Vascular endothelial growth factor-mediated angiogenesis inhibition and postoperative wound healing in rats.
BACKGROUND
Vascular endothelial growth factor (VEGF) is an angiogenic factor that acts by binding to specific high-affinity tyrosine kinase receptors. SU5416 is an antiangiogenic agent that acts as a potent and selective inhibitor of the VEGF Flk-1/KDR receptor tyrosine kinase. SU5416 has been shown to inhibit VEGF-dependent mitogenesis of human endothelial cells and to decrease the growth of xenografts of melanoma, lung carcinoma, ovarian carcinoma, and gliomas. The effect of pre- or perioperative use of this drug on angiogenesis and wound healing in the postoperative setting has not been shown. We sought to analyze the efficacy and safety with respect to functional dosing of SU5416 in the setting of wound healing. This represents an important step forward in the use of this and similar drugs in the perioperative setting of treatment for multiple types of cancers. The use of an inhibitor of VEGF receptors such as SU5416 is distinct and it is likely complementary to other agents in the treatment of such cancers.


METHODS
We injected 8-week-old male Sprague-Dawley rats with SU5416 (8 or 12 mg/kg) or dimethyl sulfoxide intraperitoneally, daily for 14 days. We then performed a right pulmonary lobectomy and 6-mm full-thickness punch biopsies of the back. Tissue perfusion measured via laser Doppler on Postoperative Day 2 was 1.65, 1.22, and 1.14 perfusion units (P < 0.0004) for control, 8 mg/kg, and 12 mg/kg groups, respectively.


RESULTS
We successfully treated a murine model with functional doses of the anti-VEGF drug SU5416 so as to achieve decreased vascularity and blood flow in postoperative wounds. There was no effect on gross wound healing or infection in either control or treatment groups. Also, no drug-related impairment of histologic healing or decrease in wound tensile strength was demonstrated at either 6 or 14 days.


CONCLUSIONS
Preoperative therapy with functional dosing of SU5416 does not appear to have any major effect on postoperative morbidity or mortality in rats. We additionally conclude that preoperative therapy with SU5416 should be investigated further with careful attention to wound integrity.
Roman
Christopher D
CD
Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Choy
Hak
H
Nanney
Lillian
L
Riordan
Colin
C
Parman
Kelly
K
Johnson
David
D
Beauchamp
R Daniel
RD
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004727:Endothelium / Q000098:blood supply; D007211:Indoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000601:surgery; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011013:Pneumonectomy; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014945:Wound Healing / Q000187:drug effects*
D020533:Angiogenesis Inhibitors; D016228:Endothelial Growth Factors; D007211:Indoles; D008222:Lymphokines; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C116890:Semaxinib