Potentiation of the anti-tumour effect of hyperthermia by combining with the vascular targeting agent 5,6-dimethylxanthenone-4-acetic acid

Abstract

The potential of the vascular targeting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) to enhance the effect of hyperthermia was investigated in a C3H mouse mammary carcinoma grown in the feet of female CDF1 mice and in normal foot skin. DMXAA, when injected intraperitoneally in restrained non-anaesthetized animals, reduced tumour perfusion, as measured using the RbCl extraction procedure, and increased necrosis in histological section, but these effects were dependent on the drug dose and time interval. At a dose of 20mg/kg, it significantly enhanced the thermal damage of this tumour, when given 1h or more before the start of heating, as assessed by a tumour growth assay. This enhancement became larger with increasing interval between the two treatments. No thermo-potentiation was seen at doses of 10mg/kg or lower. These combined effects seem to be associated with the tumour vascular shut-down by DMXAA. Thermal potentiation by DMXAA was also dependent on the heating temperature, with a greater enhancement relative to hyperthermia alone obtained at the lower temperatures at 40.5 and 41.5°C than at the higher temperature of 42.5°C. DMXAA (20mg/kg) also enhanced the heat damage of normal skin, and this could not be explained by any DMXAA-induced TNF- &#102 production. The heat enhancement-ratio by DMXAA was larger in tumours (1.9) than in normal skin (1.3 1.5), thus giving rise to a therapeutic gain.

• Words Vascular Targeting Hyperthermia H Mouse Mammary Carcinoma Normal Tissue Damage