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

摘要 阿糖胞苷（Ara-C）是治疗急性骨髓性骨髓瘤最有效的单一药物 白血病（AML）。然而，Ara-C 的功效和毒性在患有这种疾病的患者中差异很大。 因此，我们建议研究Ara-C的药物基因组学。药物基因组学是研究 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 研究所人类变异小组淋巴母细胞系。我们已经使用这些细胞系来获得 编码参与 Ara-C 运输、代谢、激活的蛋白质的基因的深入重测序数据 和目标（“Ara-C 途径”）；检测全基因组单核苷酸多态性 (SNP) 以供使用 全基因组关联研究；并生成基础表达阵列数据。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、活性药物测定 Ara-C 暴露后的代谢物和表达阵列数据，使执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。基因 显示基因型-表型相关性也将从功能上进行研究。药物基因组学假设 然后用人类变异面板细胞系生成的 DNA 样本进行测试 700 名接受 Ara-C 治疗的 AML 患者。这些研究的结果将提高我们的 了解遗传对 Ara-C 功效和毒性个体差异的影响，并将 使用这种重要的抗肿瘤药物帮助我们朝着“个体化”治疗的目标迈进 AML 的治疗。叙事 急性髓性白血病 (AML) 是成人中的一种主要血癌，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，之间存在很大差异 患者中Ara-C兼具治疗效果和毒性。拟议的研究将使用一种新颖的“人类” 超过 200 个永生化人类细胞系和来自接受 Ara-C 治疗的 AML 患者 DNA 的变异面板 确定与遗传对 Ara- 反应变异的影响有关的“药物基因组”因素 C 疗法使 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.