Methotrexate-associated alterations of the folate and methyl-transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity.
BACKGROUND
Severe neurotoxicity has been observed after systemic high-dose and intrathecal methotrexate (MTX) treatment. The role of biochemical MTX-induced alterations of the folate and methyl-transfer pathway in the development of neurotoxic symptoms is not yet fully elucidated.


METHODS
MTX, 5-methyltetrahydrofolate, calcium folinate, S-adenosylmethionine, and S-adenosylhomocysteine were measured in the cerebrospinal fluid (CSF) of 29 patients with acute lymphoblastic leukemia (ALL) who were treated with high-dose MTX (5 g/m(2)) followed by calcium folinate rescue (3 x 15 mg/m(2)) and/or intrathecal (8-12 mg) MTX. Two patients developed subacute MTX-associated neurotoxicity. CSF was obtained by lumbal puncture 1-3 weeks after administration of MTX and shortly after the occurrence of neurotoxicity. The analytes were measured using HPLC assays with UV and/or fluorescence detection.


RESULTS
In non-toxic patients, CSF concentrations of 5-methyltetrahydrofolate and S-adenosylmethionine were in the normal range 2 weeks after administration of high-dose and intrathecal MTX followed by rescue. In contrast, when these patients received intrathecal MTX without rescue, 5-methyltetrahydrofolate concentrations were significantly decreased 12 days after the first MTX administration. S-adenosylmethionine concentrations were significantly decreased up to 45 days. The two patients suffering from neurotoxicity had decreased levels of 5-methyltetrahydrofolate and S-adenosylmethionine during or following toxicity. S-adenosylhomocysteine was determined in all samples of neurotoxic patients but was below the limit of quantification in most samples of non-toxic patients. Calcium folinate was not detected; MTX was present only in samples obtained during its infusion.


CONCLUSIONS
Intrathecal MTX without folinate rescue as well as MTX-associated neurotoxicity are likely to be associated with specific alterations of the folate and methyl-transfer pathway.
Vezmar
Sandra
S
Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany.
Schüsseler
Patrick
P
Becker
Achim
A
Bode
Udo
U
Jaehde
Ulrich
U
D000293:Adolescent; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D008727:Methotrexate / Q000494:pharmacology*; D008745:Methylation; D020258:Neurotoxicity Syndromes; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications* / Q000378:metabolism*
D005492:Folic Acid; D008727:Methotrexate