Complete prevention of radiation-induced dermatitis using topical adrenergic vasoconstrictors

摘要

Radiation dermatitis is a commonly occurring, painful, side effect of cancer radiotherapy that causes some patients to withdraw from the radiotherapy course. Our goal was to test and optimize topical application of an adrenergic vasoconstrictor to rat skin in a preclinical test to prevent radiation-induced dermatitis. A radiation dermatitis assay was developed in which 17.2 Gy to a 1.5 x 3.0 cm rectangle on the clipped dorsal back of rats yielded Grade 3 radiation dermatitis over the irradiated area 13 days later. Single, topical applications of each of three adrenergic vasoconstrictors, epinephrine, norepinephrine, or phenylephrine, in various vehicle formulations, doses, and application schedules, were tested to determine their efficacy in preventing radiation dermatitis. Each of the three adrenergic agonists conferred 100 % prevention of radiation dermatitis in linear, dose-dependent manners and their EC50 potencies in preventing radiation dermatitis correlated well with their individual K (d) association constants for binding to mammalian alpha-adrenergic receptors. Topical vasoconstrictor application as little as 3-12 min before irradiation gave 80-100 % prevention, respectively, of radiation dermatitis. There was a strong correlation between the extent (0-100 %) of skin blanch present in skin immediately before irradiation and prevention of radiation dermatitis scored 13 days after irradiation. The data presented here demonstrate that topical application of adrenergic vasoconstrictors to rat skin before a large, 17.2 Gy, radiation insult confers 100 % protection against radiation dermatitis and support ongoing clinical trials and commercial development of a vasoconstrictor-based product to prevent radiotherapy-induced dermatitis.