Vadimezan (5,6-dimethyl(xanthenone-4-acetic acid), ASA404, DMXAA) is a fused tricyclic analogue of flavone acetic acid with potential antineoplastic activity. In pre-clinical mouse tumour models it was demonstrated that administration of Vadimezan rapidly leads to disruption of the existing vasculature in the tumour and consequent haemorrhagic necrosis of the tumour. This was consistent with the finding that a single dose of Vadimezan induced a prolonged reduction in the growth of xenografted tumours in animal models. The ability to disrupt the vasculature in these pre-clinical models has been attributed to a rapid induction of cytokines, particularly TNFα (tumour necrosis factor α), serotonin and nitric oxide, resulting in hemorrhagic necrosis and a decrease in angiogenesis. Despite the fact that the molecular targets for the drug remained unknown, the promising pre-clinical results led to Vadimezan being selected for clinical development. Results of Phase I trials showed some restriction of tumour blood flow within 24 h of treatment, although this was not as dramatic as seen in pre-clinical models. Unlike the animal models, there was also very little evidence for the rapid death of blood vessels or for increases in TNFα levels in human tumors. No difference in antitumour activity, cytokine induction or toxicity was observed between two parallel Phase I trials, one dosed weekly and the other dosed every 3 weeks. Therefore the drug proceeded to Phase II clinical trials, dosed every 21 days in combination with chemotherapeutic agents. These trials indicated the drug had small benefits in the treatment of non-small-cell lung cancer and prostate cancer. However, a subsequent Phase III clinical trial was not able to reproduce this response and clinical development was halted.