The Promise of Pharmacogenomics in ReducingToxicity During Acute Lymphoblastic LeukemiaMaintenance Treatment  

作　　者：Shoshana Rudin Marcus Marable R. Stephanie Huang 

机构地区：[1]Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA [2]Department of Medicine, University of Chicago, Chicago, IL 60637, USA

出　　处：《Genomics, Proteomics & Bioinformatics》2017年第2期82-93,共12页基因组蛋白质组与生物信息学报（英文版）

基　　金：supports from the NIH/NIGMS (Grant Nos. U01GM61393 and K08GM089941);NIH/NCI (Grant No. R21 CA139278);Avon Foundation Research Grant, University of Chicago Cancer Center Support Grant (Grant No. P30 CA14599);Breast Cancer SPORE Career Development Award (Grant No. CA125183);the National Center for Advancing Translational Sciences of the NIH (Grant No. UL1RR024999) of the United States

摘　　要：Pediatric acute lymphoblastic leukemia(ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2–3 years. While the primary drugs used in the maintenance phase, 6-mercaptopurine(6-MP) and methotrexate(MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment.6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase(TPMT), nudix hydrolase 15(NUDT15), and potentially inosine triphosphatase(ITPA), which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1(SLCO1B1) and dihydrofolate reductase(DHFR). Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1(SLC19A1)and thymidylate synthetase(TYMS), but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.Pediatric acute lymphoblastic leukemia(ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2–3 years. While the primary drugs used in the maintenance phase, 6-mercaptopurine(6-MP) and methotrexate(MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment.6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase(TPMT), nudix hydrolase 15(NUDT15), and potentially inosine triphosphatase(ITPA), which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1(SLCO1B1) and dihydrofolate reductase(DHFR). Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1(SLC19A1)and thymidylate synthetase(TYMS), but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.

关 键 词：Acute lymphoblastic leukemia 6-MERCAPTOPURINE METHOTREXATE PHARMACOGENOMICS Maintenance therapy 

分 类 号：R733.71[医药卫生—肿瘤]