Dihydrofolate-mediated reversal of methotrexate toxicity to hepatoma cells in vitro.

H35 hepatoma cells can be rescued from exposure to an inhibitory pulse of methotrexate (MTX) by subsequent addition of folinic acid, dihydrofolate or thymidine. Both folinic acid and dihydrofolate cause the dissociation of methotrexate--dihydrofolate reductase complex although dihydrofolate rescues less effectively than folinic acid. Thymidine does not cause a measurable dissociation of the enzyme--inhibitor complex. The results suggest that the rescue of MTX treated cells by reduced folate coenzymes can be mediated at least in part by the generation of dihydrofolate which by itself can partially reverse MTX inhibition of cell growth.