Biochemical modulation of 5‐fluorouracil with interferon α/β and γ on murine renal cell carcinoma

Abstract

AbstractBackground: Conventional therapy for renal cell carcinoma (RCC) using interferon (IFN) has shown limited antitumor action. The purpose of the present study was to investigate the synergistic antitumor effects of IFN and 5‐fluorouracil (5‐FU) and to elucidate the mechanism underlying antitumor effects.Methods: The antitumor effects and biochemical modulation of murine IFN and 5‐FU were determined using murine renal cell carcinoma (RENCA). The activity of thymidylate synthase, thymidine kinase and the concentration of 5‐FU incorporated into RNA was measured using cytosolic extracts of tumors.Results: Triple combination therapy (5‐FU, IFN α/β and IFN γ) showed a synergistic antitumor effect on RENCA tumors, because triple combination therapy suppressed growth significantly compared to combination therapy (IFN α/β and IFN γ, P = 0.0258) and 5‐FU (P < 0.0001). Total thymidylate synthase was decreased by triple combination therapy (5‐FU, IFN α/β and IFN γ, P = 0.0019) and combination therapy (5‐FU and IFN γ, P = 0.0018) compared to 5‐FU alone. Thymidine kinase activity was decreased by triple combination therapy (5‐FU, IFN α/β and IFN γ, P < 0.0001) and combination therapy (5‐FU and IFN α/β, P < 0.0001) compared to 5‐FU alone. The concentration of 5‐FU incorporated into RENCA tumors was increased by triple combination therapy (P = 0.0132) and combination therapy (5‐FU and IFN α/β, P = 0.0124) compared to 5‐FU alone.Conclusions: Interferons α/β and γ showed different biochemical modulation for 5‐FU. Therefore, combination therapy using 5‐FU and IFN showed synergistic antitumor effects on murine RCC.