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.
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