TUMOR-NECROSIS-FACTOR - CHARACTERIZATION AT THE MOLECULAR, CELLULAR AND INVIVO LEVEL

TNF was originally characterized as an antitumor agent and a factor cytotoxic for many malignant cells. It is now clear that it plays an important role in the defense against viral, bacterial and parasitic infections, - and in (auto-)immune responses. Natural induction of TNF is protective, but its overproduction may be detrimental and even lethal to the host. The structure of TNF and its interaction with the two types of cellular receptor are becoming better understood. TNF elicits a variety of events in different cell types. It subverts the electron transport system or the mitochondria into production of oxygen radicals, which can kill the (malignant) cells when these do not contain or produce protective enzymes. Furthermore, TNF induces a set of genes and at least part of this transcriptional activation is mediated by NF-kappa-B. The prospects of TNF as an antitumor drug can be improved on the one hand by agents such as LI+, which synergizes, and on the other hand by inhibitors of the systemic toxicity which do not interfere with the antitumor efficacy. Also, in tumor-bearing animals which have been rendered tolerant by administration of small doses of TNF, an effective and complete elimination of the tumors can be obtained by the combined action of TNF plus interferon.