INHIBITION OF AND SENSITIZATION TO THE LETHAL EFFECTS OF TUMOR-NECROSIS-FACTOR

The extension of the positive results obtained with tumor necrosis fac tor (TNF) in the locoregional treatment of cancer to systemic treatmen ts requires the selective inhibition of its shock-inducing properties. In this paper, recent data regarding the mechanisms by which infectio ns and tumors render mice extremely sensitive to the lethal effects of TNF as well as regarding the inhibition of the dose-limiting toxiciti es, hypotension and hepatotoxicity, are summarized. An interleukin-12 (IL-12) driven induction of interferon-gamma (IFN-gamma), probably in synergism with endogenous TNF, was found to mediate infection induced sensitization. The sensitization induced by tumors develops independen t of the IL-12/IFN-gamma axis but ultimately leads to a common step, w hich can be inhibited by alpha-CD11a and is specific for sensitization . Hypotension can be inhibited by methylene blue (MB), an inhibitor of the nitric oxide (NO)-induced activation of the cytosolic guanylate c yclase, without the indispensable protective properties of NO being af fected. Finally, two acute phase proteins, al-acid-glycoprotein (AGP) and alpha(1)-antitrypsin (AT), were able to protect against the TNF-in duced liver failure. None of these three inhibitors seems to affect th e antitumor effects of TNF. (C) 1996 Wiley-Liss, Inc.