title: Metronomic low-dose chemotherapy boosts CD95-dependent antiangiogenic effect of the thrombospondin peptide ABT-510: a complementation antiangiogenic strategy.
abstract: 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.
authors.affiliation: Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Yap
authors.forename: Dorina
authors.initials: D
authors.lastname: Veliceasa
authors.forename: Urban
authors.initials: U
authors.lastname: Emmenegger
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
authors.forename: Laura M
authors.initials: LM
authors.lastname: McKay
authors.forename: Jack
authors.initials: J
authors.lastname: Henkin
authors.forename: Olga V
authors.initials: OV
authors.lastname: Volpert
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D009842:Oligopeptides / Q000008:administration & dosage; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage; D019699:Thrombospondins / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; C500617:NAc-Sar-Gly-Val-(d-allo-Ile)-Thr-Nva-Ile-Arg-ProNEt; D009842:Oligopeptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D043823:Taxoids; D019699:Thrombospondins; D019014:fas Receptor; D000077143:Docetaxel; D003520:Cyclophosphamide; D002945:Cisplatin