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Stem Cells, Vol. 14, No. 1, 5-9, January 1996
© 1996 AlphaMed Press

Advances in Cancer Treatment: The Chabner Symposium

Resistance Mechanisms to Methotrexate in Tumors

J.R. Bertino, E. Göker, R. Gorlick, W.W. Li, D. Banerjee

Program of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

Key Words. Methotrexate • Drug resistance • Leukemia • Sarcoma • Dihydrofolate reductase • Folylpolyglutamate synthetase • {gamma}-glutamyl hydrolase • Trimetrexate

Correspondence: Dr. J.R. Bertino, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, RRL 601, New York, NY 10021 USA.

The mechanisms of intrinsic and acquired resistance to methotrexate (MTX) in human tumors are reviewed herein. In blasts from patients with acute lymphocytic leukemia, resistance mechanisms found are decreased uptake and increased dihydrofolate reductase (DHFR) activity. A major cause of intrinsic resistance to MTX in soft tissue sarcoma cells and in acute myelocytic leukemia appears to be a lack of drug retention, due mainly to low levels of polyglutamylation. A novel association between lack of the retinoblastoma protein and intrinsic MTX resistance has been found. This has been attributed to an increase in DHFR activity, due to an increased rate of transcription of this gene, stimulated by an increase in levels of free E2F, not sequestered by hypophosphorylated retinoblastoma protein.




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