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

描述（由申请人提供）：阿糖胞苷（Ara-C）是治疗急性髓性白血病（AML）的单一最有效药物。然而，Ara-C的疗效和毒性在患有这种疾病的患者中差异很大。因此，我们建议对阿糖胞苷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由200个Coriell Institute Human Variation Panel淋巴母细胞样细胞系组成的数据丰富的基于细胞的“模型系统”。我们已经使用这些细胞系来获得编码参与Ara-C转运、代谢、活化和靶点（“Ara-C途径”）的蛋白质的基因的深度重测序数据;测定用于全基因组关联研究的全基因组单核苷酸多态性（SNP）;并生成基础表达阵列数据。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，活性药物代谢产物的测定和Ara-C暴露后的表达阵列数据，以进行基因型-表型相关性分析，以鉴定与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患者中获得的DNA样本对使用Human Variation Panel细胞系生成的药物基因组学假设进行检验。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了解，并将帮助我们利用这种用于治疗急性粒细胞白血病的重要抗肿瘤药物实现“个体化”治疗的目标。公共卫生相关性：急性骨髓性白血病（AML）是成人的主要血液癌症，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，阿糖胞苷的疗效和毒性在患者之间存在很大差异。拟议的研究将使用一种新的“人类变异组”，由200多个永生化的人类细胞系和来自用Ara-C治疗的AML患者的DNA组成，以鉴定参与遗传对Ara-C治疗响应的变异的影响的“药物基因组学”因素，从而使用Ara-C更好地“个体化”AML治疗成为可能。

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.