ABT-510 induces tumor cell apoptosis and inhibits ovarian tumor growth in an orthotopic, syngeneic model of epithelial ovarian cancer.
Epithelial ovarian cancer (EOC) is the fifth most common cancer in women and is characterized by a low 5-year survival rate. One strategy that can potentially improve the overall survival rate in ovarian cancer is the use of antitumor agents such as ABT-510. ABT-510 is a small mimetic peptide of the naturally occurring antiangiogenic compound thrombospondin-1 and has been shown to significantly reduce tumor growth and burden in preclinical mouse models and in naturally occurring tumors in dogs. This is the first evaluation of ABT-510 in a preclinical model of human EOC. Tumorigenic mouse surface epithelial cells were injected into the bursa of C57BL/6 mice that were treated with either 100 mg/kg ABT-510 or an equivalent amount of PBS. ABT-510 caused a significant reduction in tumor size, ascites fluid volume, and secondary lesion dissemination when compared with PBS controls. Analysis of the vasculature of ABT-510-treated mice revealed vascular remodeling with smaller diameter vessels and lower overall area, increased number of mature vessels, and decreased tissue hypoxia. Tumors of ABT-510-treated mice had a significantly higher proportion of apoptotic tumor cells compared with the PBS-treated controls. Immunoblot analysis of cell lysates revealed a reduction in vascular endothelial growth factor, vascular endothelial growth factor receptor-2, and proliferating cell nuclear antigen protein expression as well as expression of members of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase survival pathways. In vitro, ABT-510 induced tumor cell apoptosis in mouse and human ovarian cancer cells. This study shows ABT-510 as a promising candidate for inhibiting tumor growth and ascites formation in human EOC.
Greenaway
James
J
Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada N1G 2W1.
Henkin
Jack
J
Lawler
Jack
J
Moorehead
Roger
R
Petrik
Jim
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D018955:CD36 Antigens / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D019700:Thrombospondin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D015415:Biomarkers; D018955:CD36 Antigens; D053222:Fas Ligand Protein; C500617:NAc-Sar-Gly-Val-(d-allo-Ile)-Thr-Nva-Ile-Arg-ProNEt; D009842:Oligopeptides; D019700:Thrombospondin 1