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Modulation of Experimental Doxorubicin Skin Toxicity by ß-Adrenergic Compounds¹

Section of Hematology and Oncology, Department of Internal Medicine, the Cancer Center, Colleges of Medicine [D. S. A.] and Pharmacy [R. T. D.], The University of Arizona Health Sciences Center, Tucson, Arizona 85724

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 ß-adrenergic agonists and antagonists. Three sequences of i.d. administration of ß-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 ß-receptor number (with propranolol and ISO, respectively). The results demonstrate consistent antidotal activity for ISO and propranolol as single antidotal injections. Terbutaline, a ß₂-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 ß-adrenergics in the management of experimental ADM skin ulceration and suggest that local toxicity is mediated through specific ß-receptors (possibly ß₁) in the mouse skin.

¹ Supported in part by USPHS Grants CA-17094, CA-23074, and CA-13612 from the National Cancer Institute, Department of Health, Education and Welfare, Bethesda, Md., and a donation from the Phi Beta Psi National Sorority, Lima, Ohio. Portions of this work were presented at the 71st Annual Meeting of the American Association for Cancer Research, San Diego, Calif., May 29, 1980 (9).

² To whom requests for reprints should be addressed, at Section of Hematology/Oncology, College of Medicine, University of Arizona, Tucson, Ariz. 85724.

Received 10/ 7/80. Accepted 3/13/81.

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