Pharmacogenetics of Ara-C Metabolic Pathway

Ara-C 代谢途径的药物遗传学

• 批准号: 8215851
• 负责人: Jatinder K. Lamba
• 金额: $ 27.77万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215851
• 关键词: 5' -Nucleotidase; Abbreviations; Acute Myelocytic Leukemia; Adverse reactions; Affect; African; Aftercare; Ara-C; Arabinofuranosylcytosine Triphosphate; Binding Sites; Biological Assay; Blast Cell; Candidate Disease Gene; Cell Line; Cells; Childhood Acute Myeloid Leukemia; Childhood Leukemia; Clinical; Clinical Protocols; Clofarabine; Code; Collaborations; Cytarabine; DCMP Deaminase; DNA; DNA Synthesis Inhibition; Data; Decitabine; Deoxycytidine Kinase; Development; Diagnostic; Disease remission; Disease-Free Survival; Dose; Drug toxicity; Drug usage; EMSA; Electrophoretic Mobility Shift Assay; Enrollment; Enzymes; European; Evaluation; Financial Support; Frequencies; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Goals; Government; Human; In Vitro; Individual; Inherited; International; Introns; Leukemic Cell; Luciferases; Malignant Childhood Neoplasm; Measurement; Metabolic; Metabolic Pathway; Metabolism; Molecular; Nigeria; Nucleic Acid Regulatory Sequences; Nucleoside Transporter; Outcome; Pathway interactions; Patients; Persons; Pharmacogenetics; Pharmacogenomics; Phenotype; Predisposition; Prodrugs; Protocols documentation; Reaction; Relative (related person); Reporter; Reporting; Research; Research Personnel; Resistance; Ribonucleotide Reductase; Risk; Saint Jude Children' s Research Hospital; Sampling; Series; Single Nucleotide Polymorphism; Testing; Toxic effect; Treatment outcome; Variant; base; chemotherapy; clinical phenotype; deoxycytidine deaminase; enzyme activity; ethnic difference; experience; gemcitabine; genetic profiling; genetic variant; genome-wide; improved; in vivo; lymphoblast; lymphoblastoid cell line; mRNA Expression; nucleoside analog; outcome forecast; promoter; research study; response; transcription factor; treatment response; uptake

The nucleoside analog cytarabine (ara-C) has been the mainstay of acute myeloid leukemia (AML) chemotherapy for more than 40 years and is one of the most important drugs used to induce remission in patients with AML. A number of studies suggest that the intracellular concentration of its active metabolite, ara-CTP, varies widely among patients and in turn is associated with variability in clinical response. The objective of the current proposal is to determine the molecular basis of this variation in intracellular ara-CTP levels by identifying and evaluating the pharmacogenomic effect of genetic polymorphisms in key genes in the ara-C metabolic pathway, with the long-term goal of explaining the variability observed in treatment response and toxicity profile among AML patients receiving ara-C chemotherapy. The hypothesis of this research is that genetic polymorphisms in key genes in the ara-C metabolic pathway -specifically: deoxycytidine kinase (DCK, a rate limiting activating enzyme); 5'nucleotidase (NT5C2), deoxycytidine deaminase (CDA), and deoxycytidylate deaminase (DCTD) (3 main inactivating enzymes); human equilibrative nucleoside transporter (hENT1/ SLC29A1, ara-C uptake transporter); and ribonucleotide reductase (enzyme regulating intracellular dCTP pools, and consisting of RRM1 and RRM2 subunits) -form the molecular basis of the inter-patient variability observed in intracellular ara-CTP concentration and sensitivity to ara-C. This hypothesis is based on the observations that the above mentioned candidate genes have been shown by various in vitro and in vivo studies to be associated with the clinical response and/or sensitivity to ara-C and demonstrate a wide inter- patient variability in their expression. The specific aims of the proposed research are: 1) To identify and functionally characterize the coding genetic polymorphisms in key ara-C metabolic pathway genes in lymphoblast samples with European (CEPH) or African (YRI) ancestry; 2) To identify and characterize regulatory cis-genetic polymorphisms associated with mRNA expression of the candidate genes; and 3) To determine the association of functionally significant genetic polymorphisms in the candidate genes with clinical phenotypes such as candidate gene expression and ara-C sensitivity in diagnostic blasts, and intracellular ara- CTP levels and the extent of DNA synthesis inhibition in post ara-C treatment leukemic blasts from pediatric AML patients enrolled in the St. Jude AML2002 protocol. The use of CEPH and YRI samples will allow us to use HAPMAP genotype data and to study any ethnic differences in genotype frequencies and in candidate gene expression. The results from this study would also be applicable to other nucleoside analogs such as gemcitabine, decitabine, clofarabine, etc. that are metabolized by the same pathway. Understanding genetic variation in the key candidate genes involved in the metabolism of ara-C will provide us an opportunity to identify patients at increased risk of adverse reactions or decreased likelihood of response, based upon their genetic profile, which in future could help in dose optimization to reduce drug toxicity without compromising on efficacy. Relevance Statement: Acute myeloid leukemia (AML) is the second most common childhood leukemia and has the worst outcome of all major childhood cancers. Ara-C is the main drug used in AML chemotherapy but the cellular levels of its active form, ara-CTP, vary widely among patients and in turn are associated with variability in clinical response to ara-C treatment. The proposed research seeks to explain this variability by studying the inherited genetic variation in key genes involved in ara-C metabolism and may, in future, help to optimize ara-C dosing based on patient genetics.

