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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA051001-02
Application #
3459678
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1990-04-01
Project End
1995-02-28
Budget Start
1991-03-01
Budget End
1992-02-29
Support Year
2
Fiscal Year
1991
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Pauley, Jennifer L; Panetta, John C; Crews, Kristine R et al. (2013) Between-course targeting of methotrexate exposure using pharmacokinetically guided dosage adjustments. Cancer Chemother Pharmacol 72:369-78
Pui, C H; Pei, D; Sandlund, J T et al. (2010) Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia. Leukemia 24:371-82
Crews, Kristine R; Zhou, Yinmei; Pauley, Jennifer L et al. (2010) Effect of allopurinol versus urate oxidase on methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia. Cancer 116:227-32
Morris, Van K; Spraker, Holly L; Howard, Scott C et al. (2010) Severe thrombocytopenia with iron deficiency anemia. Pediatr Hematol Oncol 27:413-9
Metzger, Monika L; Hudson, Melissa M; Krasin, Matthew J et al. (2010) Initial response to salvage therapy determines prognosis in relapsed pediatric Hodgkin lymphoma patients. Cancer 116:4376-84
Panetta, J C; Gajjar, A; Hijiya, N et al. (2009) Comparison of native E. coli and PEG asparaginase pharmacokinetics and pharmacodynamics in pediatric acute lymphoblastic leukemia. Clin Pharmacol Ther 86:651-8
French, Deborah; Yang, Wenjian; Cheng, Cheng et al. (2009) Acquired variation outweighs inherited variation in whole genome analysis of methotrexate polyglutamate accumulation in leukemia. Blood 113:4512-20
TreviƱo, Lisa R; Yang, Wenjian; French, Deborah et al. (2009) Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet 41:1001-5
Roberson, J R; Spraker, H L; Shelso, J et al. (2009) Clinical consequences of hyperglycemia during remission induction therapy for pediatric acute lymphoblastic leukemia. Leukemia 23:245-50
Yang, Jun J; Cheng, Cheng; Yang, Wenjian et al. (2009) Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 301:393-403

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