Methotrexate‐associated alterations of the folate and methyl‐transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity

Abstract

BackgroundSevere 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.ProcedureMTX, 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/m2) followed by calcium folinate rescue (3 × 15 mg/m2) 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.ResultsIn 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.ConclusionIntrathecal 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. Pediatr Blood Cancer 2009;52:26–32. © 2008 Wiley‐Liss, Inc.

Energy balance and fitness in adult survivors of childhood acute lymphoblastic leukemia

“…48 Methotrexate acts on leukemic cells and also likely impacts neurons by competitively inhibiting dihydrofolate reductase, depleting folic acid, and interfering with synthesis of DNA, RNA, thymidylates, and proteins. [49][50][51][52] We also found that higher cumulative doses of glucocorticoids, which exert catabolic effects on muscle by inhibiting protein synthesis and by activating proteolysis, were associated with lower hand grip For personal use only. on May 8, 2018.…”

Cerebrospinal Fluid Oxidative Stress During Chemotherapy of Acute Lymphoblastic Leukemia in Children

“…It seems that intrathecal methotrexate may cause subclinical meningoencephalitis and, possibly due to antifolate action, accumulation of homocysteine, which may be alternatively metabolized to excitatory sulfur-containing amino acid, leading to the excititoxcity [17,18]. Methotrexate may also cause neurotoxicity due to its effect on serotonin, dopamine, S-adenylmethionine, and adenosine metabolism [19]. Increased oxidative stress during protocol M may reflect a depletion of the nonenzymatic antioxidant system due to the higher production of ROS in the CNS.…”

Methotrexate Induced Encephalopathy in Acute Lymphoblastic Leukemia in Omani Children

“…MTX can be used as an effective alternative to radiotherapy in children. However, MTX has a significant toxic effect on CNS, and can cause acute, sub acute or chronic neurotoxity [7]. In the current cohort, incidence of methotrexate related encephalopathy was 4.8%, and all cases developed neurotoxicity in relation to IT MTX.…”