Synergy between angiostatin and endostatin: inhibition of ovarian cancer growth.
Ovarian cancer is the leading cause of fatality among gynecological malignancies. Ovarian cancer growth is angiogenesis-dependent, and an increased production of angiogenic growth factors such as vascular endothelial growth factor is prognostically significant even during early stages of the disease. Therefore, we investigated whether antiangiogenic treatment can be used to inhibit the growth of ovarian cancer in an experimental model system. Mouse angiostatin (kringle 1-4) and endostatin were expressed in yeast. Purified angiostatin and endostatin were then used to treat established ovarian cancers in athymic mice. These studies showed that both angiostatin and endostatin inhibited tumor growth. However, angiostatin treatment was more effective in inhibiting ovarian cancer growth when compared with endostatin in parallel experiments. Residual tumors obtained from angiostatin- and endostatin-treated animals showed decreased number of blood vessels and, as a consequence, increased apoptosis of tumor cells. Subsequently, the efficacy of a combined treatment with angiostatin and endostatin was investigated. In the presence of both angiostatic proteins, endothelial cell proliferation was synergistically inhibited. Similarly, a combination regimen using equal amounts of angiostatin and endostatin showed more than additive effect in tumor growth inhibition when compared with treatment with individual angiostatic protein. These studies demonstrate synergism between two angiostatic molecules and that antiangiogenic therapy can be used to inhibit ovarian cancer growth.
Yokoyama
Y
Y
Department of Pharmacology, University of Minnesota, Minneapolis 55455, USA.
Dhanabal
M
M
Griffioen
A W
AW
Sukhatme
V P
VP
Ramakrishnan
S
S
D043168:Angiostatins; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply / Q000187:drug effects; D003094:Collagen / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D018365:Neoplasm, Residual / Q000098:blood supply / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D010446:Peptide Fragments / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D010843:Pichia / Q000235:genetics; D010958:Plasminogen / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D043169:Endostatins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D043168:Angiostatins; D010958:Plasminogen; D003094:Collagen