Abstract
Ingenol mebutate has recently been approved by the Federal Drug Administration (USA) as a topical treatment for actinic keratoses. Herein, we describe the efficacy of ingenol mebutate for the topical treatment of squamous cell carcinoma (SCC) using a wild-type mouse model (SKH1) and the UV-induced mouse SCC cell line, T7. Daily treatment for 2 days with 0.25 % ingenol mebutate gel produced a cure rate of 70 %, with 0 % for placebo gel. Electron microscopy revealed swelling of cancer cell mitochondria within 1 h, with disruption of the inner mitochondrial membranes evident at 6 h post treatment. Primary necrosis of cancer cells was clearly evident by 24 h. Treatment was associated with local haemorrhage and a prodigious neutrophil infiltrate, with anti-T7 antibodies also detected. This is the first report of the successful treatment of SCC tumours with ingenol mebutate gel in wild-type mice, and supports the view that ingenol mebutate induces primary necrosis and activates the immune system.Electronic supplementary materialThe online version of this article (doi:10.1007/s00403-012-1270-0) contains supplementary material, which is available to authorized users.
Highlights
Cutaneous squamous cell carcinoma (SCC) is the second most common human cancer after basal cell carcinoma, with [250,000 cases diagnosed in the USA each year
Bottom right–T7 tumour cells 24 h after placebo treatment, showing clear signs of primary necrosis. c H&E staining of placebo treated tumour and high magnification images of haemorrhage within the tumour 6 h post ingenol mebutate treatment and prolific neutrophil infiltrates 24 h post ingenol mebutate treatment which resolved after 3–4 weeks, with a favourable cosmetic outcome evident after 2–3 months (Fig. 2a)
We show that ingenol mebutate gel treatment (0.25 %) was effective at regressing subcutaneous SCCs using the T7/SKH1 mouse model
Summary
Cutaneous squamous cell carcinoma (SCC) is the second most common human cancer after basal cell carcinoma, with [250,000 cases diagnosed in the USA each year. Following phase III studies [8], topical ingenol mebutate (ingenol-3-angelate, PEP005) was recently approved by the Federal Drug Administration (USA) for the treatment of actinic keratosis, a precursor of SCC. Ingenol mebutate was derived from the sap of Euphorbia peplus, and in a phase I/II clinical study, a complete clinical response was achieved in 2/4 SCCs treated topically with the sap from this plant [14]. Ingenol mebutate was effective against inoculated murine SCC tumours (LK2 and PAM212) grown in nude mice (Foxn1nu or BALB/cnu/nu) [9, 12], with haemorrhage [9], neutrophils and antibody-dependent cellular cytotoxicity appearing to be important for relapse-free cure in these models [4]. Mouse studies have suggested that ingenol mebutate has a dual mechanism of action against tumours involving initial induction of primary necrosis [12] followed by immune-mediated clearance of residual tumour cells [17]
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