Abstract
Background and AimIngenol mebutate (IngMeb) is an effective treatment for actinic keratosis. In this study, we hypothesized that repeated treatments with IngMeb may prevent progression of UV-induced photodamage, and that concurrent application of a corticosteroid may reduce IngMeb-induced local skin responses (LSR).MethodsHairless mice (n = 60; 3 groups of 20 mice) were irradiated with solar simulated ultraviolet radiation (UVR) throughout the study. Five single treatments with IngMeb were given at 4-week intervals (Days 21, 49, 77, 105, and 133). Clobetasol propionate (CP) was applied once daily for 5 days prior to each IngMeb application, as well as 6 h and 1 day post treatment. One week after IngMeb treatment No. 1, 3, and 5 (Days 28, 84, and 140), biopsies from four mice in each group were collected for histological evaluation of UV-damage on a standardized UV-damage scale (0–12). LSR (0–24) were assessed once daily (Days 1–7) after each IngMeb treatment.ResultsIngMeb prevented progression of photodamage in terms of keratosis grade, epidermal hypertrophy, dysplasia, and dermal actinic damage with a lower composite UV-damage score on day 140 (UVR 10.25 vs. UVR+IngMeb 6.00, p = 0.002) compared to UVR alone. IngMeb induced LSR, including erythema, flaking, crusting, bleeding, vesiculation, and ulceration. Concurrent CP increased LSR (max LSR Tx 1–5: UVR+IngMeb+CP 3.6–5.5 vs. UVR+IngMeb 2.6–4.3) and provided better prevention of photodamage compared to IngMeb alone (Day 140: UVR+IngMeb 6.00 vs. UVR+IngMeb+CP 3.00 p < 0.001).ConclusionRepeated field-directed treatments with IngMeb prevent progression of cutaneous photodamage in hairless mice, while CP cannot be used to alleviate IngMeb-induced LSR. The findings suggest that IngMeb may potentially serve as a prophylactic treatment for UV-induced tumors.
Highlights
Non-melanoma skin cancer (NMSC) is the most commonly diagnosed cancer globally and is primarily constituted by basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) [1]
We hypothesized that repeated treatments with Ingenol mebutate (IngMeb) may prevent progression of UVinduced photodamage, and that concurrent application of a corticosteroid may reduce IngMeb-induced local skin responses (LSR)
The findings suggest that IngMeb may potentially serve as a prophylactic treatment for UVinduced tumors
Summary
Non-melanoma skin cancer (NMSC) is the most commonly diagnosed cancer globally and is primarily constituted by basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) [1]. Ultraviolet radiation (UVR) is accoun for 90% of BCC and SCC and acts as a complete carcinogen capable of tumor initiation, promotion, and progression [2]. UVB (290–320 nm) is directly absorbed by DNA bases, producing photolesions such as cyclobutane pyrimidine dimers (CPD) and 6–4 photoproducts [3]. If not repaired, these photolesions cause signature UV mutations i.e. UVR (UVA 320– 400 nm and UVB), absorbed by various skin chromophores, may result in production of reactive oxygen species (ROSs) [4]. ROSs are believed to cause indirect DNA damage, and may play a role in tumor promotion [5].
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