Pharmacologic antidotes to experimental doxorubicin skin toxicity: A suggested role for beta-adrenergic compounds

Doxorubicin (ADM) skin toxicity is a serious complication of inadvertent perivenous drug infiltrations. In an attempt to identify possible antidotes, nine diverse pharmacologic agents were injected intradermally into the hair-free dorsum of BALB/c mice following an intradermal ADM dose of either 0.05 or 0.5 mg. Seven of the compounds were ineffective in reducing ADM-induced ulceration; the compounds included lidocaine, cimetidine, diphenhydramine, sodium heparin, hyaluronidase, N-acetylcysteine, and α-tocopherol. The latter five compounds actually increased ulceration induced by ADM (0.5 mg), especially N-acetylcysteine, which tripled the total toxic effect. Two opposing beta-adrenergic compounds, the antagonist propranolol and the agonist isoproterenol, reduced skin ulceration resulting from experimental treatment with intradermal ADM. A role for the beta-adrenergic receptor in mediating ADM-induced skin ulceration is suggested.