title: Comparison of in vitro and in vivo biological effects of trabectedin, lurbinectedin (PM01183) and Zalypsis® (PM00104).
abstract: This study: (i) investigated the in vitro cytotoxicity and mode of action of lurbinectedin (PM01183) and Zalypsis® (PM00104) compared with trabectedin in cell lines deficient in specific mechanisms of repair, (ii) evaluated their in vivo antitumor activity against a series of murine tumors and human xenografts. The antiproliferative activity, the DNA damage and the cell cycle perturbations induced by the three compounds on tumor lines were very similar. Nucleotide Excision Repair (NER) deficient cells were approximately fourfold more resistant to trabectedin, lurbinectedin and Zalypsis®. Cells deficient in non-homologous end joining (NHEJ), MRN complex and translesion synthesis (TLS) were slightly more sensitive to the three compounds (approximately fivefold) while cells deficient in homologous recombination (HR) were markedly more sensitive (150-200-fold). All three compounds showed a good antitumor activity in several in vivo models. Lurbinectedin and trabectedin had a similar pattern of antitumor activity in murine tumors and in xenografts, whereas Zalypsis® appeared to have a distinct spectrum of activity. The fact that no relationship whatsoever was found between the in vitro cytotoxic potency and the in vivo antitumor activity, suggests that in addition to direct cytotoxic mechanisms other host-mediated effects are involved in the in vivo pharmacological effects.
authors.affiliation: Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Romano
authors.forename: Roberta
authors.initials: R
authors.lastname: Frapolli
authors.forename: Monique
authors.initials: M
authors.lastname: Zangarini
authors.forename: Ezia
authors.initials: E
authors.lastname: Bello
authors.forename: Luca
authors.initials: L
authors.lastname: Porcu
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Galmarini
authors.forename: Luis F
authors.initials: LF
authors.lastname: García-Fernández
authors.forename: Carmen
authors.initials: C
authors.lastname: Cuevas
authors.forename: Paola
authors.initials: P
authors.lastname: Allavena
authors.forename: Eugenio
authors.initials: E
authors.lastname: Erba
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002645:Chickens; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004149:Dioxoles / Q000494:pharmacology*; D005434:Flow Cytometry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin; D023041:Xenograft Model Antitumor Assays
chemical_list: D000470:Alkaloids; D018906:Antineoplastic Agents, Alkylating; D002243:Carbolines; D004149:Dioxoles; D006576:Heterocyclic Compounds, 4 or More Rings; C500383:PM 00104; C568606:PM 01183; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
keywords: DNA damage and repair mechanisms; Zalypsis®; animal models of cancers; cellular response to anticancer drugs; control of cell cycle progression; lurbinectedin; novel marine antitumor agents; trabectedin