title: Thermal enhancement of both tumour necrosis factor alpha-induced systemic toxicity and tumour cure in rats.
abstract: 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 LD50 and TCD50 values were calculated. Systemic toxicity was increased by local hyperthermia. The LD50 values (+/- s.e.) were 1088 (+/- 61) micrograms kg-1 at normothermia and 205 (+/- 23) micrograms 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 micrograms kg-1, while this was observed at doses of 50-300 micrograms kg-1 when combined with hyperthermia (TCD50 values of 1211 and 188 micrograms kg-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.
authors.affiliation: Department of Hyperthermia, Dr Daniel de Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: van der Zee
authors.forename: G J
authors.initials: GJ
authors.lastname: van den Aardweg
authors.forename: G C
authors.initials: GC
authors.lastname: van Rhoon
authors.forename: A P
authors.initials: AP
authors.lastname: van den Berg
authors.forename: R
authors.initials: R
authors.lastname: de Wit
mesh_terms: D000818:Animals; D001831:Body Temperature; D001859:Bone Neoplasms / Q000628:therapy*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced; D007928:Lethal Dose 50; D015999:Multivariate Analysis; D012516:Osteosarcoma / Q000628:therapy*; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000627:therapeutic use / Q000633:toxicity; D012044:Regression Analysis; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use* / Q000633:toxicity*
chemical_list: D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha