CYTOKINES INDUCE THYMIDINE PHOSPHORYLASE EXPRESSION IN TUMOR-CELLS AND MAKE THEM MORE SUSCEPTIBLE TO 5'-DEOXY-5-FLUOROURIDINE

The present study shows that various cytokines such as tumor necrosis factor (TNFalpha), interleukin-1alpha (IL-1alpha), and interferon-gamm a (IFNgamma) make tumor cells much more susceptible to the cytostatic 5'-deoxy-5-fluorouridine (5'-dFUrd) than to 5-fluorouracil (5-FUra) an d other cytostatics. These three cytokines increased the susceptibilit y of human cancer cell lines (COLO201, MKN45 and WiDr) but did not aff ect that of normal fibroblast W138 cells. The cytokine mixture induced a 50-fold increase in the susceptibility of COLO201 to 5'-dFUrd, wher eas a 12-fold increase and a less than 5-fold enhancement in the susce ptibility to 5-FUra and other cytostatics, respectively, were observed . The increased susceptibility would be a result of the induction of t hymidine phosphorylase (TdR Pase), which is the essential enzyme for t he conversion of 5'-dFUrd to 5-FUra. The cytokine mixture increased Td R Pase activity by up to 47 times and greatly induced its mRNA express ion in the cancer cell lines. These results suggest that the therapeut ic benefit of 5'-dFUrd would be improved by its use in combination wit h the cytokines.