title: Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production.
abstract: Yondelis (Trabectedin) is a novel antitumor agent of marine origin extracted from the tunicate Ecteinascidia turbinata. This original compound is active against several human tumors including sarcoma and ovarian and breast adenocarcinoma, as evidenced in phase II clinical trials in advanced multitreated patients. Yondelis is a DNA minor groove binder that blocks cell cycle and interferes with inducible gene transcription in a selective manner. In this study, we investigated the immunomodulatory properties of Yondelis on leukocytes. Human blood monocytes were highly susceptible in vitro to its cytotoxic effect and underwent apoptosis at pharmacologically relevant concentrations (5 nmol/L), whereas lymphocytes were up to 5-fold less sensitive. Macrophages differentiated in vitro with macrophage colony-stimulating factor and tumor-associated macrophages (TAM), isolated from patients with ovarian cancer, were also susceptible. At subcytotoxic concentrations, Yondelis inhibited the in vitro differentiation of monocytes to macrophages. In tumor-treated patients, drug infusion caused a selective decrease of monocyte counts and of ex vivo macrophage differentiation. The in vitro production of two proinflammatory mediators, CCL2 and IL-6, was markedly reduced by Yondelis in monocytes, macrophages, TAM, and freshly isolated ovarian tumor cells. The chemokine CCL2 is the major determinant of monocyte recruitment at tumor sites, whereas IL-6 is a growth factor for ovarian tumors. In view of the protumor activity of TAM and of the strong association between chronic inflammation and cancer progression, the inhibitory effect of Yondelis on macrophage viability, differentiation, and cytokine production is likely to contribute to the antitumor activity of this agent in inflammation-associated human tumors.
authors.affiliation: Department of Immunology, Mario Negri Institute, Milan, Italy. allavena@marionegri.it
authors.forename: Paola
authors.initials: P
authors.lastname: Allavena
authors.forename: Mauro
authors.initials: M
authors.lastname: Signorelli
authors.forename: Marcello
authors.initials: M
authors.lastname: Chieppa
authors.forename: Eugenio
authors.initials: E
authors.lastname: Erba
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Bianchi
authors.forename: Federica
authors.initials: F
authors.lastname: Marchesi
authors.forename: Chiara Omero
authors.initials: CO
authors.lastname: Olimpio
authors.forename: Claudia
authors.initials: C
authors.lastname: Bonardi
authors.forename: Annalisa
authors.initials: A
authors.lastname: Garbi
authors.forename: Andrea
authors.initials: A
authors.lastname: Lissoni
authors.forename: Filippo
authors.initials: F
authors.lastname: de Braud
authors.forename: José
authors.initials: J
authors.lastname: Jimeno
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D004149:Dioxoles / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D016207:Cytokines; D004149:Dioxoles; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin