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.
Guichard
S
S
Groupe de Pharmacologie Clinique et Expérimentale, Institut Claudius Regaud, Toulouse, France.
Cussac
D
D
Hennebelle
I
I
Bugat
R
R
Canal
P
P
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005472:Fluorouracil / Q000008:administration & dosage; D019073:HT29 Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D016019:Survival Analysis; D059004:Topoisomerase I Inhibitors
D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin