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.