Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia.
OBJECTIVE
Despite its clinical success, methotrexate (MTX) therapy is associated with toxicities such as seizures, the pathogenesis of which remains unclear. It has been suggested that hyperhomocysteinemia is caused by MTX and is responsible for its neurotoxic effects. The purposes of this study were to explore whether hyperhomocysteinemia was related to MTX administration and toxicity and whether homocysteine or MTX toxicity differed by methylenetetrahydrofolate reductase (MTHFR) or reduced folate carrier (RFC) genetic polymorphisms.


METHODS
We studied 53 children with newly diagnosed acute lymphoblastic leukemia who were consecutively treated on a single clinical protocol that included two courses of high-dose MTX (high-dose methotrexate [HDMTX]; 2.5 or 5.0 g/m2 per day) as consolidation therapy.


RESULTS
The study participants' median plasma homocysteine concentrations at 23 and 44 hours after HDMTX (9.00 micromol/L and 10.12 micromol/L, respectively) were greater than the concentrations immediately before HDMTX (5.77 micromol/L, P <.0001 for both comparisons). Seven days after HDMTX treatment, their plasma concentration returned to baseline. Nine patients experienced seizures, and five patients experienced thrombosis during the first 15 months of therapy, with a tendency for there to be higher plasma homocysteine in patients with seizures across all time points (P =.063) but not in patients with thrombosis (P =.59). We observed no significant differences in plasma or cerebrospinal fluid homocysteine levels or in toxicity based on the MTHFR 677C/T or RFC 80G/A genotypes.


CONCLUSIONS
We conclude that homocysteine was transiently elevated after HDMTX and may be related to seizure risk in children with leukemia.
Kishi
Shinji
S
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
Griener
James
J
Cheng
Cheng
C
Das
Soma
S
Cook
Edwin H
EH
Pei
Deqing
D
Hudson
Melissa
M
Rubnitz
Jeffrey
J
Sandlund
John T
JT
Pui
Ching-Hon
CH
Relling
Mary V
MV
D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D006710:Homocysteine / Q000097:blood / Q000378:metabolism*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000235:genetics*; D026901:Membrane Transport Proteins; D008727:Methotrexate / Q000009:adverse effects*; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism*; D058978:Reduced Folate Carrier Protein
D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D006710:Homocysteine; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate