黄酮、菊花素和槲皮素与伊立替康的相互作用；(2)确定黄酮类化合物诱导肝脏UGT1A1是否与伊立替康的相互作用有关；(3)研究UGT1A1启动子区TATA多态性对这些黄酮类化合物诱导作用的影响。目的1将涉及伊立替康对大鼠进行慢性预处理后的体内药代动力学、胆道和尿排泄研究。在Aim 2中，将通过测量类黄酮处理大鼠肝细胞和肝微粒体中的SN-38糖醛酸化以及测量UGT1A1蛋白水平来研究UGT1A1的潜在诱导作用。在Aim 3中，荧光素酶报告基因检测将在转染了UGT1A1 TATA序列已知多态性形式（TA5、TA6、TA7、TA8）的Hep G2细胞中进行黄酮预处理后，研究UGT1A1的活性。由于伊立替康的治疗指数较窄，其配置的微小变化可显著改变治疗结果，因此这项研究将对癌症患者和肿瘤学家具有重大的潜在益处。该试点/发展项目将产生重要的初步结果，为PI及其同事计划的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理学意义提出更大（R01）拨款。

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.