Summary
To develop a new gene therapy model for cancer, a clonal cell line (KMST-6/TNF) which produces human tumor necrosis factor α (hTNF-α) has been developed by introducing hTNF-α cDNA into a human immortal fibroblast cell line (KMST-6). The conditioned medium (CM) of KMST-6/TNF cells inhibited the growth of various malignant human cell lines, but not that of normal human fibroblasts. Although the growth inhibitory effects of KMST-6/TNF CM were neutralized to a considerable degree by anti-TNF-α antibody, its inhibitory effects were more marked than the purified human natural TNF-α itself in the same units, suggesting that KMST-6/TNF CM contains some growth inhibitory substances other than TNF-α. However, interferons α, β, and γ were undetectable in the KMST-6/TNF CM.
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Abbruzzese, J. L.; Levin, B.; Ajani, J. A., et al. Phase I trial of recombinant human γ-interferon and recombinant human tumor necrosis factor in patients with advanced gastrointestinal cancer. Cancer Res. 49:4057–4061; 1989.
Bai, L.; Mihara, K.; Kondo, T., et al. Immortalization of normal human fibroblasts by treamtent with 4-nitroquinoline1-oxide. Int. J. Cancer 53:451–456; 1993.
Budd, G. T.; Green, S.; Baker, L. H., et al. A southwest oncology group phase II trial of recombinant tumor necrosis factor in metastatic breast cancer. Cancer 68:1694–1695; 1991.
Carswell, E. A.; Old, L. J.; Kassel, R. L., et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc. Natl. Acad. Sci. USA 72:3666–3670; 1975.
Chouaib, S.; Bertoglio, J.; Blay, J. Y., et al. Generation of lymphokine-activated killer cells: synergy between tumor necrosis factor and interleukin 2. Proc. Natl. Acad. Sci. USA 85:6875–6879; 1988.
Creaven, P. J.; Brenner, D. E.; Cowens, J. W., et al. A phase I clinical trial of recombinant human tumor necrosis factor given daily for five days. Cancer Chemother. Pharmacol. 23:186–191 1989.
Eggimann, P.; Chioléro, R.; Chassot, P. G., et al. Systemic and hemodynamic effects of recombinant tumor necrosis factor alpha in isolation perfusion of the limbs. Chest 107:1074–1082; 1995.
Fiers, W. Tumor necrosis factor. Characterization at the molecular, cellular and in vivo level. FEBS Lett. 285:199–212; 1991.
Fujii, S.; Liu, Y.; Neda, H., et al. Augmented systemic immunity in mice implanted with tumor necrosis factor-α gene-transduced Meth-A cells. Jpn. J. Cancer Res. 85:315–324; 1994.
Fukuda, S.; Ando, S.; Sanou, O., et al. Simultaneous production of natural human tumor necrosis factor-α, -β and interferon-α from BALL-1 cells stimulated by HVJ. Lymphokine Res. 7:175–185; 1988.
Goossens, V.; Grooten, J.; de Vos, K., et al. Direct evidence for tumor necrosis factor-induced mitochondrial reactive oxygen intermediates and their involvement in cytotoxicity. Proc. Natl. Acad. Sci. USA 92:8115–8119; 1995.
Hahne, M.; Jäger, U.; Isenmann, S., et al. Five tumor necrosis factor-inducible cell adhesion mechanisms on the surface of mouse endothelioma cells mediate the binding of leukocytes. J. Cell Biol. 121:655–664; 1993.
Irmler, M.; Thome, M.; Hahne, M., et al. Inhibition of death receptor signals by cellular FLIP. Nature 388:190–195; 1997.
Jahan, I.; Mihara, K.; Namba, M. Neoplastic transformation and characterization of human fibroblasts by treatment with 60Co gamma rays and the human c-Ha-ras oncogene. In Vitro Cell. Dev. Biol. 29A:763–767; 1993.
Johnston, M. D.; Finter, N. B.; Young, P. A. Dye uptake method for assay of interferon activity. Methods Enzymol. 78:394–399; 1981.
