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: 8292079
• 负责人: Richard M. Weinshilboum
• 金额: --
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292079
• 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; Gene Chips; 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; Single Nucleotide Polymorphism in Coding Sequence; 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; research study; response; transcription factor

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.

摘要 阿糖胞苷（Ara-C）是治疗急性髓细胞性白血病最有效的药物之一， 白血病（AML）。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一个数据丰富的基于细胞的模型系统，包括200个Coriell 研究所人类变异小组淋巴母细胞样细胞系。我们已经用这些细胞系获得了 Ara-C转运、代谢、活化相关蛋白质编码基因的深度重测序数据 和目标（阿糖胞苷-C途径）;检测全基因组单核苷酸多态性（SNP）， 在全基因组关联研究中;以及生成基础表达阵列数据。我们现建议 在相同细胞系中评估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，以使进行基因型分析成为可能。 表型相关性分析以鉴定与Ara-C应答相关的基因组标记。的基因 显示基因型-表型相关性也将在功能上进行研究。药物基因组学假说 然后，将使用从超过1000份样本中获得的DNA样本对使用人类变异样本组细胞系生成的 700例AML患者接受Ara-C治疗。这些研究的结果将增加我们的 了解遗传对Ara-C疗效和毒性个体变异的贡献，并将 帮助我们朝着个体化治疗的目标迈进， AML的治疗。叙事 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 是治疗这种癌症最有效的单一药物。然而，在不同国家之间存在着很大的差异。 患者的阿糖胞苷治疗效果和毒性。拟议的研究将使用一种新的人类 200多个永生化人类细胞系和来自Ara-C治疗的AML患者的DNA的变异组 确定参与遗传对阿糖胞苷应答变异影响的药物基因组学因素， C治疗，使其有可能更好地与阿糖胞苷AML的个性化治疗。