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 (86)Rb 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 86Rb uptake to 41% bf 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 1 h at 42.5 degrees C starting 4h after the injection of both IL-1 alpha and TNF-alpha. The changes in clonogenic cell numbers in SCK tumours, 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 tumours were heated 4h 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 tumours to reach 4 x 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.
Lin
J C
JC
University of Minnesota Medical School, Department of Therapeutic Radiology-Radiation Oncology, Minneapolis, Minnesota 55455, USA.
Park
H J
HJ
Song
C W
CW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002452:Cell Count / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism; D005334:Fever; D007375:Interleukin-1 / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D008833:Microcirculation / Q000187:drug effects; D009374:Neoplasms, Experimental / Q000097:blood / Q000378:metabolism; D012413:Rubidium / Q000378:metabolism; D013696:Temperature; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D012413:Rubidium