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 Surgery, Division of Plastic and Reconstructive Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
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.

Download full-text


Available from: Bruce Klitzman, Jul 31, 2014
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: When anti-VEGF (vascular endothelial growth factor) antibody bevacizumab is applied in neoadjuvant treatment of colorectal cancer patients with liver metastasis, 5–6 weeks between last bevacizumab dose and liver resection are currently recommended to avoid complications in wound and liver regeneration. In this context, we aimed to determine whether VEGF is inactivated by bevacizumab at the time of surgery. Methods: Fifty colorectal cancer patients with liver metastases received neoadjuvant chemotherapy±bevacizumab supplementation. The last dose of bevacizumab was administered 6 weeks before surgery. Plasma, subcutaneous and intraabdominal wound fluid were analysed for VEGF content before and after liver resection (day 1–3). Immunoprecipitation was applied to determine the amount of bevacizumab-bound VEGF. Results: Bevacizumab-treated individuals showed no increase in perioperative complications. During the entire monitoring period, plasma VEGF was inactivated by bevacizumab. In wound fluid, VEGF was also completely bound by bevacizumab and was remarkably low compared with the control chemotherapy group. Conclusion: These data document that following a cessation time of 6 weeks, bevacizumab is fully active and blocks circulating and local VEGF at the time of liver resection. However, despite effective VEGF inactivation no increase in perioperative morbidity is recorded suggesting that VEGF activity is not essential in the immediate postoperative recovery period.
    British Journal of Cancer 07/2012; 107(6):961-6. DOI:10.1038/bjc.2012.342 · 4.84 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Advances in understanding the role of vascular endothelial growth factor (VEGF) in normal physiology are giving insight into the basis of adverse effects attributed to the use of VEGF inhibitors in clinical oncology. These effects are typically downstream consequences of suppression of cellular signalling pathways important in the regulation and maintenance of the microvasculature. Downregulation of these pathways in normal organs can lead to vascular disturbances and even regression of blood vessels, which could be intensified by concurrent pathological conditions. These changes are generally manageable and pose less risk than the tumours being treated, but they highlight the properties shared by tumour vessels and the vasculature of normal organs.
    British Journal of Cancer 07/2007; 96(12):1788-95. DOI:10.1038/sj.bjc.6603813 · 4.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: System requirements: World Wide Web browser and PDF reader. Mode of access: Available through the Internet. Title from document title page. Document formatted into pages; contains xiii, 127 p. : ill. (some col.). Thesis (Ph. D.)--West Virginia University, 2007. Vita. Includes abstract. Includes bibliographical references.
Show more