Erythropoietin Improves the Healing of Skin Necrosis Resulting From Doxorubicin Extravasation in a Rat Model

BackgroundDoxorubicin is an antineoplastic agent that causes skin necrosis when extravasated. Various agents have been tried to reduce tissue damage owing to extravasation. Erythropoietin (EPO) is an obligatory growth factor for red blood cells and has beneficial effects on wound healing.ObjectiveThe aim of this study was to test the hypothesis that local EPO injection can prevent and improve healing of necrosis at the doxorubicin injection site in rats.MethodsWe used 31 female Sprague-Dawley rats. The dorsal area of each rat was shaved, and 2 mg of doxorubicin in 0.5 mL saline was injected intradermally. The rats were then divided into 3 groups: control; control with intradermal injection of saline; and treatment, which received an intradermal injection of EPO. EPO in saline was injected into 4 quadrants of the same site where doxorubicin was injected 1 hour before. The rats were monitored and the area of each ulcer was measured. Skin biopsies were excised at the end of 4 weeks using anesthetic pentobarbital. Inflammation, edema, epithelization, neovascularization, necrosis, fibroblast proliferation, and collagen synthesis were evaluated and compared between groups.ResultsThe average areas of the lesions were significantly smaller in the EPO-injected rats (P = 0.03). The histopathologic evaluation revealed that the scores for epithelization, neovascularization, fibroblast proliferation, and collagen synthesis were higher (P < 0.001, P < 0.001, P = 0.002, and P = 0.04, respectively) and the score for necrosis was lower (P < 0.001) in the EPO-injected group than in both the saline-injected and control groups.ConclusionsIn this study using female Sprague-Dawley rats, EPO treatment improved the healing of skin necrosis caused by doxorubicin injection. This finding may lead to a new therapeutic approach for the management of skin necrosis caused by doxorubicin extravasation.