title: Repeated treatments with ingenol mebutate for prophylaxis of UV-induced squamous cell carcinoma in hairless mice.
abstract: OBJECTIVE
  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 á 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 5days prior to IngMeb, as well as 6h and 1day post treatment. Tumor formation was evaluated weekly for 52weeks. LSR (scale 0-24) were assessed at baseline, 1h, 6h, 1-, 2-, 3-, 4-, 5-, 6-, and 7days 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 3.2-4.9 vs. UVR+IngMeb 1.3-2.2, p<0.001) and postponed tumor development compared to IngMeb alone (UVR+CP+IngMeb day 217 vs. UVR+IngMeb day 189, p<0.001).
  
  
  CONCLUSIONS
  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.
authors: Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark. Electronic address: andres.erlendsson@gmail.com.
authors: Andrés M
authors: AM
authors: Erlendsson
authors: Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark.
authors: Daniel
authors: D
authors: Thaysen-Petersen
authors: Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark.
authors: Christiane
authors: C
authors: Bay
authors: Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark.
authors: Catharina M
authors: CM
authors: Lerche
authors: Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark.
authors: Peter A
authors: PA
authors: Philipsen
authors: Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark.
authors: Hans Christian
authors: HC
authors: Wulf
authors: LEO Pharma A/S, Ballerup, Denmark.
authors: John R
authors: JR
authors: Zibert
authors: Department of Dermatology, Bispebjerg University Hospital, Copenhagen, Denmark.
authors: Merete
authors: M
authors: Hædersdal
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004224:Diterpenes / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008812:Mice, Hairless; D010858:Pigmentation / Q000187:drug effects / Q000528:radiation effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: C486592:3-ingenyl angelate; D004224:Diterpenes
keywords: Clobetasol propionate; Corticosteroid; Inflammation; Local skin responses; Skin cancer