Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Methotrexate Disposition in Pediatric Patients with Acute Lymphoblastic Leukemia: What Have We Learnt From the Genetic Variants of Drug Transporters

Author(s): Ya-Hui Hu, Lin Zhou, Shan-Shan Wang, Xia Jing, Hong-Li Guo, Fang Sun, Yong Zhang, Feng Chen, Jing Xu* and Xing Ji*

Volume 25, Issue 6, 2019

Page: [627 - 634] Pages: 8

DOI: 10.2174/1381612825666190329141003

Price: $65


Background: Methotrexate (MTX) is one of the leading chemotherapeutic agents with the bestdemonstrated efficacies against childhood acute lymphoblastic leukemia (ALL). Due to the narrow therapeutic range, significant inter- and intra-patient variabilities of MTX, non-effectiveness and/or toxicity occur abruptly to cause chemotherapeutic interruption or discontinuation. The relationship between clinical outcome and the systemic concentration of MTX has been well established, making the monitoring of plasma MTX levels critical in the treatment of ALL. Besides metabolizing enzymes, multiple transporters are also involved in determining the intracellular drug levels. In this mini-review, we focused on the genetic polymorphisms of MTX-disposition related transporters and the potential association between the discussed genetic variants and MTX pharmacokinetics, efficacy, and toxicity in the context of MTX treatment.

Methods: We searched PubMed for citations published in English using the terms “methotrexate”, “transporter”, “acute lymphoblastic leukemia”, “polymorphisms”, and “therapeutic drug monitoring”. The retrieval papers were critically reviewed and summarized according to the aims of this mini-review.

Results: Solute carrier (SLC) transporters (SLC19A1, SLCO1A2, SLCO1B1, and SLC22A8) and ATP-binding cassette (ABC) transporters (ABCB1, ABCC2, ABCC3, ABCC4, ABCC5, and ABCG2) mediate MTX disposition. Of note, the influences of polymorphisms of SLC19A1, SLCO1B1 and ABCB1 genes on the clinical outcome of MTX have been extensively studied.

Conclusion: Overall, the data critically reviewed in this mini-review article confirmed that polymorphisms in the genes encoding SLC and ABC transporters confer higher sensitivity to altered plasma levels, MTX-induced toxicity, and therapeutic response in pediatric patients with ALL. Pre-emptive determination may be helpful in individualizing treatment.

Keywords: Methotrexate, acute lymphoblastic leukemia, SLC transporters, ABC transporters, polymorphism, therapeutic drug monitoring, pharmacokinetics.

Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 2014; 64(2): 83-103.
Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: Where are we going and how do we get there? Blood 2012; 120(6): 1165-74.
Rudin S, Marable M, Huang RS. The promise of pharmacogenomics in reducing toxicity during acute lymphoblastic leukemia maintenance treatment. Genomics Proteomics Bioinformatics 2017; 15(2): 82-93.
de Beaumais TA, Jacqz-Aigrain E. Intracellular disposition of methotrexate in acute lymphoblastic leukemia in children. Curr Drug Metab 2012; 13(6): 822-34.
Cheok MH, Pottier N, Kager L, Evans WE. Pharmacogenetics in acute lymphoblastic leukemia. Semin Hematol 2009; 46(1): 39-51.
Csordas K, Lautner-Csorba O, Semsei AF, et al. Associations of novel genetic variations in the folate-related and ARID5B genes with the pharmacokinetics and toxicity of high-dose methotrexate in paediatric acute lymphoblastic leukaemia. Br J Haematol 2014; 166(3): 410-20.
Wall AM, Gajjar A, Link A, Mahmoud H, Pui CH, Relling MV. Individualized methotrexate dosing in children with relapsed acute lymphoblastic leukemia. Leukemia 2000; 14(2): 221-5.
Lopez-Lopez E, Ballesteros J, Piñan MA, 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.
den Hoed MA, Lopez-Lopez E, te Winkel ML, et al. Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia. Pharmacogenomics J 2015; 15(3): 248-54.
Schmiegelow K. Advances in individual prediction of methotrexate toxicity: A review. Br J Haematol 2009; 146(5): 489-503.
Bhojwani D, Sabin ND, Pei D, et al. Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol 2014; 32(9): 949-59.
Paci A, Veal G, Bardin C, et al. Review of therapeutic drug monitoring of anticancer drugs part 1--cytotoxics. Eur J Cancer 2014; 50(12): 2010-9.
Treviño LR, 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): 5972-8.
Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med 1998; 338(8): 499-505.
Inoue K, Yuasa H. Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet 2014; 29(1): 12-9.
Drew L. Pharmacogenetics: The right drug for you. Nature 2016; 537(7619): S60-2.
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): 5145-53.
DeGorter MK, Xia CQ, Yang JJ, Kim RB. Drug transporters in drug efficacy and toxicity. Annu Rev Pharmacol Toxicol 2012; 52: 249-73.
Gregers J, Christensen IJ, 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): 4671-7.
van der Heijden JW, Dijkmans BA, Scheper RJ, Jansen G. Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs--from bench to bedside. Nat Clin Pract Rheumatol 2007; 3(1): 26-34.
Whetstine JR, Gifford AJ, Witt T, et al. Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high-frequency G/A variant at position 80 and transport properties of the His(27) and Arg(27) carriers. Clin Cancer Res 2001; 7(11): 3416-22.
de Jonge R, Tissing WJ, Hooijberg JH, et al. Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia. Blood 2009; 113(10): 2284-9.
Laverdière C, Chiasson S, Costea I, Moghrabi A, Krajinovic M. 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): 3832-4.
Leyva-Vázquez MA, Organista-Nava J, Gómez-Gómez Y, Contreras-Quiroz A, Flores-Alfaro E, Illades-Aguiar B. Polymorphism G80A in the reduced folate carrier gene and its relationship to survival and risk of relapse in acute lymphoblastic leukemia. J Investig Med 2012; 60(7): 1064-7.
Wang SM, Sun LL, Zeng WX, Wu WS, Zhang GL. Effects of a microRNA binding site polymorphism in SLC19A1 on methotrexate concentrations in Chinese children with acute lymphoblastic leukemia. Med Oncol 2014; 31(7): 62.
Zaruma-Torres F, Lares-Asseff I, Lima A, et al. Genetic Polymorphisms Associated to Folate Transport as Predictors of Increased Risk for Acute Lymphoblastic Leukemia in Mexican Children. Front Pharmacol 2016; 7: 238.
Lee W, Glaeser H, Smith LH, et al. Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry. J Biol Chem 2005; 280(10): 9610-7.
Wang SM, Zeng WX, Wu WS, Sun LL, Yan D. Association between a microRNA binding site polymorphism in SLCO1A2 and the risk of delayed methotrexate elimination in Chinese children with acute lymphoblastic leukemia. Leuk Res 2018; 65: 61-6.
Laitinen A, Niemi M. Frequencies of single-nucleotide polymorphisms of SLCO1A2, SLCO1B3 and SLCO2B1 genes in a Finnish population. Basic Clin Pharmacol Toxicol 2011; 108(1): 9-13.
Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: A genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev 2011; 63(1): 157-81.
Lopez-Lopez E, Martin-Guerrero I, Ballesteros J, et al. Polymorphisms of the SLCO1B1 gene predict methotrexate-related toxicity in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2011; 57(4): 612-9.
Ramsey LB, Bruun GH, Yang W, et al. Rare versus common variants in pharmacogenetics: SLCO1B1 variation and methotrexate disposition. Genome Res 2012; 22(1): 1-8.
Ramsey LB, Panetta JC, Smith C, et al. Genome-wide study of methotrexate clearance replicates SLCO1B1. Blood 2013; 121(6): 898-904.
Zhang HN, He XL, 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): 2203-7.
Suzuki R, Fukushima H, Noguchi E, et al. Influence of SLCO1B1 polymorphism on maintenance therapy for childhood leukemia. Pediatr Int 2015; 57(4): 572-7.
Mikkelsen TS, Thorn CF, Yang JJ, et al. PharmGKB summary: methotrexate pathway. Pharmacogenet Genomics 2011; 21(10): 679-86.
Martinez D, Muhrez K, Woillard JB, et al. Endogenous metabolites-mediated communication between OAT1/OAT3 and OATP1B1 may explain the association between SLCO1B1 SNPs and methotrexate toxicity. Clin Pharmacol Ther 2018; 104(4): 687-98.
Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: An overview. Adv Drug Deliv Rev 2003; 55(1): 3-29.
Svirnovski AI, Shman TV, Serhiyenka TF, Savitski VP, Smolnikova VV, Fedasenka UU. ABCB1 and ABCG2 proteins, their functional activity and gene expression in concert with drug sensitivity of leukemia cells. Hematology 2009; 14(4): 204-12.
Wolking S, Schaeffeler E, Lerche H, Schwab M, Nies AT. Impact of genetic polymorphisms of ABCB1 (MDR1, P-glycoprotein) on drug disposition and potential clinical implications: Update of the literature. Clin Pharmacokinet 2015; 54(7): 709-35.
Gregers J, Gréen H, Christensen IJ, et al. Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia. Pharmacogenomics J 2015; 15(4): 372-9.
Gervasini G, de Murillo SG, Jiménez M, de la Maya MD, Vagace JM. Effect of polymorphisms in transporter genes on dosing, efficacy and toxicity of maintenance therapy in children with acute lymphoblastic leukemia. Gene 2017; 628: 72-7.
Ramírez-Pacheco A, Moreno-Guerrero S, Alamillo I, Medina-Sanson A, Lopez B, Moreno-Galván M. Mexican childhood acute lymphoblastic leukemia: A pilot study of the MDR1 and MTHFR gene polymorphisms and their associations with clinical outcomes. Genet Test Mol Biomarkers 2016; 20(10): 597-602.
Semsei AF, Erdélyi DJ, Ungvári I, et al. Association of some rare haplotypes and genotype combinations in the MDR1 gene with childhood acute lymphoblastic leukaemia. Leuk Res 2008; 32(8): 1214-20.
Zgheib NK, 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): 387-96.
Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov 2006; 5(3): 219-34.
Ansari M, Sauty G, Labuda M, et al. Polymorphism in multidrug resistance-associated protein gene 3 is associated with outcomes in childhood acute lymphoblastic leukemia. Pharmacogenomics J 2012; 12(5): 386-94.
Sharifi MJ, Bahoush G, Zaker F, Ansari S, Rafsanjani KA, Sharafi H. Association of -24CT, 1249GA, and 3972CT ABCC2 gene polymorphisms with methotrexate serum levels and toxic side effects in children with acute lymphoblastic leukemia. Pediatr Hematol Oncol 2014; 31(2): 169-77.
Ansari M, Sauty G, Labuda M, et al. Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia. Blood 2009; 114(7): 1383-6.
Iparraguirre L, Gutierrez-Camino A, Umerez M, et al. MiR-pharmacogenetics of methotrexate in childhood B-cell acute lymphoblastic leukemia. Pharmacogenet Genomics 2016; 26(11): 517-25.
Giacomini KM, Balimane PV, Cho SK, et al. International Transporter Consortium . International Transporter Consortium commentary on clinically important transporter polymorphisms. Clin Pharmacol Ther 2013; 94(1): 23-6.
El Mesallamy HO, Rashed WM, Hamdy NM, Hamdy N. 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): 1359-65.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy