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

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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 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.

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