title: Combination of trabectedin and irinotecan is highly effective in a human rhabdomyosarcoma xenograft.
abstract: Our objective was to evaluate in vitro and in vivo the effect of the combination of trabectedin (Yondelis, ET-743) and irinotecan (CPT-11) or its major metabolite SN-38 in a human rhabdomyosarcoma cell line. The schedule trabectedin (1 h) followed by irinotecan or SN-38 (24 h) and the opposite sequence (irinotecan or SN-38 24 h followed by trabectedin 1 h) were analyzed in a rhabdomyosarcoma cell line. In vivo studies were conducted with trabectedin and irinotecan at the doses of 0.2 and 20 mg/kg, respectively, simultaneously administered with a q4d x 3 schedule. In vitro studies indicated an overall additive effect [combination index (CI) relatively close to 1.0], with the former schedule slightly superior to the latter (at the IC50 effect levels: CI=0.89 versus 1.07). Neither transcription nor expression of DNA topoisomerase I was affected by trabectedin treatment. In vivo the therapeutic results of the combination were certainly more impressive: trabectedin and irinotecan combination caused a strong and long-lasting effect on tumor growth (tumor volume inhibition=89%, log10 cell kill=1.6), whereas each drug given as a single agent was only marginally active. The discrepancy between the in vitro and in vivo results suggests possible mechanisms involving host cells, other than tumor cells. The striking effects of the combination observed in vivo could be related to a combination of a direct cytotoxic and an anti-inflammatory indirect effect. The very marked and long-lasting effect of the trabectedin and irinotecan combination in vivo suggests a basis for a clinical evaluation in pediatric patients with rhabdomyosarcoma.
authors.affiliation: Department of Pediatric Oncology, Catholic University, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Riccardi
authors.forename: Daniela
authors.initials: D
authors.lastname: Meco
authors.forename: Paolo
authors.initials: P
authors.lastname: Ubezio
authors.forename: Giorgio
authors.initials: G
authors.lastname: Mazzarella
authors.forename: Mirko
authors.initials: M
authors.lastname: Marabese
authors.forename: Glynn T
authors.initials: GT
authors.lastname: Faircloth
authors.forename: José
authors.initials: J
authors.lastname: Jimeno
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Riccardo
authors.initials: R
authors.lastname: Riccardi
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004149:Dioxoles / Q000008:administration & dosage; D006801:Humans; D066298:In Vitro Techniques; D000077146:Irinotecan; D007546:Isoquinolines / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008819:Mice, Nude; D012208:Rhabdomyosarcoma / Q000188:drug therapy*; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D000077606:Trabectedin; D002166:Camptothecin