Ko J, Ross J, Awad H, Hurwitz H, Klitzman BThe effects of ZD6474, an inhibitor of VEGF signaling, on cutaneous wound healing in mice. J Surg Res 129: 251-259

Department of Biomedical Engineering (BME), Duke University, Durham, North Carolina, United States
Journal of Surgical Research (Impact Factor: 1.94). 01/2006; 129(2):251-9. DOI: 10.1016/j.jss.2005.05.006
Source: PubMed


ZD6474 is an inhibitor of the VEGFR-2 receptor tyrosine kinase with additional activity against EGFR-1 receptor tyrosine kinases that has been shown to inhibit tumor growth and wound-induced neovascularization in pre-clinical studies and phase I clinical trials. The purpose of this study was to determine the effects of ZD6474 on breaking strength in a murine model of cutaneous wound healing.
Balb/C mice were given ZD6474 (50 or 100 mg/kg p.o.) or vehicle starting 7 days before wounding. Two full-thickness incisions were made in each mouse and closed using suture. On post-wounding day 7 or 28, laser Doppler blood flow measurements were made, and the breaking strength of the wounded skin was determined. Microvessel density measurements were performed using computer image analysis of CD31-stained sections.
Compared with controls, mice treated with ZD6474 showed a significantly reduced dose-dependent decline in breaking strength, both at POD 7 (P < 0.001) and at POD 28 (P < 0.005). Histologically, the ZD6474-treated mice showed a qualitative reduction in the degree of fibrosis and epithelial proliferation at the wound site, but no significant difference was noted between the 50 mg/kg and 100 mg/kg ZD6474-treated groups. Also, microvessel density measurements demonstrated no significant difference between groups.
In a murine model of wound healing, ZD6474 treatment did not prevent wound healing, but was associated with a reduced skin breaking strength compared with vehicle-treated controls at both 7 and 28 days post-wounding. These observations may have clinical relevance for the perioperative management of patients treated with inhibitors of angiogenesis.

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Available from: Bruce Klitzman, Jul 31, 2014
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    • "In this context, Jacobi et al (2004) demonstrated that VEGF promotes wound angiogenesis but is not required for wound closure in mice. Comparably, VEGF inhibition did not prevent cutaneous wound healing (Ko et al, 2005) and showed a marginal effect on liver regeneration (Van Buren et al, 2008) in rodent models. These preclinical studies support our observation of normal wound and liver recovery in BV patients despite the lack of biologically active VEGF. "
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    • "Results of preclinical studies suggest that effects of inhibition of VEGF signalling are more complex than simple impairment of revascularisation (Ko et al, 2005). Wound strength, re-epithelialisation, and other factors may also be involved, and agents that block multiple targets may have different effects than agents that selectively inhibit VEGF (Ko et al, 2005). Shorter half-lives of sunitinib, sorafenib, and other small-molecule inhibitors would be expected to be accompanied by more rapid recovery of normal wound healing. "
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