Summary
Antitumor effects of i.v. injected human recombinant tumor necrosis factor (rTNF) against solid Meth A tumors in mice appeared to be critically dependent on the dose and were limited by its toxicity. Extensive necrosis and complete cures were only induced by doses having untoward effects, such as diarrhea, hypothermia, ruffled fur, and lethargy. Murine tumor necrosis serum (TNS, 0.5 ml) had about the same antitumor potential and induced all side effects except diarrhea. More extensive necrosis and approximate doubling of the incidence of complete regression in the absence of gross side effects were observed upon administration of a low dose of rTNF combined with detoxified endotoxin, nontoxic poly A:U, or submicrogram doses of toxic endotoxin. The separate constituents had little antitumor effects, if any at all. Increasing the dose of toxic endotoxin resulted in a further potentiation of necrosis, overt toxicity, but no cures. Muramyl dipeptide and interferon α/β did not potentiate effects of rTNF. In vitro growth of Meth A cells was not inhibited by toxic endotoxin, rTNF or the combination, although TNS was highly inhibitory. Data show that therapeutic effects of rTNF and its synergy with endotoxin are not due to direct effects on the tumor cells and that the extent of prompt in vivo tumor necrosis does not predict the course of tumor growth. Therapeutic effects of both TNS and toxic endotoxin probably involve a synergy between low levels of TNF and other factors/effects induced by endotoxin. Detoxified endotoxin and poly A:U probably induce the latter effects and little or no TNF, so explaining the absence of side effects, their weak antitumor potential, and their powerful synergistic action with rTNF. A role for interferon α/β as an induced synergistic factor is not likely. Muramyl dipeptide and TNF might share properties needed for synergy with endotoxins.
Similar content being viewed by others
References
Bachwich PR, Chensue SW, Larrick JW, Kunkel SL (1986) Tumor necrosis factor stimulates interleukin-1 and prostaglandin production in resting macrophages. Biochem Biophys Res Commun 136:94
Beutler B, Cerami A (1986) Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature 320:584
Beutler B, Milsark IW, Cerami AC (1985) Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Nature 229:869
Bloksma N, Schetters TP, Figdor C, Van Dijk H, Willers JM (1980) In vitro anti-tumour activity of tumour necrosis serum. Int J Immunopharmacol 2:95
Bloksma N, Hofhuis F, Benaissa-Trouw B, Willers JMN (1982) Endotoxin-induced release of tumour necrosis factor and interferon in vivo is inhibited by prior adrenoceptor blockade. Cancer Immunol Immunother 14:41
Bloksma N, De Leeuw R, Hofhuis FM, Westerdaal NA, Benaissa-Trouw B, Willers JMN (1983) Effects of various coryneforms on mononuclear phagocyte system function and on production of tumour necrosis factor in mice. Ann Immunol (Inst Pasteur) 134C:159
Bloksma N, Kuper CF, Hofhuis FMA, Benaissa-Trouw B, Williers JMN (1983) Antitumour activity of endotoxin, concanavalin A and poly I:C and their ability to elicit tumour necrosis factor, cytostatic factors and interferon in vivo. Cancer Immunol Immunother 16:35
Bloksma N, Kuper CF, Hofhuis FMA, Willers JMN (1984) Role of vasoactive amines in the antitumor activity of endotoxin. Immunopharmacology 7:201
Bloksma N, Hofhuis FMA, Willers JMN (1984) Endotoxin-induced antitumor activity in the mouse is highly potentiated by muramyl dipeptide. Cancer Lett 23:159
Bloksma N, Hofhuis FMA, Willers JMN (1984) Muramyl dipeptide is a powerful potentiator of the antitumor action of various tumor-necrotizing agents. Cancer Immunol Immunother 17:154
Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 72:3666
Collins T, Lapierre LA, Fiers W, Strominger JL, Pober JS (1986) Recombinant human tumor necrosis factor increases mRNA levels and surface expression of HLA-A, B antigens in vascular endothelial cells and dermal fibroblasts in vitro. Proc Natl Acad Sci USA 83:446
Dinarello CA, Cannon JG, Wolff SM, Bernheim HA, Beutler B, Cerami A, Figari IS, Palladino MA Jr, O'Connor JV (1986) Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med 163:1433
Gamble JR, Harlan JM, Klebanoff SJ, Vadas MA (1985) Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci USA 82:8667
Gratia A, Linz R (1931) Le phénomène de Shwartzman dans le sarcome du cobaye. CR Soc Biol (Paris) 108:427
Green S, Dobrjanski A, Carswell EA, Kassel RL, Old LJ, Fiore N, Schwartz MK (1976) Partial purification of a serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 73:381
Green S, Dobrjanski A, Chiasson MA, Carswell E, Schwartz MK, Old LJ (1977) Corynebacterium parvum as the priming agent in the production of tumor necrosis factor in the mouse. J Natl Cancer Inst 59:1519
Green S, Dobrjanski A, Chiasson MA (1982) Murine tumor necrosis-inducing factor: purification and effects on myelomonocytic leukemia cells. J Natl Cancer Inst 68:997
