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 mechan ism of tumor cells to this drug. Trimetrexate (TMTX), a second-generat ion folate antagonist, is still active against MTX-transport-resistant cells because it enters cells by passive diffusion and does not use t he reduced folate transport system for cell entry. Therefore, although leucovorin (LVI protects MTX-sensitive cells from TMTX toxicity, MTX- transport defective cells are poorly rescued by LV. Severe combined im munodeficiency mice bearing MTX-transport-resistant CCRF-CEM acute lym phoblastic leukemia tumors were treated with TMTX alone or with the co mbination of TMTX and LV, with tumor regressions in both groups (P < . 001) and without significant toxicity. These results indicate that TMT X 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 MIX sensitivit y. (C) 1995 by The American Society of Hematology.