Biomodulation of 5-fluorouracil by interferon-α in human renal carcinoma cells:: relationship to the expression of thymidine phosphorylase

Purpose: To provide the basis for improved therapeutic benefit in combination chemotherapy with interferon (IFN) and 5-fluorouracil (5-FU), we investigated the modulatory actions of human recombinant IFN alfa-2a on 5-FU in five renal cell carcinoma (RCC) cell lines in vitro, in particular focusing on thymidine phosphorylase (TP) expression. Methods: The sensitivity of RCC cell lines to the drugs was evaluated using an AlamarBlue assay. An enzyme-linked immunosorbent assay (ELISA) was used to determine TP expression. Results: IFN-alpha enhanced the sensitivity of three of five RCC cell lines to 5-FU in a dose- and schedule-dependent manner. When IFN-alpha was given prior to 5-FU, sensitivity to 5-FU was significantly higher than when IFN-alpha was given simultaneously (P < 0.05). IFN-alpha enhanced TP expression in a dose-dependent manner in three of five RCC cell lines (P < 0.05). The relative IFN-alpha-induced increase in sensitivity to 5-FU correlated with the relative IFN-alpha-induced increase in TP expression (P < 0.05). In addition, two of three RCC cell lines with more than a twofold increase in sensitivity to 5-FU induced by IFN-alpha showed a higher TP expression without IFN-alpha stimulation. Conclusions: These results suggest that IFN-alpha upregulates TP expression and modulates 5-FU anabolism thus enhancing 5-FU cytotoxicity in a dose- and schedule-dependent manner in some RCC cells. The results imply that TP expression measurement in RCC could identify subgroups of metastatic RCC that may respond to IFN-alpha/5-FU combination therapy, and sequential administration of IFN-alpha followed by 5-FU may be beneficial in such cases.