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 tumortreated 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. (Cancer Res 2005; 65(7): 2964-71)

Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach

“…Colony stimulating factor 1 (CSF-1), a cytokine commonly produced by tumours, triggers monocyte migration (Pixley and Stanley, 2004) and blocking CSF-1 or its receptor has been shown to suppress macrophage infiltration and to reduce tumour growth (Aharinejad et al, 2004). Recently, it was shown by Allavena et al (2005) that Yondelis (Trabectedin), a new anticancer agent of marine origin, markedly reduced the levels of proinflammatory cytokines CCL2 and IL-6 in monocytes and macrophages, thus inhibiting macrophage viability, differentiation and cytokine production.…”

A Review of Trabectedin (ET-743): A Unique Mechanism of Action

“…At lower concentrations causing modest cytotoxicity, trabectedin inhibits the in vitro production of the proinflammatory mediators CCL2 and interleukin (IL)-6 by monocytes, macrophages, and tumor-associated macrophages isolated from ovarian cancer biopsies (23). The modulation of cytokines and chemokines occurs at the transcriptional level, thus indicating that the mechanism of trabectedin on transcription regulation can be effective both in cancer cells and in some normal cells, which produce factors that are relevant for the tumor growth and progression.…”

Monocytes and Macrophages in Cancer: Development and Functions

“…In contrast, other therapeutic strategies aim at functional modification of TAMs, thus activating anti-tumoral functions, rather than eliminating TAMs. Such approaches include the cytokineand antibody-based therapeutic reprogramming of TAMs as well as licensing phagocytosis of targeted tumor cells by TAMs lymphocytes) were significantly less sensitive to the drug [88]. Furthermore, sub-cytotoxic doses of Trabectedin inhibited both in vitro and ex vivo differentiation of monocytes to macrophages.…”