Strategies for manipulating apoptosis for cancer therapy with tumor necrosis factor and lymphotoxin

Tumor necrosis factor (TNF) and lymphotoxin (LT), initially described as tumoricidal proteins, may be useful as adjuncts in cancer therapy. Treatment with TNF or LT was found to protect cells and animals against damage mediated by radiation or cytotoxic anticancer drugs. By contrast, tumor cells treated with TNF or LT were sensitized to these insults. We present a model in which TNF or LT induces both the synthesis of "protective" proteins such as manganous superoxide dismutase (MnSOD) and the activation of "killing" proteins, such as proteases, depending on the level of the inducing signal. Although the p55-TNF/LT receptor is structurally related to the Fas receptor, they can each signal apoptosis by distinct pathways. Furthermore, activation of both receptors acts synergistically in stimulating apoptosis.