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

描述（由申请人提供）：阿糖胞苷（Ara-C）是用于治疗急性髓性白血病（AML）的单一最有效的药物。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 研究所人类变异面板淋巴母细胞系组成。我们已经使用这些细胞系获得了编码参与 Ara-C 转运、代谢、激活和靶标（“Ara-C 途径”）的蛋白质的基因的深入重测序数据；检测全基因组单核苷酸多态性 (SNP)，用于全基因组关联研究；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、活性药物代谢物的测定和 Ara-C 暴露后的表达阵列数据，以便可以进行基因型-表型相关性分析，以确定与 Ara-C 反应相关的基因组标记。显示基因型-表型相关性的基因也将在功能上进行研究。然后，将使用从 700 多名接受 Ara-C 治疗的 AML 患者获得的 DNA 样本来测试使用 Human Variation Panel 细胞系生成的药物基因组学假设。这些研究结果将增进我们对遗传对Ara-C功效和毒性个体差异的影响的理解，并将帮助我们朝着这一用于治疗AML的重要抗肿瘤药物的“个体化”治疗目标迈进。公共健康相关性：急性髓性白血病 (AML) 是成人的一种主要血癌，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，Ara-C的治疗效果和毒性在患者之间存在较大差异。拟议的研究将使用一个由 200 多个永生化人类细胞系和来自接受 Ara-C 治疗的 AML 患者 DNA 组成的新型“人类变异面板”，以确定参与遗传对 Ara-C 治疗反应变异影响的“药物基因组”因素，从而使 Ara-C 治疗 AML 的更好“个体化”成为可能。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.