Therapeutic efficacy of endostatin exhibits a biphasic dose-response curve.
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.
Celik
Ilhan
I
Institute of Theoretical Surgery, University Hospital Marburg, Philipps University, Baldingerstrasse, Marburg, Germany. Celik@mailer.uni-marburg.de
Sürücü
Oguzkan
O
Dietz
Carsten
C
Heymach
John V
JV
Force
Jeremy
J
Höschele
Iris
I
Becker
Christian M
CM
Folkman
Judah
J
Kisker
Oliver
O
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D043169:Endostatins / Q000097:blood / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D043169:Endostatins; D011994:Recombinant Proteins