Abstract
2196
The marine natural product Trabectedin (ET-743, Yondelis) was found to be active in ovarian cancer and refractory soft tissue sarcoma. Trabectedin binds in the minor groove of DNA, affects transcription regulation in a promoter dependent fashion and blocks cell cycle.
In addition we have recently demonstrated that Trabectedin is selectively cytotoxic to monocytes/macrophages, being active at concentration that spared lymphocytes. In this study we tested the effect of sub-cytotoxic concentration of Trabectedin on the production of inflammatory mediators.
Trabectedin dose-dependently inhibited the release of the chemokine CCL2 and of IL-6 by monocytes, differentiated macrophages and by tumor associated macrophages (TAM). Trabectedin also reduced CCL2 production by freshly isolated tumor cells (ovarian adenocarcinoma) and sarcoma cell line such as 402-91 kindly provided by P. Aman (Göteborg University), indicating that the antitumor activity could be partially related to an antiflammatory effect.
The clinical observation of high activity of Trabectedin in myxoid liposarcomas has prompted us to investigate the drug mode of action in this tumor. The sensitivity of 402-91 cell line to Trabectedin was in the nanomolar range as assessed by colony formation, whereas flow cytometry analisys showed a delay progression in S phase and a block in G2M phase.
Since this cell line constitutively expresses pentraxin3 (PTX3), an IL-1/TNF-induced protein whose role is important in the inflammatory response as well as in the organization of the extracellular matrix, we have investigated whether Trabectedin was modulating the production of this protein. Trabectedin caused a dose-dependent reduction of PTX3 levels in 402-91 cell line. When this cell line was incubated with human monocytes the production of PTX3 was increased by approximately three times. By treating both 402-91 cells and monocytes with as low as 0.25 nM Trabectedin, PTX3 expression was reduced by 75%.
The down regulation of PTX3 was also confirmed in human myxoid liposarcomas primary cultures exposed to Trabectedin at nanomolar concentration for 24h.
Studies are in progress to evaluate the molecular mechanism underlying the observed effect and to investigate the relevance of these findings for the antitumor activity of Trabectedin.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA