Potentiation of 5-Fluorouracil-Leucovorin Activity by a2a-Interferon in Colon Adenocarcinoma Xenografts1

Previous studies using cultured colon adenocarcinoma cells demonstrated that a mixture of the diastereoiosomers of the biologically active (6S) and inactive (6R) forms of (6RS) leucovorin or 5-formyl-H4PteGlu (LV) and recombinant human a2a-interferon (rLFN-a2a) in combination significantly increased the cytotoxicity of 5-fluorouradil (FUra) (by 10-14fold) whereas FUra combined with single modulators was less potentiated (3-fold). Maximum cytotoxicity was achieved with 48-h drug exposures when drugs were applied continuously, and modulatory rIFN-a2a concentrations were obtained at 50 International units (IU)/ml. We therefore examined whether such interactions could occur in vivo using HXGCI clTKc3 colon adenocarcinoma xenografts, deficient in thymidine salvage. Potentiation of FUra activity was significantly greater when FUra was combined with both LV and rIFN-a2a in comparison to the use of single modulators using a 5-day schedule for 3 courses. In mice receiving LV, the maximum level of potentiation of FUra-induced growth inhibition was independent of the rIFN-a2a dose between 25,000 and 600,000 lu examined in contrast to rIFN-a2a used as a single modulator. After administration of 25,000 IU rWN-a2a, plasma rIFN-ot2a concentrations 50 lU/mI were maintained for 6-8 h, comparable to exposure times achievable clinically. Data indicate that intennittent rWN-a2a exposure potentiates FUra-LV activity in vivo. The efficacy of FUra combined with dual versus single modulators will thus be of importance to evaluate in randomized phase III clinical trials in patients with