A.E. van den Berg-Blok

Enhancement of thermal damage to the microcirculation of ‘sandwich’ tumours by additional treatment

The effects of hyperthermia on tumour microcirculation were investigated. For this purpose, transparent tumours were grown in the ‘sandwich’ system in the dorsal skin flap of the rat (Rhabdomyosarcoma BA1112 in WAG/Rij rats). Heating was performed with air; the temperature of the cover slip overlying the tumour was kept at either 42.5° or 42°C by means of an electronic controller. Evaluation of the effect was based on microscopic observation and photographic recordings and was expressed as the proportion of tumours with intact microcirculation, i.e., the proportion of tumours not showing heat damage. The results indicate that, at 42.5°C after a latent period of about 1 hr, the microcirculation of the tumours begins to slow down. At the end of a treatment time of 180 min, about 70% of the tumours show microcirculatory damage. It appears that some time is required before the majority of the tumours show heat damage. The effect is still essentially the same at 42°C, but the damage is to a much lesser extent. When the animals received additional treatment, i.e. misonidazole, glucose or 5-thio- d-glucose, the damaging effect of the hyperthermic treatment at 42°C appeared to be increased. The effects of all combined treatments approximated the degree of inactivation obtained with 42.5°C treatment.

Temporary vascular occlusion and glucose: effects on tumour and normal tissue pH in animal experiments

The relationship between duration of a period of vascular occlusion and magnitude of pH decrease in tumour and normal tissue was investigated in rats. To acidify tissue pH further, moderate dose glucose (2.4-3.0 g.kg(-1).hr(-1)) was administered intravenously through a catheter positioned in a tail vein, immediately after the clamp was released. This sequence of pH modifying modalities was chosen since it is employed in clinical regional isolation perfusion for recurrence of malignant melanoma of the limbs. Tumour pH in rat rhabdomyosarcoma BA1112 decreased more than normal tissue pH under 10, 20, 30 or 60 min of temporary vascular occlusion. Administration of glucose following any period of clamping always decreased tumour pH further. The largest pH decrease (0.29 pH units) was obtained after 30 min of clamping followed by 60 min glucose and 60 min saline infusion. In the clinic the combination of a maximum of 30 min of clamping followed by moderate dose glucose infusion, which can decrease tumour pH effectively, can be easily achieved in the setting of regional isolation perfusion. It can be used for treatment modalities that are known to be enhanced at lowered tissue pH, such as hyperthermia and certain chemotherapeutic drugs. These results form the basis for studying the therapeutic gain which can be obtained with this model.