Effect of Polymorphisms within Methotrexate Pathway Genes on Methotrexate Toxicity and Plasma Levels in Adults with Hematological Malignancies

Suthandiram, Sujatha; Gan, Gin Gin; Zain, Sharifuddin M.; Bee, Ping Chong; Lian, Lay-Hoong; Chang, Kian-Meng; Ong, Tee-Chuan; Mohamed, Zahurin

doi:10.2217/pgs.14.97

Cited by 68 publications

(54 citation statements)

References 60 publications

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“…70 . Some other authors confirmed the above analysis in recent studies [45,75]. In contrast with above results, some other authors did not find any association between MTHFR and MTX-related toxicity or other side effects [22,26,27,31,35,73,76].…”

Section: Methylenetetrahydrofolate Reductasesupporting

confidence: 57%

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Gene polymorphisms in the folate metabolism and their association with MTX-related adverse events in the treatment of ALL

Yang

Shen

2015

Tumor Biol.

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The antifolate drug methotrexate (MTX) is widely used in the treatment of various neoplastic diseases, including acute lymphoblastic leukemia (ALL). MTX significantly increases cure rates and improves patients' prognosis. Despite that it achieved remarkable clinical success, a large number of patients still suffer from treatment toxicities or side effects. Even to this date, chemotherapeutic regiments have not been personalized because of interindividual differences that affect MTX response, especially polymorphisms in key genes. The pharmacological pathway of MTX in cells is useful to identify gene polymorphisms that influence the process of treatment. The aim of this review was to discuss the gene polymorphisms of drug-metabolizing enzymes in the MTX pathway and their toxicities on ALL treatment.

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Section: Methylenetetrahydrofolate Reductasesupporting

confidence: 57%

“…In contrast, the CA genotype in A934C was associated with increasing risk of thrombocytopenia (grade 3/4, P=0.01). Suthandiram et al [45] …”

Section: Solute Carrier Organic Anion Transporter Genesmentioning

confidence: 99%

Gene polymorphisms in the folate metabolism and their association with MTX-related adverse events in the treatment of ALL

Yang

Shen

2015

Tumor Biol.

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“…As an antifolate chemotherapeutic agent, MTX has been widely used in the treatment of adults with hematological malignancy, such as ALL, Burkitt lymphoma (BL), lymphoblastic lymphoma, non-Hodgkin's lymphoma (NHL), peripheral T-cell lymphoma (PTCL) and primary central nervous system lymphoma (PCNSL) [9,[11][12][13][14][15]. Although MTHFR genetic polymorphism have been implicated in MTX-induced toxicities in adults with breast cancer [16] and rheumatoid arthritis [17], as for adults with hematological malignancy, the results of relevant studies remain inconsistent and even conflicting.…”

Section: Discussionmentioning

confidence: 99%

“…Avivi et al found that MTHFR C677T or A1298C polymorphism had no impact on liver and kidney toxicities following MTX therapy in adults with adult non-Hodgkin's lymphoma [8]. On the contrary, Suthandiram et al revealed that MTHFR 677TT were associated with increased risk of both hematopoietic and hepatic toxicities in adults with hematological malignancies [9]. Considering the different study designs and insufficient power of individual studies, we performed a meta-analysis to combine available data to assess the possible associations between common MTHFR gene polymorphisms (C677T and A1298C) and MTX-induced toxicities in adults with hematological malignancy.…”

mentioning

confidence: 99%

MTHFR Gene Polymorphisms and Methotrexate Toxicity in Adult Patients with Hematological Malignancies: A Meta-Analysis

Zhao

Liang

et al. 2016

Pharmacogenomics

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“…Suthandriam et al [30] reported that patients with MDR1 C3435T polymorphisms appear to have significantly higher methotrexate (MTX) plasma concentrations in ALL or NHL patients. Min et al [31] showed that MDR1 G2677T/A gene polymorphisms, as well as haplotypes derived from C1236T, G2677T/A, and C3435T, were associated with individual differences of glucocorticoid treatment in idiopathic thrombocytopenic purpura.…”

Section: Association Between Mdr1 and Survivalmentioning

confidence: 99%

MDR1 polymorphisms have an impact on the prognosis of Chinese diffuse large B cell lymphoma patients

Yin

Xiao

et al. 2015

Tumor Biol.

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MDR1 (multidrug resistance 1) encodes an adenosine triphosphate (ATP)-dependent efflux transporter that plays a fundamental role in transportation of harmful compounds outside cells to maintain optimal health. The present study was aimed to investigate whether the MDR1 gene single nucleotide polymorphisms (SNPs) were associated with the prognosis of diffuse large B cell lymphoma (DLBCL). Three common SNPs, including C1236T, G2677T/A, and C3435T were focused on, and a total of 150 DLBCL patients from Jiangsu Han population were successively genotyped by polymerase chain reaction-allele-specific primers (PCR-ASP) method or DNA direct sequencing. At locus C1236T, patients carrying T allele (genotype CT and TT) had a prolonged overall survival (OS) when compared with patients with CC genotype (2-year OS 82.6 vs. 60.0 %, respectively; hazard ratio (HR) = 0.1, 95 % confidence interval (CI) 0.01-0.6, p = 0.016). At locus C3435T, complete remission/ complete remission unconfirmed (CR/CRu) rate in C allele group was significantly higher than T allele group (66.7 vs. 51.9 %, respectively; p = 0.009). The progression-free survival (PFS) curves of with T (genotype CT and TT) and without T (genotype CC) were significantly different (2-year PFS 46.4 % in with T group vs. 73.7 % in without T group, respectively; HR = 1.9, 95 % CI 1.0-3.6, p = 0.045). At locus G2677T/A, the age for genotypes AG and AT groups was significantly younger than the other genotypes (51.1 ± 12.6 vs. 57.7 ± 13.4 years, respectively; p = 0.033). In the haplotype analysis of loci 1236-3435, compared with T-C group, the C-T group displayed an inferior PFS rate (2-year PFS 23.0 vs. 50.6 %, respectively; HR = 7.8, 95 % CI 1.9-32.6, p = 0.005), while C-C and T-T groups showed an intermediate PFS rate. Our findings demonstrate that genotype CT + TT at locus C1236T, allele C, and genotype CC at locus C3435T might contribute to a relatively superior prognosis in DLBCL, as well as haplotype of T-C in loci 1236-3435. Besides, genotypes at locus G2677T/A might affect age at diagnosis, which has important prognostic value for DLBCL.

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Effect of Polymorphisms within Methotrexate Pathway Genes on Methotrexate Toxicity and Plasma Levels in Adults with Hematological Malignancies

Cited by 68 publications

References 60 publications

Gene polymorphisms in the folate metabolism and their association with MTX-related adverse events in the treatment of ALL

Gene polymorphisms in the folate metabolism and their association with MTX-related adverse events in the treatment of ALL

MTHFR Gene Polymorphisms and Methotrexate Toxicity in Adult Patients with Hematological Malignancies: A Meta-Analysis

MDR1 polymorphisms have an impact on the prognosis of Chinese diffuse large B cell lymphoma patients

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