Synergistic interactions among antifolates

Many cultured human cell lines show large synergistic cytotoxicity when an inhibitor of dihydrofolate reductase (EC 1.5.1.3) is combined with an antif olate inhibitor of thymidylate synthase (EC 2.1.1.45) or with an antifolate inhibitor of glycinamide ribonucleotide formyltransferase (EC 2.1.2.2). Th ese synergistic interactions are dependent on medium folic acid concentrati on and are greatly enhanced by increasing folic acid levels. Synergism is s een only when the thymidylate synthase or glycinamide ribonucleotide formyl transferase inhibitor is polyglutamylatable. Here we will briefly outline t he rigorous method used to quantitate synergistic interactions by measuring or, a response surface-based parameter; give examples of synergistic inter actions from the current literature; and evaluate proposals offered to expl ain the metabolic basis of the synergism. (C) 2000 Elsevier Science Inc. Al l rights reserved.