Taurolidine inhibits tumour necrosis factor (TNF) toxicity--new evidence of TNF and endotoxin synergy.
The use of recombinant tumour necrosis factor (TNF) in the treatment of solid tumours has been limited by life threatening toxicity. In addition TNF may be a major mediator of the effect of endotoxins. Recent evidence suggested that a synergism between endotoxin (at the picogram level) and TNF may contribute to this toxicity. The use of the anti-endotoxin taurolidine may reduce TNF toxicity by interfering with this synergy. C57/BL6 mice (n = 140) received toxic doses (12 micrograms/mouse IV) of TNF. Four groups were studied. Group A received taurolidine 200 mg/kg IV 30 minutes before TNF, group B received TNF followed 30 minutes later by taurolidine 200 mg/kg IV, group C received an identical volume (0.5 ml) of normal saline 30 minutes prior to TNF, and group D taurolidine 200 mg/kg IP 45 minutes before TNF. The mortality rate of those mice receiving intravenous taurolidine 30 minutes prior to TNF was 8.8%. This was significantly less (P < 0.005) than the mortality rate achieved in groups B, C and D (33% vs 39.4% vs 50%). Further experiments employing an MTT (3-(4,5-dimethylthinzol-2-microliters)-2,5-diphenyl tetrazolinm bromide) assay showed that this was not due to direct interaction of taurolidine with TNF but is likely to be due to interference with the synergistic effects of endotoxin and TNF. It was also demonstrated in cotherapy studies in a murine model that taurolidine did not reduce the anti-tumour efficacy of TNF against the TNF sensitive mouse fibrosarcoma cell line Meth-A sarcoma.
Monson
J R
JR
Department of Surgery, Mayo Clinic, Rochester, MN 55905.
Ramsey
P S
PS
Donohue
J H
JH
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D004357:Drug Synergism; D004731:Endotoxins / Q000633:toxicity; D005354:Fibrosarcoma / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013829:Thiadiazines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000633:toxicity
D000890:Anti-Infective Agents; D004731:Endotoxins; D013829:Thiadiazines; D014409:Tumor Necrosis Factor-alpha; D013654:Taurine; C012566:taurolidine