Abstract 2979: Effects of VEGF inhibition on skin ulcer induced by administration of cytotoxic anticancer drugs

Abstract

Abstract Introduction: An accidental extravasation of vesicant drugs-containing chemotherapy leads to skin ulcer, necrosis and severe tissue destruction. The clinical evidences that VEGF inhibition suppresses tumorigenesis via inhibiting angiogenesis and causes delaying wound repair have been accumulated. We observed the cases that simultaneous administration of anti-human VEGF antibody, Bevacizumab, avoided critical skin ulcer which should be caused by extravasation of cytotoxic drug in the colorectal cancer combination chemotherapy. Therefore, we examined effects of VEGF or anti-VEGF-antibody and angiogenesis inhibitor on skin ulcer caused by administration of anticancer drug in a mouse model. Methods: Experiments were performed in accordance with the United Kingdom Coordinating Committee on Cancer Research Guidelines for the welfare of animals in experimental neoplasia. Subcutaneous injections of doxorubicin (0.2mg/0.2ml of saline) in mice induced dose-dependent ulcerations under general anesthesia. The ulcers reached maximal size at 2-3 weeks following doxorubicin administration and were completely healed by 9 weeks. Effects of co-administration of test drugs on the area of the skin ulcer caused by administration of Adriamycin, were compared with control. Bevacizumab is anti-human VEGF antibody, it has no reactivity with mouse VEGF. An anti-mouse VEGF antibody was used alternatively. Results: VEGF (5μg) increased the skin ulcer size up to 150%, and the healing time was increased to 11 weeks. Anti-VEGF antibody (50μg) and suramin reduced the maximum ulcer size (50%), and the healing time was reduced to 6 weeks. Hydrocortisone (100μg) slightly reduced the skin ulcer size and the healing time (8 week). Conclusion: VEGF aggravated skin ulcer caused by the administration of the Adriamycin. Anti-VEGF antibody and angiogenesis inhibitor, suramin, reduced skin ulcer caused by the administration of the Adriamycin. Discussion: Inhibition of VEGF signaling and/or anti-angiogenesis were suggested to reduce skin ulcer caused by the Adriamycin. Anti-human VEGF antibody, Bevacizumab was suggested to be an effective antidote for skin ulcer and necrosis by extravasation of anticancer drugs and had potential for clinical use. Citation Format: Tatsu Shimoyama, Kiyoshi Ogura, Yuusuke Kanemasa, Shigeo Yamaguti, Eisaku Sasaki, Yasushi Omuro, Takeshi Sawada, Fumiaki Koizumi, Yoshiharu Maeda. Effects of VEGF inhibition on skin ulcer induced by administration of cytotoxic anticancer drugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2979. doi:10.1158/1538-7445.AM2014-2979