Interaction Between Irinotecan and Dietary Flavonoids

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。这些产品虽然来自天然来源，但可能含有可能影响伴随使用的化疗药物的处置和/或治疗结果的活性成分。本申请将解决抗癌药物伊立替康（用于治疗结直肠癌）与大豆（染料木素和大豆苷元）和水果蔬菜（白杨素和槲皮素）中常见的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，具有连续的代谢活化和灭活步骤、胆汁和尿液排泄。PI广泛研究了其中一些途径，并表明酶UGT 1A 1葡萄糖醛酸化其活性代谢产物SN-38，以及多药耐药转运蛋白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槲皮素是已知的UGT 1A 1诱导剂。我们的假设是：（i）选定的膳食黄酮将通过诱导伊立替康活性代谢产物SN-38的葡萄糖醛酸化（通过UGT 1A 1）影响伊立替康的处置和毒性;（ii）膳食黄酮对UGT 1A 1的诱导受UGT 1A 1基因启动子区遗传差异的影响。具体目的是（1）研究大鼠中大豆异黄酮、白杨素和槲皮素与伊立替康的体内相互作用，（2）确定类黄酮对肝脏UGT 1A 1的诱导是否是其与伊立替康相互作用的原因，以及（3）研究UGT 1A 1启动子区TATA多态性对这些类黄酮诱导的影响。目的1将涉及在体内药代动力学，胆汁和尿排泄研究伊立替康长期预处理大鼠与选定的膳食黄酮。将在目标2中通过测定类黄酮给药大鼠肝细胞和肝微粒体中的SN-38葡萄糖醛酸化以及通过测定UGT 1A 1蛋白水平研究UGT 1A 1的潜在诱导作用。在目标3中，将进行荧光素酶报告基因试验，以研究在用UGT 1A 1的TATA序列的已知多态性形式（TA 5、TA 6、TA 7、TA 8）转染的Hep G2细胞中用类黄酮预处理后的UGT 1A 1活性。由于伊立替康的治疗指数较窄，其处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产生重大潜在益处。该试点/开发项目将产生重要的初步结果，以提出PI及其同事计划的更大（R 01）赠款，用于天然药物和膳食补充剂与常规化疗之间的相互作用及其药物遗传学意义。

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.