Inhibition of and sensitization to the lethal effects of tumor necrosis factor.
The extension of the positive results obtained with tumor necrosis factor (TNF) in the locoregional treatment of cancer to systemic treatments requires the selective inhibition of its shock-inducing properties. In this paper, recent data regarding the mechanisms by which infections and tumors render mice extremely sensitive to the lethal effects of TNF as well as regarding the inhibition of the dose-limiting toxicities, 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 independent of the IL-12/IFN-gamma axis but ultimately leads to a common step, which 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 cyclase, without the indispensable protective properties of NO being affected. Finally, two acute phase proteins, alpha 1-acid-glycoprotein (AGP) and alpha 1-antitrypsin (AT), were able to protect against the TNF-induced liver failure. None of these three inhibitors seems to affect the antitumor effects of TNF.
Molecular Pathophysiology and Experimental Therapy Unit, Ghent University, Belgium.
P
P
Brouckaert
C
C
Libert
A
A
Cauwels
B
B
Everaerdt
W
W
Van Molle
P
P
Ameloot
Y
Y
Gansemans
B
B
Grijalba
N
N
Takahashi
M J
MJ
Truong
P
P
Van Leuven
W
W
Fiers
D000818:Animals; D003141:Communicable Diseases / Q000188:drug therapy*; D016207:Cytokines / Q000627:therapeutic use; D004347:Drug Interactions; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects* / Q000627:therapeutic use
D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha