Antitumour action of 5,6-dimethylxanthenone-4-acetic acid in rats bearing chemically induced primary mammary tumours

To evaluate the antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a vascular disrupting agent currently under phase II clinical trials in combination with cancer chemotherapy, in rats bearing chemically induced primary mammary tumours. Tumours were induced in female Wistar rats by injection of N-nitroso-N-methylurea at 100 mg/kg subcutaneously. A clinically relevant single dose of DMXAA (1,800 mg/m(2)) was given to animals when tumours were measurable. Tumour volume, extent of necrosis and cytokine profiles were measured. Compared with the control group, DMXAA treatment significantly delayed tumour doubling time and extended the time from treatment to euthanasia. Four of five DMXAA-treated animals showed necrosis involving 3.7-41.2% of the area of the tumour section at 24 h compared with none of four control animals (P < 0.028, Chi-square test). Intratumoural levels of TNF alpha, IL-6, VEGF and IL-1 alpha were increased 4 h after DMXAA treatment. This study shows for the first time that DMXAA has significant in vivo antitumour activity against non-transplanted autochthonous tumours and in a host species other than the mouse.