The role of cellular folates in the enhancement of activity of the thymidylate synthase inhibitor 10-propargyl-5,8-dideazafolate against hepatoma cells in vitro by inhibitors of dihydrofolate reductase.

摘要: Abstract Exposure of growing cultures hepatoma cells in vitro to the lipid-soluble dihydrofolate reductase inhibitors metoprine (36 nM) or trimetrexate (2 at subtoxic concentrations causes little change cell growth rate, colony forming ability, cycle distribution, and de novo purine thymidylate biosynthesis. The augment cytotoxic activity synthase inhibitor, 10-propargyl-5,8-dideazafolate by nearly 10-fold under optimal conditions. Treatment with for 72 h during caused approximately a 75% reduction total cellular folates 5,10-methylenetetrahydrofolate (primarily as polyglutamates) substrate synthase. also cause doubling accumulation polyglutamates. combined antifolate treatment (metoprine plus 10-propargyl-5,8-dideazafolate) expands dUMP pool 30-fold, which is more than sum either antifolates alone. Consequently, it postulated that enhanced combination low due an increase ratio inhibitor extensive enhancement pool. These conditions predispose target enzyme effective metabolic blockade presumably formation inhibited 10-propargyl-5,8-dideazafolate[polyglutamate]-thymidylate synthase-dUMP ternary complex.