Cytokines Induce Uridine Phosphorylase in Mouse Colon 26 Carcinoma Cells and Make the Cells More Susceptible to 5′‐Deoxy‐5‐fluorouridine

Abstract

The antiproliferative activity of 5-fluorouracil (5-FUra) and 5'-deoxy-5-fluorouridine (5'-dFUrd), used in combination with typical cytokines and growth factors, was investigated in mouse colon 26 carcinoma cells. Tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), and interferon gamma (IFN gamma) at low doses showing < 50% inhibition of cell growth by themselves enhanced the susceptibility of the cells to the activity of 5'-dFUrd. In particular, a mixture of these cytokines greatly enhanced the activity of 5'-dFUrd and 5-FUra by up to 12.4- and 2.7-fold, respectively, whereas the activity of other cytostatics was only slightly changed (< 1.5-fold). Basic fibroblast growth factor also increased the susceptibility, but only to 5'-dFUrd. This preferential enhancement of the activity of 5'-dFUrd would be due to induction by the cytokines of uridine phosphorylase (Urd Pase), by which 5'-dFUrd is converted to 5-FUra. TNF alpha, IL-1 alpha, IFN gamma, and a mixture of these factors increased the enzyme activity by up to 3.7-fold in colon 26 cells. Consequently, the anabolism of 5'-dFUrd to fluoronucleotides and the incorporation of 5-FUra into RNA in colon 26 cells were increased by TNF alpha treatment. In addition, the increase by the cytokine mixture in the susceptibility to 5'-dFUrd was abolished by an inhibitor of Urd Pase, 2,2'-anhydro-5-ethyluridine. These results indicate that induction of Urd Pase activity by cytokines is a critical event that increases the susceptibility to 5'-dFUrd.