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

Andrés M Erlendsson; Daniel Thaysen-Petersen; Christiane Bay; Catharina M Lerche; Peter A. Philipsen; Hans Christian Wulf; John R. Zibert; Merete Hædersdal

doi:10.1016/j.jphotobiol.2016.08.022

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

Andrés M Erlendsson, Daniel Thaysen-Petersen, Christiane Bay, Catharina M Lerche, Peter A. Philipsen, Hans Christian Wulf, John R. Zibert, Merete Hædersdal

Department of Clinical Medicine

5 Citations (Scopus)

Abstract

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 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 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 (r² = 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). 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.

Original language	English
Journal	Journal of photochemistry and photobiology. B, Biology
Volume	163
Pages (from-to)	144-149
Number of pages	6
ISSN	1011-1344
DOIs	https://doi.org/10.1016/j.jphotobiol.2016.08.022
Publication status	Published - Oct 2016

Keywords

Clobetasol propionate
Corticosteroid
Inflammation
Local skin responses
Skin cancer

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jphotobiol.2016.08.022

Cite this

@article{c6de3197d97a4e939f4c41266d1e0703,

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

abstract = "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 (r2 = 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). 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.",

keywords = "Clobetasol propionate, Corticosteroid, Inflammation, Local skin responses, Skin cancer",

author = "Erlendsson, {Andr{\'e}s M} and Daniel Thaysen-Petersen and Christiane Bay and Lerche, {Catharina M} and Philipsen, {Peter A.} and Wulf, {Hans Christian} and Zibert, {John R.} and Merete H{\ae}dersdal",

year = "2016",

month = oct,

doi = "10.1016/j.jphotobiol.2016.08.022",

language = "English",

volume = "163",

pages = "144--149",

journal = "Journal of photochemistry and photobiology. B, Biology",

issn = "1011-1344",

publisher = "Elsevier",

}

TY - JOUR

T1 - Repeated treatments with ingenol mebutate for prophylaxis of UV-induced squamous cell carcinoma in hairless mice

AU - Erlendsson, Andrés M

AU - Thaysen-Petersen, Daniel

AU - Bay, Christiane

AU - Lerche, Catharina M

AU - Philipsen, Peter A.

AU - Wulf, Hans Christian

AU - Zibert, John R.

AU - Hædersdal, Merete

PY - 2016/10

Y1 - 2016/10

N2 - 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 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 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 (r2 = 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). 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.

AB - 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 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 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 (r2 = 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). 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.

KW - Clobetasol propionate

KW - Corticosteroid

KW - Inflammation

KW - Local skin responses

KW - Skin cancer

U2 - 10.1016/j.jphotobiol.2016.08.022

DO - 10.1016/j.jphotobiol.2016.08.022

M3 - Journal article

C2 - 27567085

AN - SCOPUS:85015355356

SN - 1011-1344

VL - 163

SP - 144

EP - 149

JO - Journal of photochemistry and photobiology. B, Biology

JF - Journal of photochemistry and photobiology. B, Biology

ER -

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

Abstract

Keywords

UN SDGs

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