Abstract��High-dose methotrexate can obviously reduce tumor recurrence and prolong disease-free survival. But in actual clinical use, the pharmacokinetics and toxicity of the drug show large interpatient variability. Metabolic enzyme and transporter gene polymorphisms may be one of the important influence factors, which are the research focus in recent years. However, different research shows various results. We reviewed the results of related literatures in recent years and the influence of gene polymorphisms of metabolic enzyme and transporter on pharmacokinetic and toxicity of methotrexate were summarized, which can provide information support for the further study of the individualized treatment of methotrexate.
��¶,�´�,����,������,����÷. ��лø��ת��������̬�ԶԴ�����װ�����ҩ��ѧ��������ӦӰ����о���չ[J]. �й�ҩѧ��־, 2016, 51(1): 10-14.
PANG Lu, CHEN Chuang, ZHU Xu, LIU Li-min, ZHAO Li-mei. Advances of the Influence of Metabolic Enzyme and Transporter Polymorphisms in Pharmacokinetics and Toxicity of High-dose Methotrexate. Chinese Pharmaceutical Journal, 2016, 51(1): 10-14.
ERCULJ N,KOTNIK B F,DEBELJAK M,et al. The influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in children with non-Hodgkin malignant lymphoma. Radio Oncol,2014,48(3):289-292.
[2]
SUTHANDIRAM S,GAN G G,ZAIN S M,et al. Effect of polymorphisms within methotrexate pathway genes on methotrexate toxicity and plasma levels in adults with hematological malignancies. Pharmacogenomics,2014,15(11):1479-1494.
[3]
JABEEN S, HOLMBOE L,ALN�tS G I,et al. Impact of genetic variants of RFC1, DHFR and MTHFR in osteosarcoma patients treated with high-dose methotrexate. Pharmacogenomics J,2015,15(5):385-390.
[4]
LIAO Q C,LI X L,LIU S T,et al. Association between the methylenetetrahydrofolate reductase gene polymorphtsms and haplotype with toxicity response of high dose methotrexate chemotherapy . Chin J Epidemiol(�л����в�ѧ��־),2012,33(7):735-739.
[5]
SEIDEMANN K,BOOK M,ZIMMERMANN M,et al. MTHFR 677 (C��T) polymorphism is not relevant for prognosis or therapy-associated toxicity in pediatric NHL: Results from 484 patients of multicenter trial NHL-BFM 95. Ann Hematol, 2006,85(5):291-300.
[6]
D��ANGELO V,RAMAGLIA M, IANNOTTA A,et al. Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia and MTHFR polymorphisms as pharmacogenetic determinants. Cancer Chemother Pharmacol,2011,68(5):1339-1346.
[7]
LIU J X,CHEN J P,TAN W,et al. Association between mthfr gene polymorphisms and toxicity of HDMTX chemotherapy in acute lymphocytic leukemia . J Exp Hematol(�й�ʵ��ѪҺѧ��־),2008,16(3):488-492.
[8]
YANG L,HU X,XU L. Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: A Meta-analysis. Tumour Biol,2012,33(5):1445-1454.
[9]
LOPEZ-LOPEZ E,MARTIN-GUERRERO I, BALLESTEROS J,et al. A systematic review and Meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia. Pharmacogenomics J,2013,13(6):498-506.
[10]
HAGLEITNER M M,COENEN M J,APLENC R,et al. The role of the MTHFR 677C>T polymorphism in methotrexate-induced liver toxicity: A Meta-analysis in patients with cancer. Pharmacogenomics J,2014,14(2):115-119.
[11]
LAVERDIERE C,CHIASSON S,COSTEA I,et al. Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. Blood,2002,100(10):3832-3834.
[12]
GREGERS J,CHRISTENSEN I J,DALHOFF K,et al. The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number. Blood,2010,115(23):4671-4677.
[13]
WANG J,WANG J H,ZHAO J,et al. The correlation of polymorphism in SLC19A1 and adverse effect by high dose methotrexate . Chin J Clin Pharmacol(�й��ٴ�ҩ��ѧ��־),2013,29(6):406-409.
[14]
HE H R,LIU P,HE G H,et al. Association between reduced folate carrier G80A polymorphism and methotrexate toxicity in childhood acute lymphoblastic leukemia: A Meta-analysis. Leuk Lymphoma,2014,55(12):2793-2800.
[15]
WANG S M,SUN L L, ZENG W X,et al. Effects of a microRNA binding site polymorphism in SLC19A1 on methotrexate concentrations in Chinese children with acute lymphoblastic leukemia. Med Oncol,2014,31(7):1-4.
