Modulation of both endogenous folates and thymidine enhance the therapeutic efficacy of thymidylate synthase inhibitors.

Plasma levels of folates and thymidine in mice are about 10-fold higher than in humans and may influence the therapeutic efficacy of thymidylate synthase (TS) inhibitors, such as 5-fluorouracil (5FU) and the antifolates pemetrexed (MTA) and raltitrexed (RTX). Therefore, we tested their therapeutic efficacy in various murine tumor models, grown in mice on a normal and a folate-depleted diet, with high and low thymidine kinase (TK) levels. MTA and RTX were inactive against Colon-26-10 [doubling times gained by treatment; growth delay factor (GDF), 0.