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

The potential of the vascular targeting agent 5,6-dimethylxanthenone-4-acet ic 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 n ormal foot skin. DMXAA, when injected intraperitoneally in restrained non-a naesthetized animals. reduced tumour perfusion, as measured using the RbC1 extraction procedure, and increased necrosis in histological section, but t hese effects were dependent on the drug dose and time interval. At a dose o f 20 mg/kg, it significantly enhanced the thermal damage of this tumour, wh en given 1 h or more before the start of heating, as assessed by a tumour g rowth assay. This enhancement became larger with increasing interval betwee n the two treatments. No thermo-potentiation was seen at doses of 10 mg/kg or lower. These combined effects seem to be associated with the tumour vasc ular shut-down by DMXAA. Thermal potentiation by DMXAA was also dependent o n the heating temperature, with a greater enhancement relative to hyperther mia alone obtained at the lower temperatures at 40.5 and 41.5 degreesC than at the higher temperature of 42.5 degreesC. DMXAA (20 mg/kg) also enhanced the heat damage of normal skin, and this could not be explained by any DMX AA-induced TNF-alpha production. The heat enhancement-ratio by DMXAA was la rger in tumours (1.9) than in normal skin (1.3-1.5), thus giving rise to a therapeutic gain.