Protection of mitomycin C induced skin extravasation with the nitroxide, 3-carbamoyl-PROXYL (3-CP)

Extravasation tissue injury from chemotherapeutic drugs is a serious clinical problem. A swine model has been useful for studying skin extravasation and evaluating potential antidotes. Mitomycin C (MMC) skin extravasation was studied. Nitroxides, a class of compounds which are protective against a variety of oxidative stresses in vitro, including MMC, were tested as antidotes. Miniature swine were anesthetized and given intradermal (ID) injections of MMC. MMC alone caused skin necrosis and ulceration. Several nitroxides were screened as protectors of MMC induced skin necrosis. 3-carbamoyl-PROXYL (3-CP) was the lone nitroxide which protected if given 5 min after extravasation. Administration of 3-CP 10 min after MMC injection was not protective. In vitro studies with monolayered V79 cells showed that 3-CP had a direct protective effect against MMC cytotoxicity in a concentration-dependent fashion. Therefore, in the swine model doses of 3-CP ranging from 25-100 mM were tested and found to protect against MMC skin necrosis 90 days after injection. Histologic sections of the 3-CP- and MMC-treated pig skin showed a marked reduction in the degree of acute inflammation and the absence of deep dermal scarring when compared to MMC alone.