Polymorphisms in the methotrexate transport pathway

López-López, Elixabet; Ballesteros, Javier; Piñán, M.A.; Toledo, José Sánchez de; Andoin, Nagore García de; García‐Miguel, Purificación; Navajas, Aurora; Garcı́a-Orad, Africa

doi:10.1097/fpc.0b013e32835c3b24

Cited by 94 publications

(52 citation statements)

References 38 publications

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“…Between March 2007 and June 2010, a total of 112 consecutive Han Chinese children with medium- to high-risk ALL [13] (age range, 1–10 years; mean age, 6.16±3.09 years; gender, 59 males, 53 females) were recruited to this study. Patients with liver or renal dysfunction, or taking non-steroidal anti-inflammatory drugs, probenecid, penicillin, or proton pump inhibitors were excluded.…”

Section: Methodsmentioning

confidence: 99%

Association of ABCC2 −24C>T Polymorphism with High-Dose Methotrexate Plasma Concentrations and Toxicities in Childhood Acute Lymphoblastic Leukemia

Liu

Yin

et al. 2014

PLoS ONE

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Methotrexate (MTX) is a key agent for the treatment of childhood acute lymphoblastic leukemia (ALL). Increased MTX plasma concentrations are associated with a higher risk of adverse drug effects. ATP-binding cassette subfamily C member 2 (ABCC2) is important for excretion of MTX and its toxic metabolite. The ABCC2 −24C>T polymorphism (rs717620) reportedly contributes to variability of MTX kinetics. In the present study, we assessed the association between the ABCC2 −24C>T polymorphism and methotrexate (MTX) toxicities in childhood ALL patients treated with high-dose MTX. A total of 112 Han Chinese ALL patients were treated with high-dose MTX according to the ALL-Berlin-Frankfurt-Muenster 2000 protocol. Our results showed that presence of the −24T allele in ABCC2 gene led to significantly higher MTX plasma concentrations at 48 hours after the start of infusion, which would strengthen over repeated MTX infusion. The −24T allele in ABCC2 gene was significantly associated with higher risks of high-grade hematologic (leucopenia, anemia, and thrombocytopenia) and non-hematologic (gastrointestinal and mucosal damage/oral mucositis) MTX toxicities. This study provides the first evidence that the −24T allele in ABCC2 gene is associated with the severity of MTX toxicities, which add fresh insights into clinical application of high-dose MTX and individualization of MTX treatment.

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Section: Methodsmentioning

confidence: 99%

Association of ABCC2 −24C>T Polymorphism with High-Dose Methotrexate Plasma Concentrations and Toxicities in Childhood Acute Lymphoblastic Leukemia

Liu

Yin

et al. 2014

PLoS ONE

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“…In fact, Treviño et al40 performed a genome-wide association study in patients with ALL and found rs4149081 and rs11045879 in SLCO1B1 strongly associated for the first time with MTX clearance, and this association was widely confirmed by subsequent studies 11,39,41. As a result, other works have focused their interest on the analysis of polymorphism in MTX transporters, finding several SNPs in genes such as SLC19A1 , ABCC4 , or ABCC2 also associated with MTX levels and other toxicities 42–44…”

Section: Resultsmentioning

confidence: 93%

MTHFR polymorphisms in childhood acute lymphoblastic leukemia: influence on methotrexate therapy

Umerez¹,

Gutiérrez-Camino²,

Muñoz-Maldonado³

et al. 2017

PGPM

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Methotrexate (MTX) is an important component in the therapy used to treat childhood acute lymphoblastic leukemia (ALL). Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme for MTX pharmacokinetics. Two single-nucleotide polymorphisms in MTHFR gene, C677T and A1298C, affecting MTHFR activity, have been widely studied as potential markers of MTX toxicity and/or outcome in pediatric ALL. In this review, we show that the majority of published reports do not find association or present opposite effect. Therefore, MTHFR C677T and A1298C polymorphisms do not seem to be good markers of MTX-related toxicity and/or outcome in pediatric ALL. The efforts should be focused on other genes, such as transporter genes or microRNA-related genes.

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“…Finally, the rs3740065 A>G polymorphism in ABCC2 has been found to cause significantly-reduced ABCC activity [53]. As expected, this variant leads to a significantly increased level of MTX and MTX-PG present within the cell, subsequently causing toxicity and resistance [53]. The effect of ABCC gene polymorphisms can be recapitulated by the up-regulation of miR-453, which decreases the activity of several ABCC family proteins [13].…”

Section: Pharmacogenetic Considerations For Mtxmentioning

confidence: 75%

“…Unlike MTHFR and TYMS , the elevated expression of DHFR is well known to be correlated with a resistance to MTX and MTX-PG [13]. Finally, the rs3740065 A>G polymorphism in ABCC2 has been found to cause significantly-reduced ABCC activity [53]. As expected, this variant leads to a significantly increased level of MTX and MTX-PG present within the cell, subsequently causing toxicity and resistance [53].…”

Section: Pharmacogenetic Considerations For Mtxmentioning

confidence: 85%

The Promise of Pharmacogenomics in Reducing Toxicity during Acute Lymphoblastic Leukemia Maintenance Treatment

Rudin

Marable

Huang

2017

Genomics, Proteomics &Amp; Bioinformatics

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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.

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Polymorphisms in the methotrexate transport pathway

Abstract: Our results suggest that polymorphisms in ABCC4 and ABCC2 could be novel markers for MTX toxicity in pediatric ALL.

Cited by 94 publications

References 38 publications

Association of ABCC2 −24C>T Polymorphism with High-Dose Methotrexate Plasma Concentrations and Toxicities in Childhood Acute Lymphoblastic Leukemia

Association of ABCC2 −24C>T Polymorphism with High-Dose Methotrexate Plasma Concentrations and Toxicities in Childhood Acute Lymphoblastic Leukemia

MTHFR polymorphisms in childhood acute lymphoblastic leukemia: influence on methotrexate therapy

The Promise of Pharmacogenomics in Reducing Toxicity during Acute Lymphoblastic Leukemia Maintenance Treatment

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