ANTITUMOR-ACTIVITY OF THE NOVEL IMMUNE MODULATOR 5,6-DIMETHYLXANTHENONE-4-ACETIC ACID (DMXAA) IN MICE LACKING THE INTERFERON-GAMMA RECEPTOR

5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a novel antitumour agent currently undergoing clinical evaluation, appears to mediate its anti tumour effects through immune modulation and the production of cytokin es. We used mice with a targeted disruption of the interferon-gamma (I FN-gamma) receptor gene as a model to evaluate the role of the host re sponse to IFN-gamma in the antitumour action of DMXAA on colon 38 tumo urs. A feature of the results was that while DMXAA treatment induced b oth IFN-gamma and tumour necrosis factor (TNF) in serum, the increase was >20-fold higher in IFN-gamma R-0/0 mice than in wild-type mice. In contrast, mRNA levels for IFN-gamma and TNF were similar in the two m ouse strains, suggesting that the concentrations of these cytokines we re controlled by a post-transcriptional mechanism. Serum nitrate level s, used as a measure of nitric oxide production, were increased by DMX AA, but to a similar extent in both strains of mice. Complete regressi ons of colon 38 tumours were obtained in response to DMXAA in the knoc kout 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-g amma is not essential for an antitumour response. Similar results were obtained in mice that were immunosuppressed by treatment with cyclosp orin A before treatment with DMXAA. The results are consistent with th e concept that the antitumour activity of DMXAA involves complex immun omodulation, probably with significant redundancy in contributing cyto kines. (C) 1998 Elsevier Science Ltd. All rights reserved.