title: Repeated Treatments with Ingenol Mebutate Prevents Progression of UV-Induced Photodamage in Hairless Mice.
abstract: OBJECTIVE
  Ingenol 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).
  
  
  METHODS
  Hairless 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.
  
  
  RESULTS
  IngMeb 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).
  
  
  CONCLUSIONS
  Repeated 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.
authors.affiliation: Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark.
authors.forename: Andrés Már
authors.identifier: http://orcid.org/0000-0002-3171-4458
authors.initials: AM
authors.lastname: Erlendsson
authors.affiliation: Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark.
authors.forename: Daniel
authors.initials: D
authors.lastname: Thaysen-Petersen
authors.affiliation: Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark.
authors.forename: Christiane
authors.initials: C
authors.lastname: Bay
authors.affiliation: Leo Pharma A/S, Ballerup, Denmark.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hald
authors.affiliation: Leo Pharma A/S, Ballerup, Denmark.
authors.forename: Kresten
authors.initials: K
authors.lastname: Skak
authors.affiliation: Leo Pharma A/S, Ballerup, Denmark.
authors.forename: John Robert
authors.initials: JR
authors.lastname: Zibert
authors.affiliation: Department of Dermatology, Division of Aesthetics and Laserdermatology, University of Leipzig, Leipzig, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Paasch
authors.affiliation: Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark.
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Wulf
authors.affiliation: Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark.
authors.forename: Merete
authors.initials: M
authors.lastname: Haedersdal
mesh_terms: D000818:Animals; D002990:Clobetasol / Q000008:administration & dosage; D018450:Disease Progression; D004224:Diterpenes / Q000008:administration & dosage*; D005260:Female; D055623:Keratosis, Actinic / Q000188:drug therapy* / Q000473:pathology; D008812:Mice, Hairless; D014466:Ultraviolet Rays
chemical_list: C486592:3-ingenyl angelate; D004224:Diterpenes; D002990:Clobetasol