Repeated treatments with ingenol mebutate for prophylaxis of UV-induced squamous cell carcinoma in hairless mice

Background and Aim: The incidence of squamous cell carcinomas (SCC) is increasing, and effective chemopreventative strategies are needed. We hypothesized that repeated treatments with ingenol mebutate (IngMeb) would postpone development of SCC in hairless mice, and that application of a corticosteroid would reduce IngMeb-induced local skin responses (LSRs) without affecting tumor postponement. Methods: Hairless mice (n = 150; 6 groups a 25 mice) were irradiated with solar simulated ultraviolet radiation (UVR) until SCC developed. During UV-irradiation and before tumor development, five single treatments (Tx) with IngMeb were given at four-week intervals (days 21, 49, 77, 105, 133). Clobetasol propionate (CP) was applied once daily for 5 days prior to IngMeb, as well as 6 h and 1 day post treatment Tumor formation was evaluated weekly for 52 weeks. LSR (scale 0-24) were assessed at baseline, 1 h, 6 h, 1-, 2-, 3-, 4-, 5-, 6-, and 7 days after each IngMeb treatment. Results: IngMeb significantly delayed tumor development compared to UVR alone (UVR day 168 vs. UVR + IngMeb day 189; p = 0.025). LSR included erythema, flaking, crusting, bleeding, vesiculation, and ulceration. The composite LSR-scores were of moderate intensity in non-UV irradiated skin (max LSR IngMeb Tx 1-5: 1.5-2.5) and more pronounced in photodamaged skin (max LSR Tx 5; IngMeb 1.5 vs. UVR + IngMeb 1.8; p < 0.001). LSR intensity correlated with tumor development by means of greater composite LSR-score resulted in longer tumor-free survival (r(2) = 0.257, p < 0.001). Contrary to our hypothesis, concurrent CP increased LSR (max LSR Tx 1-5: UVR + CP + IngMeb 32-4.9 vs. UVR + IngMeb 13-2.2, p < 0.001) and postponed tumor development compared to IngMeb alone (UVR + CP + IngMeb day 217 vs. UVR + IngMeb day 189, p < 0.001). Conclusion: Repeated field-directed treatments with IngMeb delay development of UV-induced SCC in hairless mice, and increased IngMeb induced LSRs correlated with improved clinical outcomes. The findings highlight the potential of IngMeb as a prophylactic remedy for SCC in humans. (C) 2016 Elsevier B.V. All rights reserved.