Abrogation of interferon-induced resistance to interferon-activated major histocompatibility complex-unrestricted killers by treatment of a melanoma cell line with 5-fluorouracil

Abstract

Advanced cancer responds clinically to combined therapy with recombinant interferon-alpha and 5-fluorouracil. Although the two agents may interact in the biosynthetic pathway for thymidine, we investigated, as an alternative mechanism, the regulation of susceptibility of the A375 human melanoma to natural killers activated by interferon. A375 were preincubated with 5-fluorouracil, interferon, or both sequentially prior to assay as targets for cell-mediated killing. Pretreatment of A375 with interferon decreased apparent lytic efficiency. 5-Fluorouracil alone increased the susceptibility of A375 to killing. Pretreatment of targets with 5-fluorouracil abrogated the resistance normally induced by interferon pretreatment. Thus, 5-fluorouracil modulates certain immunoregulatory effects of interferon-alpha. Thymidine does not block the effect of 5-fluorouracil. While fluorodeoxyuridine is relatively ineffective in this system, fluorouridine is more effective than 5-fluorouracil in abrogating the effect of interferon. These data suggest important interactions of 5-fluorouracil and interferon in pathways for protein synthesis. It is known that interferon both increases the activity of natural killers and increases resistance of tumors to natural killers. We have shown that 5-fluorouracil, by blocking the resistance, may allow the augmented natural killing to be effective. This observation provides an alternate hypothesis for the clinical activity of 5-fluorouracil and interferon in combination.