Interferon beta increases antitumor activity of 5-fluorouracil against human colon carcinoma cells in vitro and in vivo

The modulating effect of human fibroblast-derived interferon beta (IFN-β) on the antitumor effect of 5-fluorouracil (5-FU) against human colon carcinoma cells in vitro and in vivo was investigated. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay was carried out in vitro using the cultured human colon cancer cell line C-1. IFN-β at concentrations of 50, 500, 5,000 and 50,000 IU/ml was added to the cultured tumor cells with or without 5-FU at concentrations of 10, 50 and 500 ug/ml. The antitumor activity of 5-FU with or without IFN-β. was assessed using Co-4, a human colon carcinoma xenograft in nude mice, with reference to thymidylate synthetase inhibition. IFN-β was administered subcutaneously daily for 14 days at doses of 6,000, 60,000 and 600,000 IU/mouse. The combined antitumor effect. with 5-FU was evaluated by simultaneous intraperitoneal administration of 5-FU at doses of 10 and 20 mg/kg daily for 10 days. The antitumor activity of IFN-β alone increased in a dose-dependent manner against Co-4 in nude mice whereas its antitumor activity in vitro against C-1 was limited. The synergistic effect of 5-FU and IFN-β was observed both in vitro and in vivo, and the in vivo synergism was obtained without any enhancement of thymidylate synthetase inhibition or side effects in terms of death rate and body weight loss. These results suggest that the mechanism of the combined effect of 5-FU and IFN-β is not related to enhancement of thymidylate synthetase inhibition or the host immune system, since human fibroblastoid IFN-β is species-specific to humans. The clinical usefulness of this combination method for the treatment of advanced colorectal carcinoma is expected.