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

描述（由申请人提供）：阿拉伯糖胞嘧啶（Ara-C）是用于治疗急性髓性白血病（AML）的最有效药物。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Ara-C进行药物基因组学研究。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一个数据丰富的基于细胞的“模型系统”，该系统由200个科里尔研究所人类变异小组淋巴母细胞样细胞系组成。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度重测序数据；测定全基因组单核苷酸多态性（snp），用于全基因组关联研究；并生成基础表达式数组数据。我们现在建议在相同的细胞系中评估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暴露于Ara-C后的表达阵列数据，从而有可能进行基因型-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从功能上进行研究。人类变异小组细胞系产生的药物基因组学假设将随后用从接受Ara-C治疗的700多名AML患者获得的DNA样本进行测试。这些研究的结果将增加我们对遗传对Ara-C疗效和毒性个体差异的贡献的理解，并将帮助我们朝着使用这种重要的抗肿瘤药物治疗AML的“个体化”治疗的目标迈进。公共卫生相关性：急性髓性白血病（AML）是成人的一种主要血癌，阿糖胞嘧啶（Ara-C）是治疗这种癌症最有效的单一药物。然而，不同患者在Ara-C的治疗效果和毒性方面存在较大差异。拟议的研究将使用一个新的“人类变异小组”，包括200多个永生的人类细胞系和来自接受Ara-C治疗的AML患者的DNA，以确定遗传对Ara-C治疗反应变异影响的“药物基因组学”因素，从而使用Ara-C治疗AML更好地“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.