STIMULATION OF 5-FLUOROURACIL METABOLIC-ACTIVATION BY INTERFERON-ALPHA IN HUMAN COLON-CARCINOMA CELLS

Interferon-α (IFNα) increases the cytotoxicity of 5-fluorouracil (FUra) in vitro, and the combination has clinical efficacy against advanced colorectal cancer. IFNα treatment of HT-29 colon carcinoma cells induced a greater than two-fold increase in the intracellular levels of the active metabolite of FUra, FdUMP. Using cell extracts from HT-29 cells and FUra as substrate, IFNα produced a 1.9- and 8.7-fold increase, respectively, in the activities of uridine phosphorylase and pyrimidine nucleoside phosphorylase (PyNP). Furthermore, the effect was selective for the conversion of FUra to FdUMP, as IFNα did not increase the cellular levels of FUTP, nor did it change the extent of incorporation of FUra into RNA (or DNA). IFNα also had no effect on thymidine kinase activity, the second step in the activation of FUra. Hence the effect of IFNα on PyNP activity is likely a critical biochemical event that modulates the cytotoxicity of FUra. © 1992.