Haranaka K, Satomi N, Sakurai A (1984) Antitumor activity of murine tumor necrosis factor (TNF) against transplanted murine tumors and heterotransplanted human tumors in nude mice. Int J Cancer 34:263
Haranaka K, Carswell EA, Williamson BD, Prendergast JS, Satomi N, Old LJ (1986) Purification, characterization, and antitumor activity of nonrecombinant mouse tumor necrosis factor. Proc Natl Acad Sci USA 83:3949
Hovanessian A, Riviere Y, Montagnier L, Michelson M, Lacour J, Lacour F (1982). Enhancement of interferon-mediated protein kinase in mouse and human plasma in response to treatment with polyadenylic-polyuridylic acid. J Interferon Res 2:209
Kato N, Nakashima L, Ohta M, Naito S, Kojima T (1979) Interferon and cytotoxic factor (cytotoxin) released in the blood of mice infected with Mycobacterium bovis BCG I. Enhanced production of interferon and appearance of cytotoxin stimulated by capsular polysaccharide of Klebsiella pneumoniae or bacterial lipopolysaccharide. Microbiol Immunol 23:383
Kull FC, Cuatrecasas P (1981) Preliminary characterization of the tumor cell cytotoxin in tumor necrosis serum. J Immunol 4:1279
Kuper CF, Bloksma N, Hofhuis FM, Bruyntjes JP, Willers JM (1982) Influence of adrenoceptor blockade on endotoxin-induced histopathological changes in murine Meth A sarcoma. Int J Immunopharmacol 4:49
Lacour J (1985) Clinical trials using polyadenylic-polyuridylic acid as an adjuvant to surgery in treating different tumors. J Biol Response Mod 4:538
Männel DN, Rosenstreich DL, Mergenhagen SE (1979) Mechanism of lipopolysaccharide-induced tumor necrosis: Requirement for lipopolysaccharide-sensitive lymphoreticular cells. Infect Immun 24:573
Männel DN, Farrar JJ, Mergenhagen SE (1980) Separation of a serum-derived tumoricidal factor from a helper factor for plaque forming cells. J Immunol 124:1106
Marmenout A, Fransen L, Tavernier J, Van der Heyden J, Tizard R, Kawashima E, Shaw A, Johnson M-J, Semon M, Müller R, Ruysschaert M-R, Van Vliet A, Fiers W (1985) Molecular cloning and expression of human tumor necrosis factor and comparison with mouse tumor necrosis factor. Eur J Biochem 152:515
Morrison DC, Ulevitch RJ (1978) The effects of bacterial endotoxins on host mediation systems. Am J Pathol 93:527
Nawroth PP, Stern DM (1986) Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 163:740
O'Malley WE, Achinstein B, Shear MJ (1962) Action of bacterial polysaccharide on tumors. II. Damage of sarcoma 37 by serum of mice treated with Serratia marcescens polysaccharide, and induced tolerance. J Natl Cancer Inst 29:1169
Old LJ (1985) Tumor necrosis factor (TNF). Science 230:630
Parant M, Chedid L (1985) Dissociation between immunostimulant activities of several muramyl peptides. Int J Immunother 1:11
Parr I, Wheeler E, Alexander P (1973) Similarities of antitumor action of endotoxin, lipid A and double-stranded RNA. Br J Cancer 27:370
Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV (1984) Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature 312:724
Ribi EE, Cantrell JL, Von Eschen KB, Schwartzman SM (1979) Enhancement of endotoxin shock by N-acetylmuramyl-L-alanyl-(L-seryl)-D-isoglutamine (muramyl dipeptide). Cancer Res 39:4756
Ribi E, Amano K, Cantrell J, Schwartzman S, Parker R, Takayama K (1982) Preparation and antitumor activity of non-toxic lipid A. Cancer Immunol Immunother 12:91
Schleimer RP, Rutledge BK (1986) Cultured human vascular endothelial cells acquire adhesiveness for neutrophils after stimulation with interleukin 1, endotoxin, and tumor promoting phorbol diesters. J Immunol 136:649
Shirai T, Yamaguchi H, Ito H, Todd CW, Wallace RB (1985) Cloning and expression in Escherichia coli of the gene for human tumor necrosis factor. Nature 313:803
Shultz RM, Papamatheakis JD, Chirigos MA (1977) Interferon: An inducer of macrophage activation by polyanions. Science 197:674
Shapiro CJ (1940) The effect of a toxic carbohydrate complex from S. enteritidis on transplantable rat tumors in tissue culture. Am J Hyg 31 (B):114
Youngner JS, Stinebring W (1965) Interferon appearance stimulated by endotoxin, bacteria or viruses in mice pre-treated with Escherichia coli endotoxin, or infected with Mycobacterium tuberculosis. Nature 208:456
Yu C-L, Haskard D, Cavender D, Ziff M (1986) Effects of bacterial lipopolysaccharide on the binding of lymphocytes to endothelial cell monolayers. J Immunol 136:569
Author information
Authors and Affiliations
Additional information
Present address: Department of Immunotoxicology, State University of Utrecht, Biltstraat 172, 3572 BP Utrecht, The Netherlands
Rights and permissions
About this article
Cite this article
Bloksma, N., Hofhuis, F.M.A. Synergistic action of human recombinant tumor necrosis factor with endotoxins or nontoxic poly A:U against solid Meth A tumors in mice. Cancer Immunol Immunother 24, 165–171 (1987). https://doi.org/10.1007/BF00205595
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00205595