Tumor necrosis factor, induction

Cytokines, eg, interferons, interleukins, tumor necrosis factor (TNF), and certain growth factors, could have antitumor activity directiy, or may modulate cellular mechanisms of antitumor activity (2). Cytokines may be used to influence the proliferation and differentiation of T-ceUs, B-ceUs, macrophage—monocyte, myeloid, or other hematopoietic cells. Alternatively, the induction of interferon release may represent an important approach for synthetic—medicinal chemistry, to search for effective antiinflammatory and antifibrotic agents. Inducers of interferon release may also be useful for lepromatous leprosy and chronic granulomatous disease. The potential cytokine and cytokine-related therapeutic approaches to treatment of disease are summarized in Table 4. A combination of cytokines is a feasible modaUty for treatment of immunologically related diseases however, there are dangers inherent in such an approach, as shown by the induction of lethal disserninated intravascular coagulation in mice adrninistered TNF-a and IFN-y. 

TNF. Tumor necrosis factor. TNFs are among the important cytokines playing a key role in activation and induction of some immune system cells and cellular immunity processes responsible for proinflammatory and inflammatory response reactions as well. 

Corazza, N., Eichenberger, S., Eugster, H.P. and Mueller, C. (1999) Nonlymphocyte-derived tumor necrosis factor is required for induction of colitis in recombination activating gene (RAG)2( / ) mice upon transfer of CD4(+)CD45RB(hl) T cells. Journal of Experimental Medicine 190,1479-1492. 

Mier, J.W. et al., Induction of circulating tumor necrosis factor (TNF-alpha) as the mechanism for the febrile response to interleukin-2 (IL-2) in cancer patients, J. Clin. Immunol., 8, 426, 1988. 

Bluthe, R.M. et al., Synergy between tumor necrosis factor a and interleukin-1 in the induction of sickness behavior in mice, Psychoneuroendocrinology, 19, 197, 1994. 

Tumor Necrosis Factor There are two types of tumor necrosis factor TNF-a and TNF- 8. Of the two, TNF-a has been studied in more detail. TNF-a is a 157 amino acid polypeptide. It is a mediator of immune regulation, including the activation of macrophages and induction of the proliferation of T cells. Another TNF-a function is its cytotoxic effects on a number of tumor cells. Recent research, however, concentrates on its property in the stimulation of inflammation, particularly in the case of rheumatoid arthritis. Clinical trials are being conducted with drugs to block TNF-a with anti-TNF-a monoclonal antibodies. These antibodies target the excessive levels of TNF-a in the synovial fluid of joints and provide relief to sufferers of rheumatoid arthritis (Exhibit 4.10). 

Monney, L., Ohvier, R., Otter, 1., Jansen, B., Poirier, GG., and Bomer, C., 1998, Role ofan acidic compartment in tumor-necrosis-factor-a-induced production of ceramide, activation of caspase-3 and apoptosis. Eur. J. Biochem. 251 295-303 Morrison, H., Jemstrom, B., Nordenskjdld, M., Thor, H., and Orrenius, S., 1984, Induction of DNA damage by menadione (2-methyl-l,4-naphthoquinone) in primary cultures of rat hepatocytes. Biochem. Pharmacol. 33 1763-1769 Neuzil, J., Svensson, 1., Weber, T, Weber, C., and Brunk, U.T., 1999, alpha-tocopheryl succinate-induced apoptosis in Jurkat T cells involves caspase-3 activation, and both lysosomal and mitochondrial destabilisation. FEES Lett. 445 295-300 Ngo, E.O., Nutter, L.M., Sura, T., and Gutierrez, P. L., 1998, Induction ofp53 by the... 

Tumor necrosis factor inhibition. Ethanol (95%) extract of the rhizome, in cell culture at a concentration of 100 pg/mL, was inactive on macrophage cell line RAW 264.7 vs EPS induction of TNF-az° zp Tumor promotion inhibition. Ethyl acetate and methanol extracts of the dried rhizome, in cell culture at a concentration of 50 pg/mL, produced weak activity on G3H/ lOTl/2 cells vs tetradecanoyl phorbol acetate-induced acetate phospholipid synthesis. The hexane extract was inactiveZ . Ethanol (95%) and petroleum ether extracts of the dried rhizome, in cell culture at a concentration of 160 and 80 pg/mL, re-... 

Bruccoleri, A., Gallucci, R., Germolec, D.R., Blackshear, P, Simeonova, P, Thurman, R.G. Luster, M.I. (1997) Induction of early-immediate genes by tumor necrosis factor a contribute to liver repair following chemical-induced hepatotoxicity. Hepatology, 25, 133-141... 

Kamohara H, Takahashi M, Ishiko T, Ogawa M, Baba H. 2007. Induction of interleukin-8 (CXCL-8) by tumor necrosis factor-alpha and leukemia inhibitory factor in pancreatic carcinoma cells Impact of CXCL-8 as an autocrine growth factor. Int J Oncol 31 627-632. 

Sparwasser, T., Miethke, T., Lipford, G., Erdmann, A., Hacker, H., Heeg, K. and Wagner, H. (1997) Macrophages sense pathogens via DNA motifs induction of tumor necrosis factor-alpha-mediated shock. Eur. J. Immunol., 27, 1671-1679. 

R. Hamanaka, K. Kohno, T. Seguchi, K. Okamura, A. Morimoto, M. Ono, J. Ogata and M. Kuwano, Induction of low density lipoprotein receptor and a transcription factor SP-1 by tumor necrosis factor in human microvascular endothelial cells, J. Biol. Chem. 267 (1992) 13160-13165. 

Sanna PP, Weiss F, Samson ME, Bloom FE, Pich EM. Rapid induction of tumor necrosis factor alpha in the cerebrospinal fluid after intracerebroventricular injection of lipopolysaccharide revealed by a sensitive capture immuno-PCR assay. Proc Natl Acad Sci USA 1995 92(l) 272-275. 

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