| Abstract: |
The effects of the combination of trimetrexate and leucovorin on bone marrow progenitor cells and rat sarcoma cells with intrinsic resistance to methotrexate due to decreased methotrexate uptake were studied in vitro and in vivo and compared with methotrexate (MTX) plus leucovorin. The activity of trimetrexate on methotrexate-resistant sarcoma cells on clonogenic killing or on in situ thymidylate synthase activity was not effectively abolished by addition of leucovorin (10 and 100 mu-M, respectively). Leucovorin protected rat bone marrow cells from trimetrexate cytotoxicity to a greater extent than sarcoma cells. In rats bearing the sarcoma, leucovorin protected both the antitumour and cytotoxicity effects of MTX; leucovorin protected animals treated with trimetrexate from weight loss but less so from antitumour effects. Leucovorin also protected normal rat bone marrow from trimetrexate toxicity when these drugs were administered to rats by continuous infusion. In MTX resistant tumours due to decreased uptake of this drug, leucovorin selectively protects normal bone marrow without appreciable protection of the tumour. This strategy may be worthwhile exploring in the treatment of human malignancies in which the tumour is impaired in MTX (and leucovorin) uptake or polyglutamylation. |
