PROTECTION OF MITOMYCIN-C INDUCED SKIN EXTRAVASATION WITH THE NITROXIDE, 3-CARBAMOYL-PROXYL (3-CP)

Extravasation tissue injury from chemotherapeutic drugs is a serious c linical problem. A swine model has been useful for studying skin extra vasation and evaluating potential antidotes. Mitomycin C (MMC) skin ex travasation was studied. Nitroxides, a class of compounds which are pr otective against a variety of oxidative stresses in vitro, including M MC, were tested as antidotes. Miniature swine were anesthetized and gi ven 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 nitroxi de which protected if given 5 min after extravasation. Administration of 3-CP 10 min after MMC injection was not protective. In vitro studie s 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 wer e tested and found to protect against MMC skin necrosis 90 days after injection. Histologic sections of the 3-CP- and MMC-treated pig skin s howed a marked reduction in the degree of acute inflammation and the a bsence of deep dermal scarring when compared to MMC alone.