Combined treatment of IL-1 alpha and TNF-alpha potentiates the antitumour effect of hyperthermia

Vasoactive cytokines, such as IL-1 alpha and TNF-alpha, modulate the homeostatic state at the endothelial surface and cause various types of pathological damage in vascular systems. We investigated the potential therapeutic effects of IL-1 alpha and TNF-alpha in combination with hyperthermia on SCK tumours grown in the legs of A/J mice. We first determined the effect of cytokines on tumour blood perfusion with the Rb-86 uptake method. When the host mice were given an i.p. injection of 25 mu g/kg IL-1 alpha or 50 mu g/kg TNF-alpha, the tumour blood perfusion markedly declined to 46 and 82% of control, respectively. The combination of IL-1 alpha and TNF-alpha reduced the Rb-86 uptake to 41% of control. Hyperthermia at 42.5 degrees C for 1 h reduced the tumour blood flow to 71% of control. The tumour blood perfusion decreased further to 20% of control when the tumours were heated for Ih at 42.5 degrees C starting 4 h after the injection of both IL-1 alpha and TNF-alpha. The changes in clonogenic cell numbers in SCK rumours, as determined by the in vivo-in vitro assay, following various treatments was also investigated. At 4 h after an i.p. injection of 25 mu g/kg IL-1 alpha or 50 mu g/kg TNF-alpha, the clonogenicity of SCK tumours significantly decreased to 29 or 37% of control, respectively. Heating at 42.5 degrees C for 1 h caused a decline in the clonogenic cell number to 30% of control. When both IL-1 alpha and TNF-alpha were given and rumours were heated 4 h later at 42.5 degrees C for 1 h, the clonogenic cell number markedly declined to 0.4% of control. The time needed for control rumours to reach 4x their initial volume was about 3 days, and treatment with IL-1 alpha or hyperthermia alone induced a tumour delay growth by about 1 day. The combined injection of IL-1 alpha and TNF-alpha followed by a heating at 42.5 degrees C for 1 h delayed the tumour growth by 6 days. The results in this study suggest that prior impairment of blood circulation by the combined treatment of IL-1 alpha and TNF-alpha potentiates hyperthermic damage in tumours.