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.