Comparative antitumor activity of 5-fluorouracil and 5'-deoxy-5-fluorouridine in combination with interferon-alpha in renal cell carcinoma cell lines.

ABSTRACT

OBJECTIVES: Although interferon-alpha (IFNalpha) and interleukin-2 are used in the treatment of advanced renal cell carcinoma (RCC), the rate of efficacy is about 15% and not satisfactory. Therefore, a more effective treatment is being investigated. In this study, we examined the combined effects of IFNalpha and 5-fluorouracil (5-FU) as well as 5-deoxy-5-fluorouridine (5'-DFUR), a produrg of 5-FU, in vitro. MATERIALS AND METHODS: Four RCC cell lines (OCUU1, OCUU3, OCUU4, OCUU5) were established at our laboratory from RCC patients. OS-RC-2, RCC10RGB, TUHR14TKB, TUHR4TKB, A498 and Caki-1 were obtained from a commercial source. The sensitivity of the 10 RCC cell lines to 5-FU and 5'-DFUR was evaluated using MTT assay. The IC50 value for the cytostatics was expressed as the concentration at which growth was inhibited by 50% as compared with the control value. Thymidine phosphorylase (TP), the enzyme that converts 5'-DFUR into 5-FU and 5-FU into FdUMP, was estimated by ELISA. RESULTS: When the 10 RCC cell lines were divided into the low TP expression group and high TP expression group at 2.0 U/ml protein, TP expression was not enhanced by IFNalpha in all 4 cell lines in the low TP expression group. Antitumor effects were not enhanced by IFNalpha in 3 out of 4 cell lines for 5-FU and in all 4 cell lines for 5'-DFUR. On the other hand, in the high TP expression group, TP expression was enhanced by IFNalpha in 5 out of 6 cell lines, and antitumor effects were enhanced by IFNalpha in 5 out of 6 cell lines for 5-FU and in all 6 cell lines for 5'-DFUR. In addition, there was a significant correlation between TP expression and sensitivity to 5-FU and 5'-DFUR in all RCC cell lines. CONCLUSIONS: These results suggested that TP may be useful as a predictive factor in combination therapy with IFNalpha and 5-FU or 5'-DFUR, which may be a promising treatment for advanced RCC.