第994回千葉医学会例会・千葉大学医学部第二外科例会

BACKGROUND AND AIM: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). CONCLUSION: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

Ultraviolet damage scores 1 week after ingenol mebutate treatment No. 1, 3 and 5.

<p>Ultraviolet damage scores 1 week after ingenol mebutate treatment No. 1, 3 and 5.</p

Histology.

<p>The figure depicts histological slides from mice exposed to ultraviolet radiation (UVR; a, b and c), 2) UVR and ingenol mebutate (UVR + IngMeb; d, e, and f) 3) UVR, IngMeb and clobetasol propionate (UVR + IngMeb = CP; g, h, and i) and 4) normal skin (j). Histological findings disclose that keratosis grade, epidermal hypertrophy, dysplasia, and actinic dermal damaged increased over time in mice receiving UVR alone (R_s = 0.82, p = 0.002), while repeated treatments with ingenol mebutate prevented progression of photodamage (Day 140; UVR 10.25 vs. UVR+IngMeb 6.00, p = 0.002). Concurrent treatments with CP potentiated the prophylactic effect of IngMeb with UV-damage scores similar to normal skin at day 140 (UVR+IngMeb+CP 3.00, Normal skin 3.00). * dermal actinic damage; ** dysplasia present in lower 2/3 of epidermis and an absent basal layer with the presence of a Zytoid body; *** parakeratosis.</p

Study set-up.

<p>Study set-up.</p