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 对于一些人来说，药代动力学变异性的主要决定因素 高代谢药物是遗传调节的多态性肝 新陈代谢. 本项目的总体目标是确定 哪种遗传多态性影响药代动力学， 表鬼臼毒素是一类活性高、广泛应用于临床的表鬼臼毒素， 使用的，广泛代谢的抗过敏塑料。 的组合 将进行体外和体内研究，以建立我们的 初步研究表明，替尼泊苷（VM-26）和依托泊苷 （VP-16）可能是多态性美芬妥英羟化酶的底物 酵素 本项目的实验方法将涉及体外 美芬妥英的人肝微粒体研究广泛， 代谢者，并表达特异性人细胞色素P450的cDNA 代谢替尼泊苷，然后利用该表达系统和cDNA探针， 进一步表征替尼泊苷代谢。 临床重要性 替尼泊苷的遗传多态性代谢将在一个大的 一组儿童白血病，通过评估美芬妥英羟基化 替尼泊苷药代动力学的表型和特征，尿 代谢物模式和药理作用。 此外， 年龄对美芬妥英表型的影响将在这一大组中进行检查， 儿童;美芬妥英表达的年龄相关变化 羟化酶（蛋白质和mRNA）在肝组织中的一个子集， 这些儿童也将接受检查。 病人的身份- 细胞色素P450途径的特异性缺陷对于 这些高效抗癌药物的激活或失活将 允许前瞻性识别存在疗效降低风险的儿童 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.