Ingenol-3-mebutate

Ingenol mebutate is approved for the topical treatment of actinic keratoses and may ultimately also find utility in treating skin cancers. Here we show that relapse rates of subcutaneous B16 melanoma tumours treated topically with ingenol mebutate were not significantly different in C57BL/6 and Rag1-/- mice, suggesting B and T cells do not play a major role in the anti-cancer efficacy of ingenol mebutate. Relapse rates were, however, significantly increased in MyD88-/- mice and in C57BL/6 mice treated with the anti-IL-1 agent, anakinra. Ingenol mebutate treatment induces a pronounced infiltration of neutrophils, which have been shown to have anti-cancer activity in mice. Herein we provide evidence that IL-1 promotes neutrophil recruitment to the tumour, decreases apoptosis of infiltrating neutrophils and increases neutrophil tumour killing activity. These studies suggest IL-1, via its action on neutrophils, promotes the anti-cancer efficacy of ingenol mebutate, with ingenol mebutate treatment causing both IL-1β induction and IL-1α released from keratinocytes.

BACKGROUND: 'Hydroxyurea-induced Squamous Dysplasia' (HISD) is a cutaneous side-effect related to chronic oral treatment with Hydroxyurea. Ingenol mebutate gel is a topical drug approved for the treatment of multiple, non-hypertrophic actinic keratoses (AK) localized within a limited cancerization field. Since HISD may be considered as a drug-induced variant of classic AK, ingenol mebutate is likely to have therapeutic effects.