Comparative Antitumor Activity of 5-Fluorouracil and 5’-Deoxy-5-Fluorouridine in Combination with Interferon-α in Renal Cell Carcinoma Cell Lines

Abstract

Objectives: Although interferon-α (IFNα) 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 IFNα 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 IFNα in all 4 cell lines in the low TP expression group. Antitumor effects were not enhanced by IFNα 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 IFNα in 5 out of 6 cell lines, and antitumor effects were enhanced by IFNα 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 IFNα and 5-FU or 5′-DFUR, which may be a promising treatment for advanced RCC.