Blocking angiogenesis is a promising approach in
cancer therapy. Natural inhibitors of angiogenesis and derivatives induce receptor-mediated signals, which often result in the endothelial cell death. Low-dose
chemotherapy, given at short regular intervals with no prolonged breaks (metronomic
chemotherapy), also targets angiogenesis by obliterating proliferating endothelial cells and circulating endothelial cell precursors.
ABT-510, a
peptide derivative of
thrombospondin, kills endothelial cell by increasing
CD95L, a
ligand for the CD95
death receptor. However, CD95 expression itself is unaffected by
ABT-510 and limits its efficacy. We found that multiple
chemotherapy agents,
cyclophosphamide (
cytoxan),
cisplatin, and
docetaxel, induced endothelial CD95 in vitro and in vivo at low doses that failed to kill endothelial cells (
cytoxan >
cisplatin >
docetaxel). Thus, we concluded that some of these agents might
complement each other and together block angiogenesis with maximal efficacy. As a proof of principle, we designed an antiangiogenic cocktail combining
ABT-510 with
cytoxan or
cisplatin.
Cyclophosphamide and
cisplatin synergistically increased in vivo endothelial cell apoptosis and angiosuppression by
ABT-510. This synergy required CD95, as it was reversible with the CD95 decoy receptor. In a mouse model,
ABT-510 and
cytoxan, applied together at low doses, acted in synergy to delay
tumor take, to stabilize the growth of established
tumors, and to cause a long-term progression delay of PC-3 prostate
carcinoma. These antitumor effects were accompanied by major decreases in microvascular density and concomitant increases of the vascular CD95,
CD95L, and apoptosis. Thus, our study shows a "complementation" design of an optimal
cancer treatment with the antiangiogenic
peptide and a metronomic
chemotherapy.