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

阿糖胞苷 (Ara-C) 与急性髓性白血病的药物基因组学

• 批准号: 7826593
• 负责人: Richard M. Weinshilboum
• 金额: $ 33.93万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7826593
• 关键词: Acute Myelocytic Leukemia; Adult; Adverse effects; African American; Antineoplastic Agents; Ara-C; Arabinofuranosylcytosine Triphosphate; Binding; Biological Assay; Biological Models; Candidate Disease Gene; Cell Line; Cells; Chinese American; Clinical; Cytarabine; DNA; DNA Resequencing; Data; Databases; Diagnosis; Disease; Disease remission; Drug Exposure; Drug usage; Electrophoresis; Electrophoretic Mobility Shift Assay; Exons; Exposure to; Funding; Genes; Genetic Polymorphism; Genomics; Genotype; Goals; Haplotypes; Hematopoietic Neoplasms; High Pressure Liquid Chromatography; Human; Human Cell Line; Individual; Institutes; Introns; Linkage Disequilibrium; Luciferases; Malignant Neoplasms; Mammalian Cell; Metabolism; Outcome; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Platelet Count measurement; Process; Promoter Regions; Proteins; RNA Splicing; Relapse; Reporter Genes; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Series; Single Nucleotide Polymorphism; Small Interfering RNA; Testing; Therapeutic Effect; Time; Toxic effect; Treatment Efficacy; Untranslated Regions; Validation; Variant; base; caucasian American; clinically relevant; cytotoxicity; design; genome wide association study; genome-wide; interest; lymphoblastoid cell line; mRNA Expression; mRNA Stability; neutrophil; novel; overexpression; public health relevance; research study; response; transcription factor

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.

描述(由申请人提供)：阿糖胞苷(Ara-C)是治疗急性髓细胞白血病(AML)最有效的单一药物。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系组成。我们已经使用这些细胞系获得了编码参与Ara-C运输、代谢、激活和靶点的蛋白质的深入重新测序数据(“Ara-C途径”)；分析用于全基因组关联研究的基因组范围的单核苷酸多态(SNPs)；以及产生基本的表达阵列数据。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、活性药物代谢物的分析和Ara-C暴露后的表达阵列数据，以便进行基因-表型相关性分析，以确定与Ara-C反应相关的基因组标记。表现出基因型-表型相关性的基因也将从功能上进行研究。然后，将用700多名接受Ara-C治疗的AML患者的DNA样本来检验由人类变异小组细胞系产生的药物基因组假说。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。公共卫生相关性：急性髓细胞白血病(AML)是成人的一种主要血癌，而阿糖胞苷(Ara-C)是治疗这种癌症最有效的单一药物。然而，Ara-C的疗效和毒性在患者之间都有很大的差异。拟议的研究将使用一个由200多个永生化的人类细胞系和接受Ara-C治疗的AML患者的DNA组成的新的“人类变异小组”，以确定遗传对Ara-C治疗变异的影响中涉及的“药物基因组”因素，从而使使用Ara-C更好地“个体化”治疗AML成为可能。