New developments in the treatment of actinic keratosis: focus on ingenol mebutate gel

Abstract

Actinic keratosis is a common disease in older, fair-skinned people, and is a consequence of cumulative ultraviolet exposure. It is part of a disease continuum in photodamaged skin that may lead to invasive squamous cell carcinoma. Treatment options frequently used include cryosurgery and topical pharmacologic agents, which are examples of lesion-directed and field-directed strategies. Ingenol mebutate gel was recently approved by the US Food and Drug Administration for topical treatment of actinic keratosis. While the mechanism of action of ingenol mebutate is not fully understood, in vitro and in vivo studies using tumor models indicate it has multiple mechanisms. Ingenol mebutate directly induces cell death by mitochondrial swelling and loss of cell membrane integrity preferentially in transformed keratinocytes. It promotes an inflammatory response characterized by infiltration of neutrophils and other immunocompetent cells that kills remaining tumor cells. The ability of ingenol mebutate to eliminate mutant p53 patches in ultraviolet-irradiated mouse skin suggests that it may have the potential to treat chronically ultraviolet-damaged skin. In human studies, ingenol mebutate achieved high clearance of actinic keratosis on the head and body after 2-3 consecutive daily treatments when measured by complete or partial clearance of lesions. Localized inflammatory skin responses were generally mild to moderate and resolved in less than a month.

Keywords: actinic keratosis; field therapy; ingenol mebutate gel; nonmelanoma skin cancer; protein kinase C delta.

Figure 1

Chemical structure of ingenol mebutate, C₂₅H₃₄O₆.

Figure 2

Schematic model of proposed mechanisms of ingenol mebutate. (A) Ingenol mebutate penetrates skin in a gradient-dependent manner whereby it preferentially induces death in proliferating undifferentiated cells by increases in intracellular calcium, mitochondrial swelling, and loss of cell membrane integrity. (B) Cell death and protein kinase C activation lead to an inflammatory activation of the treated field. Ingenol mebutate increases local production of tumor necrosis factor-alpha and interleukin-8, which recruit and activate neutrophils, and directly activate endothelial cell expression of the adhesion receptors E-selectin and intercellular adhesion molecule-1.

Figure 3

Treatment of skin in ultraviolet B–irradiated SKH1/hr mice with ingenol mebutate 0.05% gel reduced the number of skin lesions and mutant p53 patches that subsequently developed compared with placebo and no treatment. After 30 doses of ultraviolet B radiation, mice were untreated (control) or treated with placebo gel or ingenol mebutate 0.05% gel on days 0 and 2. (A) Representative mice from ingenol mebutate, placebo, and control groups taken at 21 weeks after treatment initiation. (B) The number of mutant p53 patches analyzed by immunohistochemistry in the skin of ultraviolet B–irradiated mice. Each symbol represents an individual mouse, and bars indicate the mean ± standard error of the mean. Copyright © 2012. Nature Publishing Group. Reprinted with permission from Cozzi SJ, Ogbourne SM, James C, et al. Ingenol mebutate field-directed treatment of UVB-damaged skin reduces lesion formation and removes mutant p53 patches. J Invest Dermatol. 2012;132(4):1263–1271.

Figure 4

Time course of mean (± standard error of the mean) composite score for local skin reactions from pooled analyses at each study visit. Copyright © 2012. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society from Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, Berman B. Ingenol mebutate gel for actinic keratosis. N Engl J Med. 2012;366(11):1010–1019. Abbreviation: LSR, local skin reaction.

Figure 5

Clinical photographs of three patients. Photographs were taken at screening, before treatment on day 1, and on days 3 or 4 (one day after last treatment), 8, 15, 29, and 57. The composite local skin reaction score was calculated at each visit. (A) Forehead lesions. Intermediate peak composite local skin reaction score (10) on day 4 returned to baseline by day 29. (B) Forehead lesions. High peak composite local skin reaction score (19) on day 4 returned to baseline by day 57. (C) Arm lesions. Intermediate peak composite local skin reaction score (12) on day 3 returned to baseline by day 57. Data on file. Clinical study reports PEP005-016 and PEP005-028. Parsippany, NJ: LEO Pharma Inc.; 2010. Abbreviation: LSR, local skin reaction.