核苷类似细胞蛋白酸酯（ARA-C）一直是急性髓样白血病（AML）化学疗法的中流，已有40多年的历史，并且是用于诱导AML患者缓解的最重要药物之一。许多研究表明，其活性代谢产物ARA-CTP的细胞内浓度在患者中差异很大，进而依次与临床反应的差异有关。当前提案的目的是通过鉴定和评估ARA-C代谢途径中关键基因中遗传多态性的药物基因组的作用，确定细胞内ARA-CTP水平的分子基础，该遗传基因的药物基础效应，其长期目标的长期目标是在治疗响应中观察到的可变异性在Aml Chem Ara ARA ARA ARA ARA ARA中观察到的可变性。这项研究的假设是，ARA -C代谢途径中的关键基因中的遗传多态性 - 特别是：脱氧胞苷激酶（DCK，限制激活酶的速率）； 5'N核苷酸酶（NT5C2），脱氧胞苷脱氨酸酶（CDA）和脱氧胞苷酸脱氨酶（DCTD）（3个主要失活酶）；人平衡核苷转运蛋白（Hent1/ slc29a1，ara-c摄取转运蛋白）；和核糖核苷酸还原酶（调节细胞内DCTP池，由RRM1和RRM2亚基组成） - 在细胞内ARA-CTP浓度和对ARA-C的敏感性中观察到的患者间变异性的分子基础。该假设基于以下观察结果：上述候选基因已通过各种体外和体内研究表明与临床反应和/或对ARA-C的敏感性相关，并证明其表达的患者间变异性很大。拟议的研究的具体目的是：1）识别并在功能上表征与欧洲（CEPH）或非洲（YRI）血统的淋巴细胞样本中关键ARA-C代谢途径基因中的编码遗传多态性； 2）识别和表征与候选基因的mRNA表达相关的调节性顺式基因多态性； 3）为确定候选基因中功能显着的遗传多态性与临床表型与诊断性爆炸中候选基因表达和ARA-C敏感性等临床表型的关联，以及在ARA-C治疗pediactric aml aml aml aml aml aml aml and and and的a ana-c治疗Lukemic Blast中DNA抑制的细胞内ARA-CTP水平。 CEPH和YRI样品的使用将使我们能够使用HAPMAP基因型数据，并研究基因型频率和候选基因表达中的任何种族差异。这项研究的结果也适用于其他核苷类似物，例如吉西他滨，去足滨，克洛滨等，这些类似物由相同的途径代谢。了解与ARA-C代谢有关的关键候选基因中的遗传变异将为我们提供一个机会，可以根据其遗传特征来识别患者的不良反应风险增加或反应的可能性降低，这将来可能有助于剂量优化，以降低药物毒性而不会造成效果而降低药物毒性。相关性陈述：急性髓性白血病（AML）是第二个最常见的儿童白血病，并且在所有主要儿童期癌症中都具有最差的结果。 ARA-C是AML化学疗法中使用的主要药物，但其活性形式的细胞水平ARA-CTP在患者中差异很大，反过来又与ARA-C治疗的临床反应变化有关。拟议的研究旨在通过研究ARA-C代谢涉及的关键基因的遗传遗传变异来解释这种变异性，并且将来可能有助于根据患者遗传学来优化ARA-C给药。