THERMAL ENHANCEMENT OF BOTH TUMOR-NECROSIS-FACTOR ALPHA-INDUCED SYSTEMIC TOXICITY AND TUMOR CURE IN RATS

In vitro and in vivo studies have suggested synergistic anti-tumour activity of combined hyperthermia and tumour necrosis factor alpha (TNF-alpha). However, some studies indicated an increased systemic toxicity of TNF by additional hyperthermia. The aim of this study was to obtain starting dosages for a clinical phase I study on the application of deep local hyperthermia and systemic TNF. We investigated the effect of local hyperthermia on the toxicity and efficacy of systemic TNF. Rats (Wag/Rij) carrying a subcutaneously transplanted osteosarcoma in the hind leg received a single intravenous dose of recombinant human (rh) TNF-alpha, either at normothermia or at hyperthermia, by positioning the tumour bearing hind leg in a water bath of 43 degrees C. Dose-effect curves for lethality and tumour cure were established and LD(50) and TCD50 values were calculated. Systemic toxicity was increased by local hyperthermia. The LD(50) values (+/-s.e.) were 1088 (+/- 61)mu g kg(-1) at normothermia and 205 (+/- 23)mu g kg(-1) at hyperthermia, resulting in a thermal enhancement ratio (TER) of 5.3. Following normothermia, tumour cures were observed at TNF concentrations of 1000-1300 mu g kg(-1), while this was observed at doses of 50-300 mu g kg(-1) when combined with hyperthermia (TCD50 values of 1211 and 188 mu gkg(-1) respectively), resulting in a TER of 6.4. Systemic toxicity and anti-tumour activity of TNF are both increased by local hyperthermia. A safe starting dose for the combined clinical treatment would be 10% of the dose of TNF-alpha that has been recommended for phase II studies on intravenous bolus administration of TNF-alpha at normothermia. In view of the large variability in tumour sensitivity for TNF-alpha the clinical usefulness of this combined treatment modality has to be determined.