Interaction between 5-fluorouracil, [6RS]leucovorin, and recombinant human interferon-α2a in cultured colon adenocarcinoma cells

Recombinant human interferon-α2a (rIFN-α2a; 500 or 5,000 IU/mL) or [6RS] leucovorin ([6RS]LV; 1 μM) each potentiated the cytotoxic activity of 5-fluorouracil (FUra) by 2.6- to 3.2-fold during 72 hr exposures in two human colon adenocarcinoma cell lines (GC₃/cl; VRC₅/cl). When all three agents were combined, FUra cytotoxicity was further potentiated by 3.2- to 4.3-fold (total 10- to 14-fold). Potentiation of FUra cytotoxicity occurred at clinically achievable concentrations of rIFN-α2a and [6RS]LV. Effects were reversed by dThd (20 μM), although the activity of CB3717, a quinazoline-based, specific inhibitor of thymidylate synthase, was not potentiated by rIFN-α2a. Data suggest the requirement of a 5-fluoropyrimidine for biochemical modulation and interaction at the level of thymidylate synthase or DNA.