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

摘要 阿糖胞苷(Ara-C)是治疗急性髓系白血病最有效的单一药物。 白血病(AML)。然而，Ara-C的疗效和毒性在这种疾病的患者中差异很大。 因此，我们建议对阿糖胞苷进行药物基因组学研究。药物基因组学是对 遗传在药物反应表型个体变异中的作用。拟议的ARA-C 药物基因组学研究将利用一个数据丰富的基于细胞的模型系统，该系统由200个Coriell组成 研究所人类变异研究小组淋巴母细胞系。我们已经用这些细胞系获得了 对编码参与Ara-C转运、代谢、激活的蛋白的基因进行深度重测序 和靶点(Ara-C途径)；用于分析全基因组单核苷酸多态(SNPs) 在全基因组关联研究中；以及生成基本表达阵列数据。我们现在建议 评估相同细胞系中的Ara-C药物反应表型，包括细胞毒性、活性药物分析 Ara-C暴露后的代谢物和表达阵列数据，使进行基因分型成为可能。 表型相关分析以确定与Ara-C反应相关的基因组标记。这些基因 还将从功能上研究显示基因-表型的相关性。药物基因组学假说 用人类变异面板细胞系产生的DNA样本将用从Over 700例急性髓系白血病患者接受阿糖胞苷治疗。这些研究的结果将增加我们的 了解遗传对阿糖胞苷疗效和毒性个体差异的贡献，并将 使用这一重要的抗肿瘤药物帮助我们朝着个性化治疗的目标迈进 急性髓系白血病的治疗。叙事 急性髓系白血病(AML)是成人的主要血癌，阿糖胞苷(Ara-C)是 用于治疗这种癌症的最有效的单一药物。然而，它们之间有很大的差异 患者在阿糖胞苷治疗效果和毒性方面均有不同程度的提高。拟议的研究将使用一种新的人类 用Ara-C治疗的200多个永生化人类细胞系和AML患者DNA的变异小组 确定参与遗传对Ara反应变异的影响的药物基因组学因素 C治疗，使用Ara-C更好地个体化治疗AML成为可能。

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.