title: Combination of irinotecan (CPT11) and 5-fluorouracil with an analysis of cellular determinants of drug activity.
abstract: We evaluated the combination SN38 (7-ethyl-10-hydroxycamptothecin) -5fluorouracil (5FU) +/- folinic acid (FA) on six human colon cancer cell lines expressing spontaneous sensitivity to both drugs. Tumoral parameters potentially related to drug sensitivity were investigated: topoisomerase I (topo I) cleavable complexes formed with SN38, thymidylate synthase (TS) activity, folylpolyglutamate synthetase activity and dihydropyrimidine dehydrogenase activity. Drugs (SN38 and/or 5FU +/- FA) were applied for 72 hr, either sequentially or together. The concentration ratio between SN38 and 5FU was 100. Cytotoxicity (MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] test), DNA flow cytometry and isobologram analysis (Chou and Talatay) were performed. Based on 5FU IC50 values and isobologram analyses, the most cytotoxic schedule was SN38 followed by 5FU - FA, with high synergistic effects. Flow cytometry indicated that SN38 induced a more or less marked S-G2 block in all cell lines. Sensitivity to SN38, 5FU +/- FA, or combinations were not linked to the potential above-cited tumoral parameters. Interestingly, an inverse correlation was demonstrated between TS activity and topo I cleavable complexes (r2 = 0.78, P = 0.019). These data emphasize the critical importance of the irinotecan-5FU schedule and strongly support this association for the treatment of potentially 5FU-sensitive tumors.
authors.affiliation: Oncopharmacology Unit, Centre Antoine Lacassagne, Nice, France.
authors.forename: V
authors.initials: V
authors.lastname: Pavillard
authors.forename: P
authors.initials: P
authors.lastname: Formento
authors.forename: P
authors.initials: P
authors.lastname: Rostagno
authors.forename: J L
authors.initials: JL
authors.lastname: Formento
authors.forename: J L
authors.initials: JL
authors.lastname: Fischel
authors.forename: M
authors.initials: M
authors.lastname: Francoual
authors.forename: M C
authors.initials: MC
authors.lastname: Etienne
authors.forename: G
authors.initials: G
authors.lastname: Milano
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D003110:Colonic Neoplasms / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D014407:Tumor Cells, Cultured
chemical_list: D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin