INTERFERON-BETA INCREASES ANTITUMOR-ACTIVITY OF 5-FLUOROURACIL AGAINST HUMAN COLON-CARCINOMA CELLS-INVITRO AND INVIVO

The modulating effect of human fibroblast-derived interferon beta (IFN -beta) 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) as say was carried out in vitro using the cultured human colon cancer cel l line C-1. IFN-beta 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 conc entrations of 10, 50 and 500 mug/ml. The antitumor activity of 5-FU wi th or without IFN-beta was assessed using Co-4, a human colon carcinom a xenograft in nude mice, with reference to thymidylate synthetase inh ibition. IFN-beta was administered subcutaneously daily for 14 days at doses of 6,000, 60,000 and 600,000 IU/mouse. The combined antitumor e ffect with 5-FU was evaluated by simultaneous intraperitoneal administ ration of 5-FU at doses of 10 and 20 mg/kg daily for 10 days. The anti tumor activity of IFN-beta alone increased in a dose-dependent manner against Co-4 in nu mice, whereas its antitumor activity in vitro again st C-1 was limited. The synergistic effect of 5-FU and IFN-beta was ob served both in vitro and in vivo, and the in vivo synergism was obtain ed without any enhancement of thymidylate synthetase inhibition or sid e effects in terms of death rate and body weight loss. These results s uggest that the mechanism of the combined effect of 5-FU and IFN-beta is not related to enhancement of thymidylate synthetase inhibition or the host immune system, since human fibroblastoid IFN-beta is species- specific to humans. The clinical usefulness of this combination method for the treatment of advanced colorectal carcinoma is expected.