DMXAA: an antivascular agent with multiple host responses.
OBJECTIVE
To measure host responses to the antivascular agent DMXAA (5,6-dimethylxanthenone-4-acetic acid) and to compare them with those of other antivascular agents.


METHODS
Induction of tumor necrosis was measured in s.c. murine Colon 38 carcinomas growing in normal or tumor necrosis factor (TNF) receptor-1 knockout mice. Plasma and tumor tissue TNF concentrations were measured by ELISA. Plasma concentrations of 5-hydroxyindoleacetic acid (as a measure of serotonin release) and nitrite (as a measure of nitric oxide release) were measured by high-performance liquid chromatography.


RESULTS
Administration of DMXAA to tumor-bearing mice increased plasma and tumor tissue-associated TNF, in addition to increasing plasma nitric oxide, distinguishing its action from that of mitotic poisons that had an antivascular action. Results from TNF receptor-1 knockout mice showed that TNF played an important role in both its antitumor action and its host toxicity. Release of serotonin occurred in response to mitotic poisons, as well as to DMXAA. CONCLUCIONS: The antivascular action of DMXAA involves in situ production in tumor tissue of a cascade of vasoactive events, including a direct effect on vascular endothelial cells and indirect vascular effects involving TNF, other cytokines, serotonin, and nitric oxide. Now that Phase I clinical trials of DMXAA are completed, the optimization of this cascade in cancer patients is a major challenge. Plasma 5-hydroxyindoleacetic acid concentrations may provide a useful surrogate marker for the antivascular effects of DMXAA and other antivascular agents.
Baguley
Bruce C
BC
Auckland Cancer Society Research Centre, The University of Auckland, Auckland, New Zealand. b.baguley@auckland.ac.nz
Ching
Lai Ming
LM
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D006897:Hydroxyindoleacetic Acid / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D008956:Models, Chemical; D009336:Necrosis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D012701:Serotonin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014966:Xanthenes / Q000627:therapeutic use*; D044004:Xanthones
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan; D009569:Nitric Oxide; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid