Pharmacogenomics of cytosine arabinoside (Ara-C) and acute myelogenous leukemia

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ABSTRACT Cytosine arabinoside (Ara-C) is the single most effective drug used in the treatment of acute myelogenous leukemia (AML). However, Ara-C efficacy and toxicity vary widely among patients with this disease. Therefore, we propose to study the pharmacogenomics of Ara-C. Pharmacogenomics is the study of the role of inheritance in individual variation in drug response phenotypes. The proposed Ara-C pharmacogenomic studies will utilize a data-rich cell-based ¿model system¿ consisting of 200 Coriell Institute Human Variation Panel lymphoblastoid cell lines. We have already used these cell lines to obtain indepth resequencing data for genes encoding proteins involved in Ara-C transport, metabolism, activation and targets (the ¿Ara-C pathway¿); to assay genome-wide single nucleotide polymorphisms (SNPs) for use in genome-wide association studies; and to generate basal expression array data. We now propose to assess Ara-C drug response phenotypes in the same cell lines, including cytotoxicity, assays of active drug metabolites and expression array data after Ara-C exposure to make it possible to perform genotype- phenotype correlation analyses to identify genomic markers associated with Ara-C response. Genes that display genotype-phenotype correlations will also be studied functionally. Pharmacogenomic hypotheses generated with Human Variation Panel cell line will then be tested with DNA samples obtained from over 700 AML patients who were treated with Ara-C. The results of these studies will increase our understanding of the contribution of inheritance to individual variation in Ara-C efficacy and toxicity, and will help us to move toward the goal of ¿individualized¿ therapy with this important antineoplastic drug used in the treatment of AML. NARRATIVE Acute myelogenous leukemia (AML) is a major blood cancer in adults, and cytosine arabinoside (Ara-C) is the most effective single drug used to treat this form of cancer. However, there are large differences among patients in both Ara-C therapeutic effect and toxicity. The proposed studies will use a novel ¿Human Variation Panel¿ of over 200 immortalized human cell lines and DNA from AML patients treated with Ara-C to identify ¿pharmacogenomic¿ factors involved in the effects of inheritance on variation in response to Ara- C therapy to make it possible to better ¿individualize¿ therapy of AML with Ara-C.