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Therapeutic Efficacy of Endostatin Exhibits a Biphasic Dose-Response Curve

¹ Institute of Theoretical Surgery and ² Department of General Surgery, University Hospital Marburg, Philipps University, Baldingerstrasse, Marburg; ³ Charité, Department of Obstetrics and Gynecology, Campus Benjamin Franklin, Hindenburgdamm, Berlin, Germany; ⁴ Vascular Biology Program and Department of Surgery, Children's Hospital Boston, Harvard Medical School; ⁵ Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School; and ⁶ Dana-Farber Cancer Institute, Boston, Massachusetts

Requests for reprints: Ilhan Celik, Institute of Theoretical Surgery, Philipps-University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. Phone: 49-6421-286-2229; Fax: 49-6421-286-8926; E-mail: Celik{at}mailer.uni-marburg.de.

We show here that recombinant endostatin protein has a biphasic effect on the inhibition of endothelial cell migration in vitro. In tumor-bearing animals, there is a similar biphasic effect on the inhibition of tumor growth and on circulating endothelial cells after once-daily s.c. injections. This biphasic effect is revealed as a U-shaped curve in which efficacy is optimal between very low and very high doses depending on the tumor type. This result may be applicable to other inhibitors of endothelial growth and to angiogenesis. Furthermore, these results have important implications for clinicians who administer angiogenesis inhibitors for cancer or other angiogenesis-dependent diseases. When these results are taken together with two previous reports of angiogenesis inhibitors with a U-shaped dose-response, they suggest that other regulators of endothelial growth may display a similar pattern.

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