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Arizona Cancer Center [D. S. A., R. T. D., J. G. E., K. S., M. J. X., Y-M. P., R. G., J. A. F., S. S., D. J. R., G. T. B.], and Department of Surgery, College of Medicine [J. A. W.], University of Arizona, Tucson, Arizona 85724; and Kaiser Center for Health Research, Portland, Oregon 97227-1098 [M. A.]
-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 randomized,
placebo-controlled study using a topical hydrophilic ointment
formulation with or without 10% (w/w) DFMO. Forty-eight participants
with moderate-severe actinic keratoses (AKs) on their forearms
(i.e., at least 10 well-circumscribed lesions on the
lateral surface) completed a 1-month run-in on placebo ointment. Before
randomization, all lateral forearm AKs were circled, counted,
photographed, and skin biopsies were obtained for DFMO and polyamine
levels. Then participants were randomized to receive DFMO ointment on
the right versus the left forearm and placebo
hydrophilic ointment on the contralateral 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 subsample of 17 placebo forearms
had measurable concentrations of DFMO, whereas 13 of the corresponding
DFMO-treated forearms had high DFMO skin levels. As compared with
placebo, the 6-month DFMO treatment caused a 23.5% reduction 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%) participants experienced severe (2;
4.2%) or moderate (5; 10.4%) inflammatory reactions 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.
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