Selective treatment of SCID mice bearing methotrexate-transport-resistant human acute lymphoblastic leukemia tumors with trimetrexate and leucovorin protection.
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.
Lacerda
J F
JF
Program of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Göker
E
E
Kheradpour
A
A
Dennig
D
D
Elisseyeff
Y
Y
Jagiello
C
C
O'Reilly
R J
RJ
Bertino
J R
JR
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001692:Biological Transport; D004351:Drug Resistance; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage*; D008727:Methotrexate / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D014183:Transplantation, Heterologous; D016597:Trimetrexate / Q000008:administration & dosage*
D002955:Leucovorin; D016597:Trimetrexate; D008727:Methotrexate