Fractionated hyperthermia in vivo: thermotolerance, sensitivity to BCNU and thermochemosensitivity in the BT4An rat glioma.

Although hyperthermia has been shown to increase the effect of some cytotoxic drugs both in vitro and in vivo, there is sparse data on the interaction of the two modalities during fractionated treatment in vivo. In vitro data suggest that, parallel to development of thermotolerance, tumour cell sensitivity to drugs may be modified. Thermotolerance in tumour and surrounding normal tissue and the sensitivity to the alkylating agent BCNU given alone i.p., or as thermochemotherapy, was investigated in the subcutaneously transplanted BT4An rat glioma. Tumours treated by 44 degrees C water bath hyperthermia alone minutes after the priming hyperthermia were initially sensitive to hyperthermia, but decreased heat sensitivity developed during continued heating. Thermotolerance in the skin was greatest at 24 h. When the skin reaction was compared with the effect on tumours, a therapeutic gain using hyperthermia alone was seen at 168 h. Tumours were most sensitive to BCNU just after the priming hyperthermia, least sensitive at 48 h. When thermochemotherapy with BCNU was given at different intervals after priming hyperthermia, an interaction between the modalities was seen, with the greatest tumour effect just after priming (six of 12 tumours controlled). At 24 h the summary effect of priming treatment and subsequent thermochemotherapy was not greater than thermochemotherapy treatment alone. The thermochemotherapy effect on tumours was more dependent on the hyperthermia sensitivity, i.e. thermotolerant state, than the sensitivity to BCNU alone at that time.