Sequence‐dependent activity of the irinotecan‐5FU combination in human colon‐cancer model HT‐29 in vitro and in vivo

Irinotecan, a DNA‐topoisomerase‐I inhibitor, is active against metastatic colon carcinoma. We investigated the effects of irinotecan and 5FU combinations in human colon‐carcinoma cell line HT‐29, both in vitro and in vivo. Cytotoxicity of 24‐hr exposure was evaluated by SRB technique and the nature of interactions were determined by median‐effect analysis. Strong synergism between irinotecan and 5FU was observed after sequential exposure, and only additivity after simultaneous exposure. At 50% level of kill, the mean sums of fractional effects were 0.13 ± 0.05 and 0.18 ± 0.02 respectively for the 2 sequential schedules, indicating that the combined amount of the 2 drugs necessary to kill 50% cells was only 0.18 and 0.13 times respectively, as much as would be required if they demonstrated purely additive behavior. In nude‐mice xenografts, schedule‐dependent toxicity was observed: the schedule in which irinotecan was administered i.v. 6 hours before 5FU was the most toxic. Higher anti‐tumoral activity was noted when 20 mg/kg/day of each drug was administered sequentially (a delay of 6 hr between the 2 drugs) to mice over 5 days, in comparison with simultaneous administration. In vivo data confirmed those obtained in vitro in the same human colon‐cancer model. These results suggest that irinotecan and 5FU combinations are of clinical interest and that the schedule of administration is a critical parameter for chemotherapeutic efficacy. Int. J. Cancer 73: 729–734, 1997. © 1997 Wiley‐Liss, Inc.