Synergistic antitumor activity of irinotecan in combination with 5-fluorouracil in rats bearing advanced colorectal cancer: role of drug sequence and dose.

The basis for current clinical trials in the treatment of colorectal cancer with the combination of irinotecan (CPT-11) and 5-fluorouracil (FUra) with or without leucovorin (LV) is their proven activity as single agents, their different mechanisms of action, and lack of CPT-11 cross-resistance to previous FUra/LV treatment. The role of drug dose and administration sequence in this combination was studied in vivo using a rat colon tumor model (Ward colon carcinoma); we administered CPT-11 and FUra by i.v. push once a week for four consecutive weeks (weekly x 4), a clinically relevant schedule. The maximum tolerated doses (MTDs) of CPT-11 and FUra administered as single agents were 100 mg/kg/week for both agents. Three different combination administration sequences were evaluated: (a) CPT-11 administered simultaneously with FUra (sequence I); (b) FUra administered 24 h before CPT-11 (sequence II); and (c) CPT-11 administered 24 h before FUra (sequence III). When combining the two drugs at 50% of their respective MTD, the antitumor efficacy was sequence dependent with 62, 38, and 95% complete tumor regression rate for sequences I, II, and III, respectively. For sequences I and II, dose escalation to 75% of the MTD for each drug was paralleled by reversible host toxicity with no significant increase in the antitumor activity of the combination. With sequence III, however, the combination was lethal in 100% of treated animals when the doses of both drugs were at 75% of the MTD or higher. With the sequential combination of CPT-11 followed 24 h later by FUra (sequence III), the high complete tumor regression rate (cure) could be maintained, even when the dose of CPT-11 was reduced to 12.5% of the MTD as long as the doses of FUra was kept at 50 -75 % of the MTD. The data demonstrate that the antitumor activity and toxicity of combining CPT-11 with FUra is highly sequence dependent and that a sequence of CPT-11 preceding FUra is superior with a significant increase in the therapeutic index over the other sequences tested. In addition, the data also demonstrate that toxicity associated with high dose of CPT-11 can be eliminated without loss of the antitumor efficacy by reducing the dose of CPT-11 to at least 50% of its MTD, whereas the dose of FUra is kept at 50-75 % of its MTD.