Induction of Hypoxia in the KHT Sarcoma by Tumour Necrosis Factor and Flavone Acetic Acid

Abstract

The interaction of FAA or TNF with radiation was studied in the murine KHT sarcoma. When used alone both agents showed a dose- and time-dependent toxicity towards the tumour cells and significantly reduced tumour blood flow within 1 h of treatment. When used in combination with radiation, both TNF and FAA caused an increase in the fraction of hypoxic cells in the KHT tumour. This was assessed by an in vivo/in vitro clonogenic assay and by a comparison with the radioprotection provided by clamping tumours prior to and during irradiation. When TNF was given at a dose of 2·5 × 10⁵ U/kg an increase in tumour hypoxia was seen after 30 min. Close to 100% radiobiological hypoxia was reached by 1 h after treatment, lasting for up to 16 h. Doses of TNF below 0·25 × 10⁵ U/kg did not induce levels of hypoxia comparable to clamping when administered 3 h prior to irradiation. Similarly, FAA produced a rapid increase in tumour hypoxia: a dose of 200 mg/kg induced close to 100% radiobiological hypoxia when give 1 h prior to irradiation. Complete tumour hypoxia was still apparent 18 h after treatment with FAA. Administered doses of FAA below 100 mg/kg did not produce close to 100% radiobiological hypoxia when administered 3 h prior to irradiation.