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Cancer Cell. 2013 Feb 11;23(2):249-62. doi: 10.1016/j.ccr.2013.01.008.

Role of macrophage targeting in the antitumor activity of trabectedin.

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1
Department Immunology and Inflammation, IRCCS Clinical and Research Institute Humanitas, 20089 Rozzano, Milan, Italy.

Abstract

There is widespread interest in macrophages as a therapeutic target in cancer. Here, we demonstrate that trabectedin, a recently approved chemotherapeutic agent, induces rapid apoptosis exclusively in mononuclear phagocytes. In four mouse tumor models, trabectedin caused selective depletion of monocytes/macrophages in blood, spleens, and tumors, with an associated reduction of angiogenesis. By using trabectedin-resistant tumor cells and myeloid cell transfer or depletion experiments, we demonstrate that cytotoxicity on mononuclear phagocytes is a key component of its antitumor activity. Monocyte depletion, including tumor-associated macrophages, was observed in treated tumor patients. Trabectedin activates caspase-8-dependent apoptosis; selectivity for monocytes versus neutrophils and lymphocytes is due to differential expression of signaling and decoy TRAIL receptors. This unexpected property may be exploited in different therapeutic strategies.

PMID:
23410977
DOI:
10.1016/j.ccr.2013.01.008
[Indexed for MEDLINE]
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