Exploring the effects of antifolates on one-carbon metabolism in tumor cells: Experimental and SPICE2 network thermodynamic analyses

Recent advances in the understanding of (anti)folate biochemistry and pharmacology made possible by the application of network thermodynamic modeling are discussed. The data indicate, and simulations predict, that low levels of residual dihydrofolate reductase catalytic activity can have an important effect on the steady-state dihydrofolate level achieved by inhibitors of this enzyme. With low residual levels of dihydrofolate reductase catalytic activity, modest inhibition of thymidylate synthase can influence the extent of interconversion of tetrahydrofolate cofactors to dihydrofolate. The studies indicate that the observed partial interconversion of tetrahydrofolate cofactors to dihydrofolate can be accounted for on the basis of compartmentation of a portion of cellular folates which makes them unavailable for oxidation through thymidylate synthase.