Synergistic antitumor activity of irinotecan in combination with 5-fluorouracil in rats bearing advanced colorectal cancer: Role of drug sequence anddose

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, thei r different mechanisms of action, and lack of CPT-11 cross-resistance to pr evious FUra/LV treatment. The role of drug dose and administration sequence in this combination was studied in vivo using a rat colon tumor model (War d colon carcinoma); wet administered CPT-11 and FUra by i.v. push once a we ek for four consecutive weeks (weekly x 4), a clinically relevant schedule. The maximum tolerated doses (MTDs) of CPT-11 and FUra administered as sing le agents were 100 mg/kg/week for both agents, Three different combination administration sequences were evaluated: (a) CPT-11 administered simultaneo usly with FUra (sequence I); (b) FUra administered 24 h before CPT-11 (sequ ence 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 effi cacy was sequence dependent with 62, 38, anti 95% complete tumor regression rate for sequences I, II, and III, respectively. For sequences I and II, d ose escalation to 75% of the MTD for each drug was paralleled by reversible host toxicity with no significant increase in the antitumor activity of th e combination. With sequence III, however, the combination was lethal in 10 0% of treated animals when the doses of both drugs were at 75% of the MTD o r higher. With the sequential combination of CPT-11 Followed 24 h later by FUra (sequence III), the high complete tumor regression rate (cure) could b e 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 demo nstrate that the antitumor activity and toxicity of combining CPT-11 with F Ura is highly sequence dependent and that a sequence of CPT-11 preceding FU ra is superior with a significant increase in the therapeutic index over th e other sequences tested. In addition, the data also demonstrate that toxic ity associated with high dose of CPT-11 can be eliminated without loss of t he 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.