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Synergy between Angiostatin and Endostatin: Inhibition of Ovarian Cancer Growth¹

Department of Pharmacology [Y. Y., S. R.], Obstetrics and Gynecology, and Comprehensive Cancer Center [S. R.], University of Minnesota, Minneapolis, Minnesota 55455; Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215 [M. D., V. P. S.]; and Tumor Angiogenesis Laboratory, Department of Internal Medicine, University Hospital Maastricht, Maastricht, The Netherlands [A. W. G.]

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.

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