Cytokines induce uridine phosphorylase in mouse colon 26 carcinoma cells and make the cells more susceptible to 5'-deoxy-5-fluorouridine

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 α (TNFα), interleukin-1a (IL-1α), and interferon γ (IFNγ) 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. TNFα, IL-1α, IFNγ, 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 TNFα 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.