Global methylation in relation to methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia

Natanja Oosterom, Pieter H. Griffioen, Marissa A. H. den Hoed, Rob Pieters, Robert de Jonge, Wim J. E. Tissing, Marry M. van den Heuvel-Eibrink, Sandra G. Heil

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Abstract

Background

Children with acute lymphoblastic leukemia (ALL) often suffer from toxicity of chemotherapeutic drugs such as Methotrexate (MTX). Previously, we reported that 20% of patients receiving high-dose MTX developed oral mucositis. MTX inhibits folate metabolism, which is essential for DNA methylation. We hypothesize that MTX inhibits DNA methylation, which results into adverse effects. We studied DNA methylation markers during high-dose methotrexate treatment in pediatric acute lymphoblastic leukemia (ALL) in relation to developing oral mucositis.

Materials & methods

S-Adenosyl-Methionine (SAM) and S-Adenosyl-Homocysteine (SAH) levels and LINE1 DNA methylation were measured prospectively before and after high-dose methotrexate (HD-MTX 4 x 5g/m2) therapy in 82 children with ALL. Methotrexate-induced oral mucositis was registered prospectively. Oral mucositis (grade >= 3 National Cancer Institute Criteria) was used as clinical endpoint.

Results

SAM levels decreased significantly during methotrexate therapy (-16.1 nmol/L (-144.0 - +46.0), p

Conclusions

This was the first study that assessed DNA methylation in relation to MTX-induced oral mucositis in children with ALL. Although global methylation markers did change during methotrexate therapy, methylation status was not associated with developing oral mucositis.

Original languageEnglish
Article number0199574
Number of pages10
JournalPLoS ONE
Volume13
Issue number7
DOIs
Publication statusPublished - 9-Jul-2018

Keywords

  • DNA METHYLATION
  • S-ADENOSYLHOMOCYSTEINE
  • ONCOLOGY GROUP
  • HYPOMETHYLATION
  • ADENOSYLMETHIONINE
  • METHIONINE
  • EXPRESSION
  • ARTHRITIS
  • TOXICITY
  • SURVIVAL

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