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 antifolate inhibitor of thymidylate synthase (EC 2. 1.1.45) or with an antifolate inhibitor of glycinamide ribonucleotide formyltransferase (EC 2.1.2.2). These synergistic interactions are dependent on medium folic acid concentration and are greatly enhanced by increasing folic acid levels. Synergism is seen only when the thymidylate synthase or glycinamide ribonucleotide formyltransferase inhibitor is polyglutamylatable. Here we will briefly outline the rigorous method used to quantitate synergistic interactions by measuring alpha, a response surface-based parameter; give examples of synergistic interactions from the current literature; and evaluate proposals offered to explain the metabolic basis of the synergism.
Kisliuk
R L
RL
Department of Biochemistry, Tufts University, 136 Harrison Avenue, Boston, MA, USA. rkisliuk@opal.tufts.edu
D000818:Animals; D018929:Cell Culture Techniques; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005492:Folic Acid / Q000737:chemistry; D005493:Folic Acid Antagonists / Q000378:metabolism*; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000378:metabolism*; D008223:Lymphoma / Q000188:drug therapy; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D051026:Phosphoribosylglycinamide Formyltransferase; D011624:Pteroylpolyglutamic Acids / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*
D005493:Folic Acid Antagonists; D011624:Pteroylpolyglutamic Acids; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D019877:Hydroxymethyl and Formyl Transferases; D051026:Phosphoribosylglycinamide Formyltransferase