The Antitumor Function of Tumor

Tumor necrosis factor (TNF) is a protein synthesized and secreted by mononuclear phagocytes in response to stimulation with bacterial endotoxin and other agents . Originally TNF was defined functionally as the factor in postendotoxin serum from Propionibacterium acnes-treated mice that mediated hemorrhagic necrosis of established fibrosarcomas in recipient mice (1). More recently, it has been established that TNF, and cachectin, the molecule responsible for the toxic symptoms of endotoxin, are one and the same molecule (2, 3) . The genes for human (4-7) and mouse (7, 8) TNFhave been cloned andexpressed in Escherichia coli . Consequently, adequate quantities of pure humanand mouse rTNF are now available for study. For the most part, the antitumor function of rTNF has been studied in terms of its cytotoxic activity for neoplastic cells in vitro. Such studies are an extension, therefore, of those originally performed (9) with TNF-containing postendotoxin serum (TNS)' from P. acnes-treated mice . TNS was shown to be capable of killing certain neoplastic cells in vitro, as well as causing hemorrhagic necrosis of established tumors in vivo. Indeed, it has been often assumed, since these original findings, that the in vivo therapeutic action of TNF is based on its ability to directly kill cells of the tumor. However, the evidence that TNF is therapeutic in vivo is not particularly convincing in that it is not based on the ability of TNF to cause tumor regression, but on its ability to cause hemorrhagic necrosis of the centers of established tumors . In other words, treatment with TNF rarely results in complete regression of the ring of living tumor tissue that survives central hemorrhagic necrosis . The same shortcoming applies to therapy with bacterial endotoxin, which has been known for many years to be capable ofcausing central hemorrhagic necrosis of most tumors, but complete regression of only some (10) . The possible reason for the limited therapeutic effect of endotoxin was supplied by Parr et al . (11), who demonstrated that only immunogenic tumors are susceptible to endotoxin-