Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms.
Redundant mechanisms mediate colon cancer angiogenesis. Targeting multiple angiogenic factors simultaneously may improve survival of mice with colon cancer metastases. BALB/c mice underwent splenic injection with CT-26 colon cancer cells to generate liver metastases and received administration of either vehicle alone or a tyrosine kinase inhibitor for vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor receptors (SU6668). Mice were sacrificed when they became moribund as determined by a blinded observer. In a parallel experiment, groups of mice were sacrificed at earlier time points to better define the kinetics of the effect of SU6668 on angiogenic parameters over time. SU6668 increased median survival by 58% (P < 0.001) and led to a progressive increase in tumor cell and endothelial cell apoptosis that increased over time. In addition, pericyte vessel coverage and tumor vascularity were significantly decreased in mice treated with SU6668. Based on current knowledge of endothelial cell survival, these data suggest that SU6668 may prevent tumor endothelial cell survival directly (vascular endothelial growth factor) and indirectly (pericyte coverage) by affecting endothelial cell survival mechanisms.
Department of Surgical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
R M
RM
Shaheen
W W
WW
Tseng
D W
DW
Davis
W
W
Liu
N
N
Reinmuth
R
R
Vellagas
A A
AA
Wieczorek
Y
Y
Ogura
D J
DJ
McConkey
K E
KE
Drazan
C D
CD
Bucana
G
G
McMahon
L M
LM
Ellis
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor
D020533:Angiogenesis Inhibitors; D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D011758:Pyrroles; D017468:Receptors, Fibroblast Growth Factor; D017978:Receptors, Growth Factor; C412603:orantinib; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor