Possible relationships between in vivo antitumour activity and toxicity of tumour necrosis factor-alpha.

The discoveries of a tumour necrosis-inducing substance in sera of experimental mice and of cytotoxic factor(s) in cultures of stimulated lymphoid cells triggered intense research efforts which have culminated in the production of two distinct but related recombinant materials, human tumour necrosis factors TNF-alpha (cachectin) and TNF-beta (lymphotoxin). The necrosis of tumours by TNF is but one feature of high doses of these immune system hormones that possess numerous biological activities. Apart from their direct cytotoxic/cytostatic activities against tumours in vitro and in vivo, the in vivo antitumour activities of TNF-alpha or TNF-beta may involve the following biological activities: the induction of interleukin 1 production; activation of polymorphonuclear neutrophil functions; modulation of endothelial cell functions; and augmentation of specific immune functions. Many of these activities are associated with an irreversible acute inflammation which appears to be the immediate lethal effect of TNF on transplantable tumours in mice. This inflammation leads to thrombosis, disruption of the tumour's blood supply and, finally, tumour death. Inflammatory effects of high doses of TNF are also seen in the rodent gastrointestinal tract but here the inflammation seems to be reversible.