THE ROLE OF INTERFERON-ALPHA AS A MODULATOR OF FLUOROURACIL AND LEUCOVORIN

Several preclinical studies have demonstrated that interferon-alpha (I FN-alpha) may enhance the cytotoxicity of fluoropyrimidines in a great er-than-additive manner in a variety of human cancer cell lines. The u nderlying mechanism(s) have varied in different cancer cell lines, and include increased fluorouracil anabolism to fluorodeoxyuridine monoph osphate, further inhibition of thymidylate synthase, stimulation of th ymidine and uridine phosphorylase activities, greater DNA damage, and enhanced natural killer cell-mediated lysis of tumour targets. These p reclinical studies stimulated clinical evaluation of IFN-alpha in comb ination with 5-fluorouracil (5-FU) with and without leucovorin (LV), a nd the initial clinical results appeared promising. We summarise precl inical research concerning the interaction of 5-FU and IFN-alpha. The rationale for combining 5-FU with IFN-alpha and LV is discussed, and w e describe our clinical experience with the combination of 5-FU, LV an d IFN-alpha-2a. The insights and unresolved questions concerning the c linical application of this combination are also discussed.