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Changes in Plasma Methionine and Total Homocysteine Levels in Patients Receiving Methotrexate Infusions¹

Department of Pediatrics, Wright-Patterson AFB, Dayton, Ohio 45433 [E. H. B.]; C. Henry Kempe Center, The Children's Hospital, Denver, Colorado 80218 [L. C. S.]; and Department of Medicine, Division of Hematology, University of Colorado School of Medicine, Denver, Colorado 80262 [R. H. A., S. P. S., J. F. K.]

Methotrexate reduces intracellular pools of 5-methyltetrahydrofolate and could result in reduced conversion of homocysteine to methionine by methionine synthetase. This study was designed to investigate the effects of moderate dose to very high dose methotrexate on methionine and total homocysteine as reflections of methotrexate induced intracellular events. Methionine and total homocysteine were measured prior to, during, and following twenty-six 24-h i.v. infusions of 33.6 g/m² methotrexate (very high dose methotrexate) in 16 children with acute lymphocytic leukemia and seven 4-h i.v. infusions of 8 g/m² methotrexate (high dose methotrexate) in 5 children with osteogenic sarcoma. Amino acids were measured by gas chromatography/mass spectrophotometry. Mean methionine levels decreased by 70.0 ± 3.1% (SE) with very high dose methotrexate and 72.6 ± 5.9% with high dose methotrexate at 24 and 4.5 h, respectively, after beginning methotrexate infusions. Mean total homocysteine levels increased by 61.7 ± 3.1% with very high dose methotrexate and 55.6 ± 17.5% with high dose methotrexate at 36 and 24 h, respectively, after beginning methotrexate infusions. No consistent or significant changes were noted in levels of total cysteine, leucine, isoleucine, or valine. Similar changes did not occur in patients receiving prednisone, vincristine, daunomycin, and intrathecal methotrexate as therapy for acute lymphocytic leukemia. These changes in homocysteine and methionine may reflect biological effects of methotrexate that may predict cytotoxicity of methotrexate.

¹ This work was supported by a gift from the Veterans of Foreign Wars, Colorado Chapter (E. H. B., L. C. S.); National Institute of Diabetes and Digestive and Kidney Diseases, Department of Health and Human Services, Grants DK21365-12 (R. H. A.) and DK37165-02 (S. P. S.), NIH Grant DK37165 (S. P. S.), and National Institute of General and Medical Sciences, Department of Health and Human Services, Grant GM26486-09 and March of Dimes Birth Defects Foundation Grant 1-805 (J. F. K.).

The opinions and assertations expressed are those of the authors and are not to be construed as official or as if reflecting the policy of the United States Air Force.

Presented in part at the 79th American Society of Clinical Oncology Meeting, May 24, 1988.

² To whom requests for reprints should be addressed.

Received 12/19/88. Revised 4/13/89. Revised 7/19/89. Accepted 8/ 4/89.

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