High-dose leucovorin reverses acute high-dose methotrexate neurotoxicity in the rat.
Intravenous high-dose methotrexate (HD-MTX) reduces cerebral glucose metabolism and produces behavioral abnormalities and electroencephalographic slowing in an animal model of acute HD-MTX neurotoxicity and in cancer patients undergoing HD-MTX chemotherapy. We used our model of HD-MTX neurotoxicity in the rat to determine if leucovorin (5-formyltetrahydrofolate) reduces this neurotoxicity, and extended our characterization of this model to identify regional as well as global HD-MTX treatment effects and to investigate HD-MTX-induced alterations in regional brain pH. Intravenous high-dose leucovorin reversed the HD-MTX-induced decrease in cerebral glucose metabolism and associated behavioral and electroencephalographic abnormalities in the rat, but low-dose leucovorin was ineffective. The major effect of HD-MTX on cerebral glucose metabolism was a global reduction; however, smaller region-specific treatment effects were identified in auditory, thalamic, and white matter structures. HD-MTX did not alter regional brain pH. These findings suggest a potential clinical role for high-dose leucovorin in severe or prolonged acute HD-MTX neurotoxicity and provide an important justification for the role of positron emission tomography in the early detection of clinical HD-MTX neurotoxicity.
Phillips
P C
PC
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY.
Thaler
H T
HT
Allen
J C
JC
Rottenberg
D A
DA
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D005947:Glucose / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D002955:Leucovorin / Q000494:pharmacology*; D008297:Male; D008727:Methotrexate / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D005947:Glucose; D002955:Leucovorin; D008727:Methotrexate