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-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) assay was carried out in vitro using the cultured human colon cancer cell 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 concentrations of 10, 50 and 500 micrograms/ml. The antitumor activity of 5-FU with or without IFN-beta was assessed using Co-4, a human colon carcinoma xenograft in nude mice, with reference to thymidylate synthetase inhibition. IFN-beta 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-beta 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-beta 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-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.
Kase
S
S
Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.
Kubota
T
T
Watanabe
M
M
Furukawa
T
T
Tanino
H
H
Ishibiki
K
K
Teramoto
T
T
Kitajima
M
M
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D016899:Interferon-beta / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D016899:Interferon-beta; D013940:Thymidylate Synthase; D005472:Fluorouracil