title: Unique features of the mode of action of ET-743.
abstract: This paper describes the current knowledge of the primary mode of action of a natural product, ecteinascidin 743 (ET-743), derived from the marine tunicate Ecteinascidia turbinata. ET-743 was initially selected for preclinical development because of its potent antitumor activity observed against several human solid tumor types. In vitro, the drug is cytotoxic in the nanomolar range, and in the case of some very sensitive cell lines, in the picomolar range. The large potency differences observed among several solid tumor types indicate that this compound possesses some tumor selectivity, but the molecular basis of these differential effects remains to be elucidated. The present studies were undertaken to evaluate the mechanism of action of ET-743 in this context. The available information on ET-743 binding to DNA and its effects on transcriptional regulation point to a unique behavior of this drug, as it independently affects specific gene transcription in a promoter-dependent way. In addition, ET-743 shows a peculiar pattern of selectivity in cells with different defects in their DNA-repair pathways. These results highlight a unique property of ET-743, possibly explaining why it possesses antitumor activity against tumors that are refractory to standard anticancer drugs, all of which certainly act by mechanisms that are different from that of ET-743.
authors.affiliation: Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. dincalci@marionegri.it
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Eugenio
authors.initials: E
authors.lastname: Erba
authors.forename: Giovanna
authors.initials: G
authors.lastname: Damia
authors.forename: Emanuela
authors.initials: E
authors.lastname: Galliera
authors.forename: Laura
authors.initials: L
authors.lastname: Carrassa
authors.forename: Sergio
authors.initials: S
authors.lastname: Marchini
authors.forename: Roberto
authors.initials: R
authors.lastname: Mantovani
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tognon
authors.forename: Robert
authors.initials: R
authors.lastname: Fruscio
authors.forename: José
authors.initials: J
authors.lastname: Jimeno
authors.forename: Glynn T
authors.initials: GT
authors.lastname: Faircloth
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004268:DNA-Binding Proteins; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin