R. Murata et al., Potentiation of the anti-tumour effect of hyperthermia by combining with the vascular targeting agent 5,6-dimethylxanthenone-4-acetic acid, INT J HYPER, 17(6), 2001, pp. 508-519
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.