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. PROCEDURE: 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. CONCLUSION: 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.
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. PROCEDURE: 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 neurotoxicpatients 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. CONCLUSION: 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.
Authors: Kirsten K Ness; James P DeLany; Sue C Kaste; Daniel A Mulrooney; Ching-Hon Pui; Wassim Chemaitilly; Robyn E Karlage; Jennifer Q Lanctot; Carrie R Howell; Lu Lu; Deo Kumar Srivastava; Leslie L Robison; Melissa M Hudson Journal: Blood Date: 2015-03-26 Impact factor: 22.113
Authors: Kala Y Kamdar; Kevin R Krull; Randa A El-Zein; Pim Brouwers; Brian S Potter; Lynnette L Harris; Suzanne Holm; Zoann Dreyer; Fernando Scaglia; Carol J Etzel; Melissa Bondy; M Fatih Okcu Journal: Pediatr Blood Cancer Date: 2011-05-25 Impact factor: 3.167
Authors: Deepa Bhojwani; Noah D Sabin; Deqing Pei; Jun J Yang; Raja B Khan; John C Panetta; Kevin R Krull; Hiroto Inaba; Jeffrey E Rubnitz; Monika L Metzger; Scott C Howard; Raul C Ribeiro; Cheng Cheng; Wilburn E Reddick; Sima Jeha; John T Sandlund; William E Evans; Ching-Hon Pui; Mary V Relling Journal: J Clin Oncol Date: 2014-02-18 Impact factor: 44.544
Authors: Hauke Rühs; Achim Becker; Anne Drescher; John C Panetta; Ching-Hon Pui; Mary V Relling; Ulrich Jaehde Journal: PLoS One Date: 2012-09-25 Impact factor: 3.240