DUAL MODULATION BY L-LEUCOVORIN AND RECOMBINANT HUMAN INTERFERON ALPHA(2A) OF 5-FLUOROURACIL ANTITUMOR-ACTIVITY AGAINST THE HUMAN COLON-CARCINOMA XENOGRAFT CO-4

We investigated the dual modulation by l-leucovorin (LV) and recombina nt human interferon-alpha(2a), (IFN-alpha(2a)) of 5-fluorouracil (5-FU ) antitumor activity against human colon carcinoma cells (Co-4) using a nude mouse system, 5-FU was administered intraperitoneally (IP) at 1 0 or 90 mg/kg, 5-FU (10 mg/kg) was administered daily for 10 days, and 80 mg/kg was administered once, LV was administered IP 1 and 0 h befo re 5-FU treatment at 200 mg/kg, IFN-alpha(2a) was administered subcuta neously (SC) daily for 14 days at 60,000 IU/mouse. When 5-FU was admin istered at 10 or 90 mg/kg with these two modulators, the antitumor eff ect was increased significantly, with T/C ratios of 18.1 and 6.1, resp ectively, These modulatory effects were assessed as synergistic, witho ut associated severe side effects or death during the experimental per iod, LV augmented the antiturnor activity of 5-FU through increment of thymidylate synthetase (TS) inhibition, and IFN-alpha(2a), showed a m odulatory effect in elevating the intratumoral concentration of fluoro uridine without change in TS inhibition, These results suggest that 5- FU antitumor activity against human colon carcinoma could be significa ntly potentiated without severe side effects by these two modulators, which possess different modes of action.