PMID: 22571483May 11, 2012Paper

Intracellular disposition of methotrexate in acute lymphoblastic leukemia in children

Current Drug Metabolism
Tiphaine Adam de Beaumais, Evelyne Jacqz-Aigrain

Abstract

Methotrexate (MTX) is a key agent for the treatment of acute lymphoblastic leukemia in children and the benefit of high-dose MTX is well established as it significantly increases cure rates and improves patients' prognosis. However, the determinants of MTX therapeutic effect are not clearly identified, although intracellular polyglutamation is essential. MTX, the monoglutamate form (MTXG₁) inhibits the dihydrofolate reductase (DHFR) implicated in the folate cycle. MTXG₁ is metabolized to active methotrexate polyglutamates (MTXPG) with sequential gamma-linkage of 2 to 6 glutamyl residues by the folylpolyglutamate synthetase (FPGS). Long chain MTXPG have higher affinity than MTX for the enzymes involved in de novo purine synthesis such as 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) and thymidilate synthase (TS), which results in a reinforcement of MTX inhibition. Thus, intracellular formation of MTXPG enhances the cytotoxic and antileukemic effect of MTX. Different pharmacogenetic polymorphisms contribute to interindividual variability in MTX response to treatment. In addition, pharmacokinetic interactions with 6-mercaptopurine (6-MP), frequently co-administered, have been reported. And factors affecting i...Continue Reading

Citations

Mar 22, 2014·Neurotoxicity Research·Tânia CapelôaAna P Silva
Nov 29, 2013·Drug Metabolism and Pharmacokinetics·Katsuhisa Inoue, Hiroaki Yuasa
Oct 27, 2017·Nanoscale Research Letters·Jinyu WangPeizhi Zhu
Feb 2, 2019·Current Drug Metabolism·Guillermo Gervasini, Sonia Mota-Zamorano
Aug 28, 2019·Oncology Letters·Jorge Organista-NavaMarco Antonio Leyva-Vázquez
Jun 25, 2015·Asian Pacific Journal of Cancer Prevention : APJCP·Duangjai PiwkhamBudsaba Rerkamnuaychoke
Jun 20, 2019·Journal of Cancer Research and Clinical Oncology·Somayeh Rahimi BabasheikhaliMahboubeh Mohammadi
Dec 27, 2019·Pediatric Blood & Cancer·Sebastiaan D T SassenRon A A Mathôt
Jul 10, 2019·Annual Review of Pharmacology and Toxicology·Laura B RamseySara L Van Driest
Aug 28, 2021·International Journal of Molecular Sciences·Ludovica Di MartinoErich Piovan

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