title: Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients.
abstract: OBJECTIVE
  Methotrexate administration is associated with frequent adverse neurological events during treatment for childhood acute lymphoblastic leukemia. Here, we present evidence to support the role of common drug interactions and low vitamin B12levels in potentiating methotrexate neurotoxicity.
  
  
  METHODS
  We review the published evidence and highlight key potential drug interactions as well as present clinical evidence of severe methotrexate neurotoxicity in conjunction with nitrous oxide anesthesia and measurements of vitamin B12levels among pediatric leukemia patients during therapy.
  
  
  RESULTS
  We describe a very plausible mechanism for methotrexate neurotoxicity in pediatric leukemia patients involving reduction in methionine and consequential disruption of myelin production. We provide evidence that a number of commonly prescribed drugs in pediatric leukemia management interact with the same folate biosynthetic pathways and/or reduce functional vitamin B12levels and hence are likely to increase the toxicity of methotrexate in these patients. We also present a brief case study supporting out hypothesis that nitrous oxide contributes to methotrexate neurotoxicity and a nutritional study, showing that vitamin B12deficiency is common in pediatric leukemia patients.
  
  
  CONCLUSIONS
  Use of nitrous oxide in pediatric leukemia patients at the same time as methotrexate use should be avoided especially as many suitable alternative anesthetic agents exist. Clinicians should consider monitoring levels of vitamin B12in patients suspected of having methotrexate-induced neurotoxic effects.
authors.affiliation: Paul O'Gorman Building, Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. victoria.forster@ncl.ac.uk.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Forster
authors.affiliation: Paul O'Gorman Building, Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Frederik W
authors.initials: FW
authors.lastname: van Delft
authors.affiliation: Royal Hospital for Sick Children, Edinburgh, UK.
authors.forename: Susan F
authors.initials: SF
authors.lastname: Baird
authors.affiliation: Royal Hospital for Sick Children, Edinburgh, UK.
authors.forename: Shona
authors.initials: S
authors.lastname: Mair
authors.affiliation: Great North Children's Hospital, Newcastle upon Tyne, UK.
authors.forename: Roderick
authors.initials: R
authors.lastname: Skinner
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Halsey
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007938:Leukemia / Q000150:complications* / Q000188:drug therapy; D008715:Methionine / Q000378:metabolism; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use; D009186:Myelin Sheath / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000453:epidemiology* / Q000523:psychology; D009609:Nitrous Oxide / Q000378:metabolism; D009752:Nutritional Status; D012640:Seizures / Q000139:chemically induced; D014806:Vitamin B 12 Deficiency / Q000139:chemically induced / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D008715:Methionine; D009609:Nitrous Oxide; D008727:Methotrexate
keywords: Hematology; Leukemia; Methotrexate; Neurotoxicity; Nitrous oxide; Toxicity