Modulation of experimental doxorubicin skin toxicity by beta-adrenergic compounds.

Doxorubicin [Adriamycin (ADM), a potent intercalating antineoplastic agent, occasionally causes severe local skin toxicity if extravasated during administration. Previous experiments using intradermal (i.d.) ADM in BALB/c mice have shown limited antidotal activity for local i.d. corticosteroids in preventing ADM-induced ulceration and no effect for a number of other compounds except beta-adrenergic agonists and antagonists. Three sequences of i.d. administration of beta-adrenergics were evaluated in this study: a single dose immediately after 0.05 or 0.5 mg ADM; 8 daily doses of isoproterenol (ISO) or 0.9% NaCl solution, 0.05 ml after ADM; and 5 days of pre-ADM to ostensibly "up" or "down"-regulate beta-receptor number (with propranolol and ISO, respectively). The results demonstrate consistent antidotal activity for ISO and propranolol as single antidotal injections. Terbutaline, a beta 2-specific agonist, was not effective as an antidote. Continuous daily ISO did not improve results, whereas continuous i.d. NaCl solution significantly increased skin lesion size and duration. ISO pretreatment significantly decreased subsequent ADM-induced ulceration, while propranolol pretreatment was not different from control. The results confirm a role for beta-adrenergics in the management of experimental ADM skin ulceration and suggest that local toxicity is mediated through specific beta-receptors (possibly beta 1) in the mouse skin.