Tumour-specific enhancement of thermoradiotherapy at mild temperatures by the vascular targeting agent 5,6-dimethylxanthenone-4-acetic acid

Abstract

The effect of combining the vascular targeting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) with both radiation and hyperthermia treatments was investigated in a transplanted C3H mouse mammary carcinoma and a normal mouse tissue. Tumours were grown on the right rear foot of female CDF1 mice and treated when sized 200 mm³. The foot skin of non-tumour-bearing CDF1 mice was used to assess normal tissue damage. Radiation and hyperthermia were given locally to the tumour/skin of restrained non-anaesthetized animals. DMXAA (20 mg/kg) was dissolved in saline and injected intraperitoneally 1 h after irradiating and then heating started 3 h later. The endpoints were local tumour control within 90 days or the development of moist desquamation in skin between 11 and 23 days after treatment. The radiation dose (±95% confidence intervals) producing local tumour control in 50% of treated animals was 53 (51–55) Gy for radiation alone. This value was significantly (Chi-squared test; p < 0.05) decreased to 47 (42–52) Gy by DMXAA and to 47 (44–51) Gy by heating (41.5°C/60 min) 4 h after irradiation. Combining both DMXAA and heating further reduced this to 30 (26–35) Gy. When the heating temperature was decreased to 40.5°C, the effect of the triple combination was decreased but was still significant compared with radiation + DMXAA or radiation + hyperthermia. However, this enhancement disappeared at 39.5°C. Radiation damage of normal foot skin was not enhanced by combining DMXAA and hyperthermia at 41.5°C. In conclusion, adding DMXAA to thermoradiotherapy at 40.5–41.5°C significantly improved local tumour control without enhancing normal tissue damage. Thus, including a vascular targeting agent in a mild thermoradiotherapy treatment regimen is a useful approach that may lead to a re-evaluation of the use of hyperthermia in cancer treatment.

• Vascular targeting
• DMXAA
• radiation
• hyperthermia
• C3H mammary carcinoma