[TNF: antitumoral agent at the border lines of immunity and inflammation].
Tumor Necrosis Factor-alpha (TNF) is mainly produced by activated monocytes and exerts pleiotropic biological effects on a wide variety of both normal and transformed cells. Originally described for its capacity to induce hemorrhagic necrosis of transplantable tumors in vivo and cytolysis of some tumor cells in vitro, TNF has also been shown to play an essential role during the inflammatory response, exerting dual, both beneficial and deleterious, effects. TNF, via a local production appears to be a key cytokine involved in antiviral, antibacterial and antiparasitic host defense mechanisms. Contreversely, deregulation of the inflammatory and immune reactions can be associated with a systemic TNF production, leading to toxic secondary effects. Recent cloning of the TNF receptors has provided additional insights in the complex physiology of TNF. It is now clearly established that both type I and type II TNF receptors can be cleaved and released as TNF binding proteins. The soluble fragments of TNF receptors can inhibit TNF-mediated tumor cell lysis in vitro and might therefore serve as regulators of TNF action. The antitumor potency of TNF also reflects the pleiotropic aspect of TNF. TNF-induced tumor regression, observed in various preclinical studies, appears to result from at least three distinct biological effects: mainly hemorrhagic necrosis via TNF action on tumor endothelium, TNF immunomodulatory activity on immune effector cells, and presumably a direct TNF-mediated cytotoxic effect against tumor cells. From the clinical trials performed with distinct recombinant materials a consensus has emerged about the disappopinting anticancer efficacy of TNF used in systemic administration. Further studies, aimed at better understanding the complex action of TNF, are required to possibly enhance its therapeutic index and subsequently to assess whether TNF still remains a promising therapeutic agent.
Branellec
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D
UA 1156 CNRS, Institut Gustave-Roussy, Villejuif, France.
Chouaib
S
S
D000818:Animals; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D009369:Neoplasms / Q000188:drug therapy; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use
D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha
Le TNF: un agent antitumoral aux frontières de l'immunité et de l'inflammation.