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Vascular endothelial growth factor-mediated angiogenesis inhibition and postoperative wound healing in rats
Christopher D Roman1, Hak Choy, Lillian Nanney
1Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
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.
Conclusion:
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.
Insights
Preoperative SU5416 therapy, an anti-angiogenic drug, effectively reduced vascularity in rat wounds without impacting healing or infection. Further investigation into wound integrity is warranted.
Area of Science:
- Oncology
- Vascular Biology
- Surgical Research
Background:
- Vascular endothelial growth factor (VEGF) drives angiogenesis by binding tyrosine kinase receptors.
- SU5416 is a selective inhibitor of VEGF receptor tyrosine kinase (Flk-1/KDR).
- SU5416 inhibits VEGF-driven endothelial cell growth and xenograft tumor progression.
Purpose of the Study:
- To evaluate the efficacy and safety of SU5416 in promoting wound healing.
- To determine functional dosing of SU5416 in a perioperative setting.
- To assess the impact of SU5416 on angiogenesis and wound healing postoperatively.
Main Methods:
- Male Sprague-Dawley rats received daily intraperitoneal injections of SU5416 (8 or 12 mg/kg) or vehicle for 14 days.
- Pulmonary lobectomy and back biopsies were performed.
- Tissue perfusion was measured using laser Doppler on postoperative Day 2.
Main Results:
- SU5416 treatment led to decreased vascularity and blood flow in postoperative wounds.
- No significant effects on gross wound healing or infection rates were observed.
- Histologic healing and wound tensile strength remained unaffected at 6 and 14 days.
Conclusions:
- Preoperative SU5416 therapy did not increase postoperative morbidity or mortality in rats.
- Functional dosing of SU5416 warrants further investigation for perioperative cancer treatment.
- Careful evaluation of wound integrity is recommended in future SU5416 studies.