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Selective treatment of SCID mice bearing methotrexate-transport- resistant
human acute lymphoblastic leukemia tumors with trimetrexate and leucovorin
protection
JF Lacerda, E Goker, A Kheradpour, D Dennig, Y Elisseyeff, C Jagiello, RJ O'Reilly and JR Bertino
Program of Molecular Pharmacology and Therapeutics, Memorial Sloan-
Kettering Cancer Center, New York, NY 10021, USA.
Impaired transport of methotrexate (MTX) is a common resistance mechanism
of tumor cells to this drug. Trimetrexate (TMTX), a second- generation
folate antagonist, is still active against MTX-transport- resistant cells
because it enters cells by passive diffusion and does not use the reduced
folate transport system for cell entry. Therefore, although leucovorin (LV)
protects MTX-sensitive cells from TMTX toxicity, MTX-transport defective
cells are poorly rescued by LV. Severe combined immunodeficiency mice
bearing MTX-transport-resistant CCRF-CEM acute lymphoblastic leukemia
tumors were treated with TMTX alone or with the combination of TMTX and LV,
with tumor regressions in both groups (P < .001) and without significant
toxicity. These results indicate that TMTX with LV protection may be a
useful therapeutic regimen for patients with MTX-transport-defective acute
lymphoblastic leukemia. Furthermore, resistance to TMTX plus LV may result
in reversion to MTX sensitivity.
Volume 85,
Issue 10,
pp. 2675-2679,
05/15/1995
Copyright © 1995 by The American Society of Hematology
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