The role of interferon-alpha as a modulator of fluorouracil and leucovorin.

Several preclinical studies have demonstrated that interferon-alpha (IFN-alpha) may enhance the cytotoxicity of fluoropyrimidines in a greater-than-additive manner in a variety of human cancer cell lines. The underlying mechanism(s) have varied in different cancer cell lines, and include increased fluorouracil anabolism to fluorodeoxyuridine monophosphate, further inhibition of thymidylate synthase, stimulation of thymidine and uridine phosphorylase activities, greater DNA damage, and enhanced natural killer cell-mediated lysis of tumour targets. These preclinical studies stimulated clinical evaluation of IFN-alpha in combination with 5-fluorouracil (5-FU) with and without leucovorin (LV), and the initial clinical results appeared promising. We summarise preclinical research concerning the interaction of 5-FU and IFN-alpha. The rationale for combining 5-FU with IFN-alpha and LV is discussed, and we describe our clinical experience with the combination of 5-FU, LV and IFN-alpha-2a. The insights and unresolved questions concerning the clinical application of this combination are also discussed.