Antitumour 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 antitumour effects through immune modulation and the production of cytokines. We used mice with a targeted disruption of the interferon-gamma (IFN-gamma) receptor gene as a model to evaluate the role of the host response to IFN-gamma in the antitumour action of DMXAA on colon 38 tumours. A feature of the results was that while DMXAA treatment induced both IFN-gamma and tumour necrosis factor (TNF) in serum, the increase was > 20-fold higher in IFN-gamma R0/0 mice than in wild-type mice. In contrast, mRNA levels for IFN-gamma 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-gamma is not essential for an anti-tumour 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.
Pang
J H
JH
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Cao
Z
Z
Joseph
W R
WR
Baguley
B C
BC
Ching
L M
LM
D000818:Animals; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000276:immunology*; D016572:Cyclosporine / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D017471:Receptors, Interferon / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha; D014966:Xanthenes / Q000276:immunology* / Q000627:therapeutic use; D044004:Xanthones; D000096743:Interferon gamma Receptor
D016572:Cyclosporine; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D014966:Xanthenes; D044004:Xanthones; D000096743:Interferon gamma Receptor; C066668:vadimezan