[PDF][PDF] Role of macrophage targeting in the antitumor activity of trabectedin

G Germano, R Frapolli, C Belgiovine, A Anselmo… - Cancer cell, 2013 - cell.com
G Germano, R Frapolli, C Belgiovine, A Anselmo, S Pesce, M Liguori, E Erba, S Uboldi…
Cancer cell, 2013cell.com
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 …
Summary
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.
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