Potent pleiotropic anti-angiogenic effects of TM601, a synthetic chlorotoxin peptide.
Chemically synthesized chlorotoxin (TM601) has been studied as a tumor targeting peptide. In this study, the anti-angiogenic properties of TM601 are reported.


METHODS
In vitro and in vivo models of angiogenesis and tumor growth were used to characterize the anti-angiogenic effects of TM601.


RESULTS
TM601 bound to proliferating vascular endothelial cells, decreased human umbilical vein endothelial cell (HUVEC) invasion, and reduced secretion of bioactive matrix metalloproteinase-2 (MMP-2). Using the chick chorioallantoic membrane assay (CAM), TM601 inhibited angiogenesis stimulated by any of eight pro-angiogenic factors, and when TM601 was co-administered with bevacizumab, the combination was significantly more potent than a ten-fold increase in bevacizumab dose. TM601 did not alter tumor or vascular endothelial cell growth in vitro, but TM601 treatment of tumors grown on the CAM decreased tumor growth and intra-tumoral hemoglobin levels. Intravenously injected TM601 was also shown to significantly decrease new blood vessel growth in mice.


CONCLUSIONS
TM601 inhibits angiogenesis stimulated by many factors and potentiates the anti-angiogenic effect of bevacizumab.
Jacoby
Douglas B
DB
TransMolecular, Inc., 840 Memorial Drive, Cambridge, MA 02139, USA. jacoby@transmolecular.com
Dyskin
Evgeny
E
Yalcin
Murat
M
Kesavan
Kamala
K
Dahlberg
William
W
Ratliff
Judson
J
Johnson
Eric W
EW
Mousa
Shaker A
SA
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply; D004357:Drug Synergism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009498:Neurotoxins / Q000493:pharmacokinetics / Q000494:pharmacology*; D012604:Scorpion Venoms / Q000493:pharmacokinetics / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D009498:Neurotoxins; D012604:Scorpion Venoms; C091539:Chlorotoxin; D000068258:Bevacizumab