The new folate antagonist trimetrexate is an inhibitor of dihydrofolate reductase, but unlike methotrexate (MTX) it is not polyglutamylated. We have compared the cell killing effects of MTX and trimetrexate/5-fluorouracil (FUra) and 5-fluoro-2′-deoxyuridine (FdUrd) combinations on HCT-8 cells in vitro, in an attempt to explore indirectly the role of polyglutamylation of the antifol in determining the known sequence-dependent synergism between MTX and FUra. The comparisons were made in a number of equitoxic concentrations and times of exposure. Trimetrexate given for 4, 24 or 48 h followed by FUra, for 4, 24 or 196 h, produced synergistic HTC-8 cell kill, whereas antagonism was observed when FUra preceded or was given simultaneously with trimetrexate. The degree of interaction was essentially identical to those obtained when MTX was combined with FUra. The interactions between MTX/FdUrd and trimetrexate/FdUrd were also similar: synergistic cell kill resulted from the sequences trimetrexate or MTX followed by FdUrd, while additive effects were produced by trimetrexate or MTX + FdUrd combinations or FdUrd followed by MTX or trimetrexate. Because the same interactions observed with MTX/FUra or FdUrd combinations were also obtained when trimetrexate was combined with the fluoropyrimidines, it is unlikely that polyglutamylation of the antifols plays a significant role in determining the different sequence-dependent effects of these antimetabolites. However, these studies do not rule out the possibility that increased levels of dihydrofolate polyglutamates increase fluoropyrimidine cytotoxicity.
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