Doxorubicin-induced skin necrosis in the swine model: protection with a novel radical dimer.

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Abstract
The treatment of doxorubicin (DOX) extravasation tissue injury is poorly defined. A swine model has been developed to study DOX skin toxicity and potential pharmacologic antidotes. Intradermal injections of DOX in miniature female weanling swine produced predictable and dose-dependent ulcerations that closely resemble lesions observed in humans following extravasation of DOX. The ulcers reached maximal size at 3 weeks following DOX administration and were completely healed by 7 weeks. Bi(3,5-dimethyl-5-hydroxymethyl-2-oxomorpholin-3-yl) (DHM3) is a radical dimer that can react with DOX in vitro to produce deoxydoxorubicin aglycone, an inactive anthracycline metabolite. When DHM3 was administered into the same intradermal injection site 15 minutes after DOX, the maximum ulcer size was reduced 80%, and the healing time was reduced to 5 weeks. The protection from toxicity was highly dependent on the time interval between DOX and DHM3 injections, with no protection noted after a 60-minute interval. Our data verify the swine model as a useful tool to study DOX-induced extravasation injury. Furthermore, DHM3 is an effective antidote for DOX-induced skin necrosis and has potential for clinical use.