Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis.
Increased vascular endothelial growth factor (VEGF) expression is associated with colon cancer metastases. We hypothesized that inhibition of VEGF receptor activity could inhibit colon cancer liver metastases. BALB/c mice underwent splenic injection with CT-26 colon cancer cells to generate metastases. Mice received daily i.p. injections of vehicle, tyrosine kinase inhibitor for Flk-1/KDR (SU5416) or tyrosine kinase inhibitor for VEGF, basic fibroblast growth factor, and platelet-derived growth factor receptors (SU6668). SU5416 and SU6668 respectively inhibited metastases (48.1% and 55.3%), microvessel formation (42.0% and 36.2%), and cell proliferation (24.4% and 27.3%) and increased tumor cell (by 2.6- and 4.3-fold) and endothelial cell (by 18.6- and 81.4-fold) apoptosis (P<0.001). VEGF receptor inhibitors increased endothelial cell apoptosis, suggesting that VEGF may serve as an endothelial survival factor.
Shaheen
R M
RM
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Davis
D W
DW
Liu
W
W
Zebrowski
B K
BK
Wilson
M R
MR
Bucana
C D
CD
McConkey
D J
DJ
McMahon
G
G
Ellis
L M
LM
D000818:Animals; D017209:Apoptosis; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004727:Endothelium / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011758:Pyrroles / Q000494:pharmacology*; D011897:Random Allocation; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects*; D017978:Receptors, Growth Factor / Q000187:drug effects*; D040262:Receptors, Vascular Endothelial Growth Factor; D014407:Tumor Cells, Cultured
D007211:Indoles; D011758:Pyrroles; D017978:Receptors, Growth Factor; C116890:Semaxinib; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor