Recombinant human interferon alpha-2a increases 5-fluorouracil efficacy by elevating fluorouridine concentration in tumor tissue.
The modulating effect of recombinant human interferon alpha (IFN-alpha) on the antitumor efficacy of 5-fluorouracil (5-FU) against human carcinoma cell lines was investigated in vitro and in vivo. 5-FU, fluorouridine (FUR) or fluoro-5'-deoxyuridine (FUdR) were tested against cultured human colon tumor C-1 cells with or without IFN-alpha. The in vitro antitumor activity of 5-FU was enhanced by the addition of IFN-alpha, but IFN-alpha did not increase the effect of FUR or FUdR. The in vivo antitumor activity of 5-FU with or without IFN-alpha was assessed using Co-4, a human colon carcinoma xenograft, in nude mice. Thymidylate synthetase inhibition and concentration of FUR in the treated tumor tissues were concomitantly measured. A synergistic effect of 5-FU and IFN-alpha was observed on Co-4 in nude mice, and this in vivo synergism was obtained without any increment of thymidylate synthetase inhibition or side effects in terms of death rate and body weight loss. The intratumoral concentration of FUR was significantly increased by the addition of IFN-alpha in Co-4 tumor tissue treated with 5-FU. These results suggest that the mechanism of the combined effect of 5-FU and IFN-alpha is not related to enhancement of thymidylate synthetase inhibition, but to an increase of FUR concentration in the target tumor tissue. It is expected that this combination method will be clinically useful for the treatment of advanced colorectal carcinoma.
Kase
S
S
Department of Surgery, School of Medicine, Keio University, Tokyo, Japan.
Kubota
T
T
Watanabe
M
M
Teramoto
T
T
Kitajima
M
M
Hoffman
R M
RM
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005472:Fluorouracil / Q000008:administration & dosage* / Q000378:metabolism; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D011994:Recombinant Proteins; D013940:Thymidylate Synthase / Q000032:analysis; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014529:Uridine / Q000031:analogs & derivatives / Q000378:metabolism
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; C001943:5-fluorouridine; D013940:Thymidylate Synthase; D005472:Fluorouracil; D014529:Uridine