Kessler, M.; Höper, J.; Harrison, D. K., et al. Tissue O2 supply under normal and pathological conditions. In: Lübbers, D. W.; Acker, H.; Leniger-Follert, E., et al., ed. Oxygen transport to tissue-V. New York: Plenum; 1984:69–80.
Matthews, N.; Neale, M. L.; Jackson, S. K., et al. Tumour cell killing by tumour necrosis factor: inhibition by anaerobic conditions, free-radical scavengers and inhibitors of arachidonate metabolism. Immunology 62:153–155; 1987.
Mihara, K.; Bai, L.; Kano, Y., et al. Malignant transformation of human fibroblasts previously immortalized with 60Co gamma rays. Int. J. Cancer 50:639–643; 1992.
Namba, M.; Nishitani, K.; Hyodoh, F., et al. Neoplastic transformation of human diploid fibroblasts (KMST-6) by treatment with 60Co gamma rays. Int. J. Cancer 35:275–280; 1985.
Orita, K.; Fuchimoto, S.; Kurimoto, M., et al. Early phase II study of interferon-α and tumor necrosis factor-α combination in patients with advanced cancer. Acta Med. Okayama 46:103–112; 1992.
Østensen, M. E.; Thiele, D. L.; Lipsky, P. E. Tumor necrosis factor-α enhances cytolytic activity of human natural killer cells. J. Immunol. 138:4185–4191; 1987.
Pfizenmaier, K.; Scheurich, P.; Schlüter, C., et al. Tumor necrosis factor enhances HLA-A,B,C and HLA-DR gene expression in human tumor cells. J. Immunol. 138:975–980; 1987.
Retsas, S.; Leslie, M.; Bottomley, D. Intralesional tumour necrosis factor combined with interferon gamma in metastatic melanoma. Br. Med. J. 298:1290–1291; 1989.
Rosenberg, S. A. Gene therapy for cancer. JAMA 268:2416–2419; 1992.
Rothe, M.; Pan, M. G.; Henzel, W. J., et al. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell 83:1243–1252; 1995.
Shalaby, M. R.; Aggarwal, B. B.; Rinderknecht, E., et al. Activation of human polymorphonuclear neutrophil functions by interferon-γ and tumor necrosis factors, J. Immunol. 135:2069–2073; 1985.
Shaw, G.; Kamen, R. A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell 46:659–667; 1986.
Takebe, Y.; Seiki, M.; Fujisawa, J., et al. SRα promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat. Mol. Cell. Biol. 8:466–472; 1988.
Talmage, J. E.; Phillips, H.; Schneider, M., et al. Immunomodulatory properties of recombinant murine and human tumor necrosis factor. Cancer Res. 48:544–550; 1988.
Uren, A. G.; Pakusch, M.; Hawkins, C. J., et al. Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor associated factors. Proc. Natl. Acad. Sci. USA 93:4974–4978; 1996.
Van Antwerp, D. J.; Martin, S. J.; Kafri, T., et al. Suppression of TNF-α-induced apoptosis by NF-κB. Science 274:787–789; 1996.
Wang, C. Y.; Mayo, M. W.; Baldwin, A. S., Jr. TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB. Science 274:784–787; 1996.
Wölfel, T.; Herr, W.; Coulie, P., et al. Lysis of human pancreatic adenocarcinoma cells by autologous HLA-class I-restricted cytolytic T-lymphocyte (CTL) clones. Int. J. Cancer 54:636–644; 1993.
Wong, G. H. W.; Elwell, J. H.; Oberley, L. W., et al. Manganous superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor. Cell 58:923–931; 1989.
Yamazaki, S.; Onishi, E.; Enami, K., et al. Proposal of standardized methods and reference for assaying recombinant human tumor necrosis factor. Jpn. J. Med. Sci. Biol. 39:105–118; 1986.
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Fushimi, K., Torigoe, K., Yamauchi, H. et al. Establishment of a human fibroblast cell line producing tumor necrosis factor α (KMST-6/TNF) and growth inhibitory effects of its conditioned medium on malignant cells in culture. In Vitro Cell.Dev.Biol.-Animal 34, 463–467 (1998). https://doi.org/10.1007/s11626-998-0079-9
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DOI: https://doi.org/10.1007/s11626-998-0079-9