Changes in intracellular folate metabolism during high-dose methotrexate and Leucovorin rescue therapy in children with acute lymphoblastic leukemia

Autoři: Natanja Oosterom aff001;  Robert de Jonge aff003;  Desiree E. C. Smith aff003;  Rob Pieters aff001;  Wim J. E. Tissing aff001;  Marta Fiocco aff001;  Bertrand D. van Zelst aff002;  Marry M. van den Heuvel-Eibrink aff001;  Sandra G. Heil aff002
Působiště autorů: Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands aff001;  Erasmus MC, University Medical Center Rotterdam, Department of Clinical Chemistry, Rotterdam, The Netherlands aff002;  VU Medical Center, Department of Clinical Chemistry, Amsterdam, The Netherlands aff003;  Academic Medical Center, Department of Clinical Chemistry, Amsterdam, The Netherlands aff004;  Department of Pediatric Oncology, University of Groningen, Beatrix Children’s Hospital, University Medical Center Groningen, Groningen, The Netherlands aff005;  Mathematical Institute, Leiden University, Leiden, The Netherlands aff006;  Leiden University Medical Center, Department of Biomedical Data Sciences, Leiden, The Netherlands aff007
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0221591



Methotrexate (MTX) is an important anti-folate agent in pediatric acute lymphoblastic leukemia (ALL) treatment. Folinic acid rescue therapy (Leucovorin) is administered after MTX to reduce toxicity. Previous studies hypothesized that Leucovorin could ‘rescue’ both normal healthy cells and leukemic blasts from cell death. We assessed whether Leucovorin is able to restore red blood cell folate levels after MTX.


We prospectively determined erythrocyte folate levels (5-methyltetrahydrofolate (THF) and non-methyl THF) and serum folate levels in 67 children with ALL before start (T0) and after stop (T1) of HD-MTX and Leucovorin courses.


Erythrocyte folate levels increased between T0 and T1 (mean ± SD: 416.7 ± 145.5 nmol/L and 641.2 ± 196.3 nmol/L respectively, p<0.001). This was due to an increase in 5-methyl THF levels (mean increase: 217.7 ± 209.5 nmol/L, p<0.001), whereas non-methyl THF levels did not change (median increase: 0.6 nmol/L [-9.9–11.1], p = 0.676). Serum folate levels increased between T0 and T1 (median increase: 29.2 nmol/L [32.9–74.0], p<0.001). Results were not significantly affected by age, sex, ALL immunophenotype and MTHFR c.677C>T genotype.


Intracellular folate levels accumulate after HD-MTX and Leucovorin therapy in children with ALL, suggesting that Leucovorin restores the intracellular folate pool. Future studies are necessary to assess concomitant lower uptake of MTX.

Klíčová slova:

Biology and life sciences – Cell biology – Cellular types – Animal cells – Blood cells – Red blood cells – Anatomy – Body fluids – Blood – Blood plasma – Physiology – Medicine and health sciences – Oncology – Cancers and neoplasms – Hematologic cancers and related disorders – Leukemias – Lymphoblastic leukemia – Acute lymphoblastic leukemia – Cancer treatment – Hematology – Pediatrics – Pharmacology – Drugs – Methotrexate – Physical sciences – Chemistry – Chemical compounds – Organic compounds – Vitamins – B vitamins – Cobalamins – Organic chemistry


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