Oral activity and pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice.

PURPOSE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), an anticancer drug with an antivascular action, has recently completed phase I clinical trials. Since oral administration has many advantages, we compared the biological activity and pharmacokinetics of DMXAA in mice following oral and intraperitoneal (i.p.) administration. METHODS: Growth delays of Colon 38 tumours were measured in C57Bl/6 mice. Plasma concentrations of DMXAA, 5-hydroxyindole-3-acetic acid (5HIAA) as a measure of serotonin production, and nitrate as a measure of nitric oxide production, were determined by high-performance liquid chromatography. Tumour necrosis factor (TNF) concentrations in serum and tumour tissues were measured by ELISA. RESULTS: The antitumour activity of DMXAA at the maximum tolerated oral dose (32.5 mg/kg) was low (4-day growth delay, no cures) compared to that (19-day growth delay, 40% cures) at the maximum tolerated i.p. dose (27.5 mg/kg). The pharmacokinetics of DMXAA in plasma, liver and tumour tissue indicated a bioavailability of 73%. Elevation of plasma 5HIAA, measured 4 h following i.p. administration of DMXAA, was linear with DMXAA dose, and the 5HIAA response to oral administration was consistent with its bioavailability. TNF concentrations increased following oral administration (30 mg/kg) and were particularly evident in tumour tissue, but were lower and less prolonged than those in response to i.p. administration at 25 mg/kg. Plasma nitrate levels were not increased following oral administration (30 mg/kg). CONCLUSIONS: DMXAA exhibits good bioavailability, and changes in serum TNF, tissue TNF, plasma 5HIAA and plasma nitrate, as markers of biological response, are consistent with this bioavailability. The low maximal plasma DMXAA concentration following oral administration, resulting in reduced retention of intratumoral TNF, may be responsible for the low antitumour activity.