[16]
RAMSEY L B,PANETTA J C, SMITH C,et al. Genome-wide study of methotrexate clearance replicates SLCO1B1. Blood,2013,121(6):898-904.
[17]
RADTKE S,ZOLK O,RENNER B,et al.Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia. Blood,2013,121(26):5145-5153.
[18]
ZHANG H N,HE X L,WANG C,et al. Impact of SLCO1B1 521T>C variant on leucovorin rescue and risk of relapse in childhood acute lymphoblastic leukemia treated with high-dose methotrexate. Pediatr Blood Cancer,2014,61(12):2203-2207.
[19]
TREVI��O L R,SHIMASAKI N,YANG W,et al. Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J Clin Oncol,2009,27(35):5972-5978.
[20]
LIU S T,LI X L,ZHANG Y,et al. Association of ABCB1, ABCC2 and SLCO1B1 gene polymorphisms with toxicity response of high dose methotrexate chemotherapy . Chin J Lab Med(�л�����ҽѧ��־),2014,37(1):60-65.
[21]
EL MESALLAMY H O,RASHED W M,HAMDY N M,et al. High-dose methotrexate in Egyptian pediatric acute lymphoblastic leukemia:The impact of ABCG2 C421A genetic polymorphism on plasma levels, what is next? . J Cancer Res Clin Oncol,2014,140(8):1359-1365.
[22]
GREGERS J,GR�FEN H,CHRISTENSEN I J,et al. Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia. Pharmacogenomics J,2015,15(4):372-379.
[23]
LIU Y,YIN Y,SHENG Q,et al. Association of ABCC2 -24C>T polymorphism with high-dose methotrexate plasma concentrations and toxicities in childhood acute lymphoblastic leukemia. PLoS One,2014,9(1):e82681.
[24]
ZGHEIB N K,AKRA-ISMAIL M,ARIDI C,et al. Genetic polymorphisms in candidate genes predict increased toxicity with methotrexate therapy in Lebanese children with acute lymphoblastic leukemia. Pharmacogenet Genomics,2014,24(8):387-396.
[25]
SIMON N,MARSOT A,VILLARD E,et al.Impact of ABCC2 polymorphisms on high-dose methotrexate pharmacokinetics in patients with lymphoid malignancy. The Pharmacogenomics J,2013,13(6):507-513.
[26]
LOPEZ-LOPEZ E,BALLESTEROS J,PI��AN M A,et al. Polymorphisms in the methotrexate transport pathway: A new tool for MTX plasma level prediction in pediatric acute lymphoblastic leukemia. Pharmacogenet Genomics,2013,23(2):53-61.
[27]
WANG S M,SUN L L,ZENG W X,et al. Influence of genetic polymorphisms of FPGS, GGH, and MTHFR on serum methotrexate levels in Chinese children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol,2014,74(2):283-289.
[28]
KOOMDEE N,HONGENG S,APIBAL S,et al. Association between polymorphisms of dihydrofolate reductase and gamma glutamyl hydrolase genes and toxicity of high dose methotrexate in children with acute lymphoblastic leukemia. Asian Pac J Cancer Prev,2012,13(7):3461-3464.
[29]
HUANG L,TISSING W J,DE JONGE R,et al. Polymorphisms in folaterelated genes: Association with side effects of high-dose methotrexate in childhood acute lymphoblastic leukemia. Leukemia,2008,22(9):1798-1800.
[30]
KISHI S,CHENG C,FRENCH D,et al. Ancestry and pharmacogenetics of antileukemic drug toxicity. Blood,2007,109(10): 4151-4157.
[31]
ER��ULJ N,KOTNIK B F,DEBELJAK M,et al. Influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in childhood acute lymphoblastic leukemia. Leuk Lymphoma,2012,53(6):1096-1104.
[32]
ONGARO A,DE MATTEI M,DELLA PORTA M G,et al. Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: Effects on methotrexate-related toxicity and survival. Haematologica,2009,94(10):1391-1398.
[33]
FAGANEL KOTNIK B,GRABNAR I,BOHANEC GRABAR P,et al. Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma.Eur J Clin Pharmacol,2011,67(10):993-1006.
[34]
KODIDELA S,SURESH CHANDRA P,DUBASHI B. Pharmacogenetics of methotrexate in acute l ymphoblastic leukaemia: Why still at the bench level. Eur J Clin Pharmacol,2014,70(3):253-260.
2016, Vol. 51 
