Imiquimod is a strong inhibitor of tumor cell-induced angiogenesis

Background Imiquimod, a potent immunomodulator, not having a direct antiproliferative activity, was found to be effective in genital and cutaneous premalignancies and malignancies. As tumor development depends on blood vessel supply, the inhibition of angiogenesis could be responsible for the antitumor activity. Objective To find in a murine model whether imiquimod has antiangiogenic activity and whether this activity is mediated by locally induced cytokines. Methods The study was performed in two cell lines: Skv human keratinocytes containing multiple integrated copies of HPV16 derived from bowenoid papulosis, and murine L1 lung sarcoma cells of Balb/c mice. The murine model of cutaneous angiogenesis was used to assess and count the new blood vessel formation. The mice were immunosuppressed by a total body X-ray irradiation and treated with 5% or 2.5% imiquimod cream before or after induction of angiogenesis with intradermally injected tumor cell suspension. In some experiments the mice were, in addition, treated intraperitoneally with monoclonal antibodies against murine IFNalpha, TNFgamma or IL-18. Results Topical application of imiquimod on the murine skin resulted in reduction of angiogenesis (P < 0.001) induced by intradermal injection of both human and mouse tumor cells, more pronounced when 5% cream was applied on three consecutive days. Antibodies against murine IFNgamma, TNFalpha and IL-18 completely abolished the inhibitory effect of imiquimod on angiogenesis induced by murine L1 sacroma cells. When human Skv cells were used in angiogenesis assay, the effect of imiquimod was abolished by antibodies against IL-18 but not against TNFalpha, which may be due to overproduction of TNFalpha by Skv cells. Conclusions Antiangiogenic effect of imiquimod was found to be mediated by IL-18, probably through promoting production of INFgamma, the most important inhibitor of angiogenesis.