Biologic Effects of Tumor Necrosis Factors Alpha and Beta

As early as 1891, clinical reports suggested that major components of the cell wall of gram-negative bacteria such as endotoxins were associated with antitumor activities; Bruns ( 1 ) and Coley ( 2 ) described the regression of tumors in patients with tumors who were deliberately injected with mixtures of killed bacterial toxins. Gratia and Linz ( 3 ) and Shear et al. ( 4 ) subsequently demonstrated that bacterial filtrates or endotoxins were capable of inducing hemorrhagic necrosis of specific transplanted tumors. A significant advance in distinguishing the effects of endotoxin from a specific “tumor necrosis factor” was reported in 1975 by Carswell et al. ( 5 ). They were impressed with the observations and hypothesis of Algire ( 6 ), who suggested that hemorrhagic necrosis of tumors might be secondary to endotoxin-induced hypotension resulting in circulatory stasis and ischemia of the tumor. They argued, however, that rather than an indirect action, endotoxin probably caused the host to release a factor that was directly toxic to the tumor. This hypothesis led Carswell et al. ( 5 ) to the discovery of an endotoxin-induced serum factor, which caused necrosis of tumors and which they termed tumor necrosis factor (TNF-like).