Antitumour activity of the novel immune modulator 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice lacking the interferon-gamma receptor

Abstract

5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a novel antitumour agent currently undergoing clinical evaluation, appears to mediate its antitumour effects through immune modulation and the production of cytokines. We used mice with a targeted disruption of the interferon-gamma (IFN-γ) receptor gene as a model to evaluate the role of the host response to IFN-γ in the antitumour action of DMXAA on colon 38 tumours. A feature of the results was that while DMXAA treatment induced both IFN-γ and tumour necrosis factor (TNF) in serum, the increase was >20-fold higher in IFN-γR 0/0 mice than in wild-type mice. In contrast, mRNA levels for IFN-γ and TNF were similar in the two mouse strains, suggesting that the concentrations of these cytokines were controlled by a post-transcriptional mechanism. Serum nitrate levels, used as a measure of nitric oxide production, were increased by DMXAA, but to a similar extent in both strains of mice. Complete regressions of colon 38 tumours were obtained in response to DMXAA in the knockout mice, although the dose required for 100% cure was higher and the reduction in tumour volume occurred more slowly than in the wild-type counterparts. The results demonstrate that the host response to IFN-γ is not essential for an antitumour response. Similar results were obtained in mice that were immunosuppressed by treatment with cyclosporin A before treatment with DMXAA. The results are consistent with the concept that the antitumour activity of DMXAA involves complex immunomodulation, probably with significant redundancy in contributing cytokines.