The effects of ZD6474, an inhibitor of VEGF signaling, on cutaneous wound healing in mice.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Ko
Jason
J
Department of Surgery, Division of Plastic and Reconstructive Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. j-ko2@md.northwestern.edu
Ross
Joel
J
Awad
Hani
H
Hurwitz
Herbert
H
Klitzman
Bruce
B
D000818:Animals; D001835:Body Weight; D062109:Dermatologic Surgical Procedures; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000293:injuries*; D013314:Stress, Mechanical; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology; D014947:Wounds and Injuries / Q000473:pathology / Q000503:physiopathology*
D010880:Piperidines; D011799:Quinazolines; D040301:Vascular Endothelial Growth Factor Receptor-2; C452423:vandetanib