Genetic markers in methotrexate treatments

Giletti, Andrea; Esperón, Patricia

doi:10.1038/s41397-018-0047-z

Cited by 38 publications

(36 citation statements)

References 112 publications

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“…According to a meta-analysis, it was demonstrated that G80A, a variant which affects the activity of SLC19A1, is not a good marker of MTX-related toxicity in pediatric ALL [33]. Another study concluded that the same variant is associated with increased MTX toxicity [47]. This is another example of the inconsistency of the assessment of relevance of PGx markers for MTX toxicity.…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment

Kotur

Lazić

Ristivojević

et al. 2020

Genes

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Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients.

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Section: Discussionmentioning

confidence: 99%

Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment

Kotur

Lazić

Ristivojević

et al. 2020

Genes

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“…Enzyme activity is reduced by 30% and 65% in genotypes CT and TT carriers, respectively . Patients harboring T allele were almost accompanied by an increased toxicity and decreased efficacy in several studies, while those results are still contradictory . Chen Y et al concluded that C677T polymorphism of MTHFR predicts nonresponse and adverse effects of MTX in juvenile idiopathic arthritis .…”

Section: Discussionmentioning

confidence: 99%

Contribution of genetic polymorphism of methylene tetrahydrofolate reductase on the effect of methotrexate in ectopic pregnancy patients

Deng

Chen

Xue

et al. 2019

Clinical Laboratory Analysis

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Background: Methotrexate (MTX) is the prior drug in ectopic pregnancy (EP).However, approximately 10% of patients suffer from failure by MTX therapy.Reduced folate carrier 1 (RFC1), methylene tetrahydrofolate reductase (MTHFR), and dihydrofolate reductase (DHFR) are involved in the transport and effects of MTX in vivo. In the present study, we aim to investigate the relationship between the genetic polymorphisms of RFC1, MTHFR, and DHFR and the clinical efficacy of MTX in tubal pregnancies.Methods: 100 patients of EP were enrolled in this study. Polymorphisms of RFC1 G80A, MTHFR C677T, and DHFR A-317G were genotyped. β-hCG level was detected in day 0, 4, and 7 after MTX injection. Association of MTX efficacy and genetic polymorphisms was analyzed.Results: Methylene tetrahydrofolate reductase C677T was associated with MTX treatment (P = .017). The success rate of first MTX injection was superior in patients with harboring mutation allele of MTHFR gene than that in patients with wild-type gene (P = .001). However, there was no significant association between the polymorphisms of RFC1 G80A, DHFR A-317G, and surgical treatment (P = .709 and .476, respectively). In addition, β-hCG level decrement was not significantly changed by MTX injection with different polymorphisms of RFC1, MTHFR, and DHFR on either day 4 (P = .214, 0.197 and 0.270, respectively) or day 7 (P = .172, .554, and .726, respectively). Conclusion:Our results suggested that the reliable indicator was polymorphism of MTHFR C677T in failure by MTX injection. K E Y W O R D Sclinical efficacy, dihydrofolate reductase, ectopic pregnancy, genetic polymorphisms, methotrexate, methylene tetrahydrofolate reductase, reduced folate carrier 1

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“…Therefore, DHFR couples with thymidylate synthase (TS), which catalyzes the reductive methylation of deoxyuridine monophosphate in deoxythymidine monophosphate using N5 -N10-methylenetetrahydrofolate (5,10-Methylene THF) as a cofactor [165][166][167][168]. Despite the extensive targeting of DHFR in pathogenic organisms [153,[169][170][171], hDHFR is also targeted by anticancer agents [172][173][174][175]. MTX targets hDHFR and is a wellknown anticancer drug for the treatment of leukemia, breast cancer, lung cancer, osteosarcoma, and lymphoma [176].…”

Section: Dhfr Enzyme As Anticancer Targetmentioning

confidence: 99%

Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors

Arciszewska²,

et al. 2019

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The development of new mechanisms of resistance among pathogens, the occurrence and transmission of genes responsible for antibiotic insensitivity, as well as cancer diseases have been a serious clinical problem around the world for over 50 years. Therefore, intense searching of new leading structures and active substances, which may be used as new drugs, especially against strain resistant to all available therapeutics, is very important. Dihydrofolate reductase (DHFR) has attracted a lot of attention as a molecular target for bacterial resistance over several decades, resulting in a number of useful agents. Trimethoprim (TMP), (2,4-diamino-5-(3′,4′,5′-trimethoxybenzyl)pyrimidine) is the well-known dihydrofolate reductase inhibitor and one of the standard antibiotics used in urinary tract infections (UTIs). This review highlights advances in design, synthesis, and biological evaluations in structural modifications of TMP as DHFR inhibitors. In addition, this report presents the differences in the active site of human and pathogen DHFR. Moreover, an excellent review of DHFR inhibition and their relevance to antimicrobial and parasitic chemotherapy was presented.

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Genetic markers in methotrexate treatments

Cited by 38 publications

References 112 publications

Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment

Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment

Contribution of genetic polymorphism of methylene tetrahydrofolate reductase on the effect of methotrexate in ectopic pregnancy patients

Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors

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