Biochemical modulation of 5-fluorouracil with murine interferon-alpha/beta against murine renal cell carcinoma.

Abstract

Conventional therapy for renal cell carcinoma using interferon (IFN) has shown limited antitumor action. The purpose of our study was to investigate synergistic antitumor effects of IFN and 5-fluorouracil (5-FU), and to elucidate the mechanisms of interaction between the 2 agents in mice. Antitumor effects and biochemical modulation of murine IFN-alpha/beta and 5-FU were determined against the murine renal cell carcinoma cell line, Renca, in vivo. The activity of thymidylate synthetase and thymidine kinase was measured using cytosolic extracts of the tumors. Combination treatment with IFN-alpha/beta and 5-FU produced a significant enhancement of growth inhibition against Renca tumor. Treatment with 5-FU resulted in a 2.7-fold increase in the total amount of thymidylate synthetase and an 11.6-fold increase in the thymidylate synthetase inhibition rate, while the administration of IFN-alpha/beta did not significantly reduce the 5-FU-induced increase in thymidylate synthetase. The administration of IFN-alpha/beta decreased thymidine kinase activity to 65.5% maximally, compared with that in the control mice or the mice treated with 5-FU. The reduction of thymidine kinase caused by treating the mice with IFN-alpha/beta changes the utilization of exogenous thymidine for DNA synthesis, and may represent the mechanism of the additive antitumor effect of the 2 agents, through the suppression of the salvage pathway for deoxythymidine monophosphate induction.