Tumor necrosis factors

Tumor necrosis factor (TNF) is a well-described and characterized cytokine which can be elicited in the intact animal by endotoxin. This factor produces necrosis of subcutaneous tumors in the classic model: Meth A sarcoma in the Balb C mouse. It has been shown to be cytostatic or cytotoxic for a variety of human cancer cell lines, as well as to have effects against both mouse tumors and human cancers carried in the nude mouse. TNF is most likely produced by the macrophage. TNF has been cloned, and has been shown to have a molecular weight of 17,000 and to contain approximately 157 acids in its active form. The genes responsible for TNF are contained on chromosome 6 in man, which also contains genes of the major histocompatibility complex. Although there are similarities to lymphotoxin, which is produced by mitogen-stimulated lymphocytes, and to interleukin-1 (IL-1), which is also produced by macrophages, TNF has distinctive differences, primarily in its antiproliferative effects. TNF is also allied with the effects of cachexia and has been shown to be similar to, if not exactly the same as, cachectin. Although it appears that effects of TNF require expression of receptors to facilitate binding to the cell, there is not a quantitative relationship between receptors and the sensitivity. TNF cytotoxic effects appeared to be amplified by pretreatment of cells with chemotherapeutic agents such as Actinomycin D, Adriamycin, and Cytoxan as well as to have synergistic effects with gamma interferon, alpha interferon, and IL-2. Although initial phase I and phase II studies of TNF in man have shown the expected toxicity, there have been minimal antitumor effects. It is anticipated that with more sophisticated studies, perhaps combining TNF with either biological or chemotherapeutic agents, TNF's true role in cancer therapy may well unfold.