Chemoprevention of human actinic keratoses by topical 2-(difluoromethyl)-dl-ornithine

alpha -2-(Difluoromethyl) dl-ornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, has been shown to suppress skin carcinogenesis in murine models after oral or topical administration. We designed a randomiz ed, placebo-controlled study using a topical hydrophilic ointment formulati on with or without 10% (W/W) DFMO. Forty-eight participants with moderate-s evere actinic keratoses (AKs) on their forearms (i,e,, at least 10 well-cir cumscribed lesions on the lateral surface) completed a 1-month run-in on pl acebo ointment. Before randomization, all lateral forearm AKs were circled, counted, photographed, and skin biopsies were obtained for DFMO and polyam ine levels. Then participants were randomized to receive DFMO ointment on t he right versus the left forearm and placebo hydrophilic ointment on the co ntralateral forearm twice daily for 6 months, DFMO was not detected in the blood of any subject, and there were no systemic toxicities. None of a subs ample of 17 placebo forearms had measurable concentrations of DFMO, whereas 13 of the corresponding DFMO-treated forearms had high DFMO skin levels, A s compared with placebo, the 6-month DFMO treatment caused a 23.5% reductio n in the number of AKs (P = 0,001) as well as significant suppression of AK biopsy spermidine levels (26%; P = 0,04), Seven of the 48 (14.6%) particip ants experienced severe (2; 4.2%) or moderate (5; 10.4%) inflammatory react ions on their DFMO-treated arms which required dosing modification. Topical DFMO for 6 months can reduce the number of AK lesions and skin spermidine concentrations in high-risk participants and deserves additional study as a skin cancer chemopreventive agent.