POLYMORPHIC METABOLISM OF ANTINEOPLASTICS IN CHILDREN

抗癌药物的药代动力学变异性已被证明 转化为儿童临床疗效和毒性的变异性 得了癌症。一些药物动力学变异性的主要决定因素 高代谢药物是受基因调控的多形性肝脏 新陈代谢。该项目的总体目标是定义 哪种基因多态会影响药物动力学和 高效、广谱的表鬼臼毒素的药效学 用于儿童的广泛代谢的抗肿瘤药物。一种组合 体外和体内研究将在我们的基础上进行 初步研究表明替尼平苷(Vm-26)和依托泊苷 (VP-16)可能是多态的苯妥英羟基酶的底物 酵素。这个项目的实验方法将涉及到体外 美苯妥因对人肝微粒体的广泛和贫乏研究 代谢物，并表达了特异性的人细胞色素P450的cDNA 代谢替尼平苷，然后利用该表达系统和cDNAs探针 进一步研究替尼平的代谢。血吸虫病的临床重要性 替尼平苷的遗传多态代谢将在大范围内确定 一组儿童白血病，通过评估美苯妥因羟化程度 尿替尼平的表型和药代动力学特征 代谢产物模式和药理作用。此外， 将在这一大群人中检查美苯妥英表型的年龄 儿童；美苯妥因表达与年龄相关的变化 肝组织中的羟基酶(蛋白质和mRNA) 这些儿童也将接受检查。病人的身份识别- 细胞色素P450信号转导通路的特殊缺陷 这些高效抗癌药物的激活或失活将 允许前瞻性地识别有疗效下降风险的儿童 和(或)增强其抗癌方案的毒性。

Pharmacokinetic variability for anticancer drugs has been shown to translate into variability in clinical efficacy and toxicity in children with cancer. A major determinant of pharmacokinetic variability for some highly metabolized drugs is genetically regulated polymorphic hepatic metabolism. The overall goal of this project is to define the extent to which genetic polymorphism affects the pharmacokinetics and pharmacodynamics of epipodophyllotoxins, a class of highly active, widely used, extensively metabolized antineoplastics in children. A combination of in vitro and in vivo studies will be performed to build upon our preliminary studies which indicate that teniposide (VM-26) and etoposide (VP-16) may be substrates for the polymorphic mephenytoin hydroxylase enzyme. The experimental approach of this project will involve in vitro studies with human liver microsomes from mephenytoin extensive and poor metabolizers, and expressed cDNA's for specific human cytochrome P450 metabolizes teniposide, then use this expression system and cDNA probe to further characterize teniposide metabolism. The clinical importance for genetic polymorphic metabolism of teniposide will be determined in a large group of children with leukemia, by assessment of mephenytoin hydroxylation phenotype and characterization of teniposide pharmacokinetics, urinary metabolite pattern, and pharmacologic effect. In addition, the effects of age on mephenytoin phenotype will be examined in this large group of children; age related changes in the expression of the mephenytoin hydroxylase enzyme (protein and mRNA) in liver tissue from a subset of these children will also be examined. The identification of patient- specific deficiencies in cytochrome P450 pathways essential for the activation or inactivation of these highly effective anticancer drugs will allow prospective identification of children at risk for decreased efficacy and(or) enhanced toxicity of their anticancer regimens.