Summary
We investigated the ability of various tumournecrotizing agents with diverging toxicity to induce tumour necrosis factor (TNF) and cytostatic activity inPropionibacterium-acnes-primed Swiss and tumour-bearing BALB/c mice, and the capacity of anti-TNF antibodies to inhibit induction of tumour necrosis by the agents. Lipid A and especially its combination with muramyl dipeptide induced high TNF levels in Swiss mice, as measured in the serum. Lower levels were induced by detoxified lipid A and the nontoxic dsRNA, polyadenylic polyuridylic acid, either alone or combined with muramyl dipeptide. The toxic agents also appeared the strongest inducers of mediators with cytostatic activity against cultured endothelial cells and MethA tumour cells. Anti-TNF antibodies partially reduced the cytostatic activity of the sera against MethA cells. Tumour-bearing BALB/c mice produced only low levels of TNF and cytostatic factors in response to all agents. Recombinant mouse TNF hardly reduced the DNA synthesis of MethA cells, unless normal mouse serum was added. Serum fromP.-acnes-treated Swiss mice and tumour-bearing BALB/c mice, that were inhibitory on their own, failed to potentiate the action of TNF. Serum from Swiss mice treated with toxic, but not detoxified, lipid A caused extensive tumour necrosis upon injection into MethA-bearing BALB/c mice. This activity was completely abolished by pre-incubation of the serum with anti-TNF. The tumour-necrotizing activity of the agents could be partially reduced by prior injection of these antibodies. Results show that the capacity of the agents to induce TNF and cytostatic activity is not related to their antitumour potential. Although TNF is likely to be a crucial mediator of the tumour-necrotizing action of the toxic as well as the nontoxic agents, it is probably not the sole mediator. Data also indicate that induction of tumour necrosis does not require induction of high and, thus toxic, TNF levels in the serum.
Similar content being viewed by others
References
Bloksma N, Hofhuis FMA (1987) 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 25: 165
Bloksma N, Schetters TP, Figdor C, Van Dijk H, Willers JMN (1980) In vitro anti-tumour activity of tumour necrosis serum. Int J Immunopharmacol 2: 95
Bloksma N, Hofhuis FMA, Willers JMN (1982) Effect of adrenoceptor blockade on hemorrhagic necrosis of MethA sarcomata induced by endotoxin or tumor necrosis serum. Immunopharmacology 4: 163
Bloksma N, Hofhuis FMA, Willers JMN (1983) Macrophage-dependence of endotoxin-induced antitumor action in the mouse. Ann Immunol Hung 23: 55
Bloksma N, Kuper CF, Hofhuis FMA, Benaissa-Trouw B, Willers 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, Hofhuis FMA, Willers JMN (1984) Endotoxin-induced antitumor activity 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 tumornecrotizing agents. Cancer Immunol Immunother 17: 154
Bloksma N, Hofhuis FMA, Willers JMN (1984) Role of mononuclear phagocyte function in endotoxin-induced tumor necrosis. Eur J Cancer Clin Oncol 20: 397
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
Cerami A, Beutler B (1988) The role of cachectin/TNF in endotoxic shock and cachexia. Immunol Today 9: 28
Creagan ET, Kovack JS, Moertel CG, Frytak S, Kvols LK (1988) A phase I clinical trial of recombinant human tumor necrosis factor. Cancer 62: 2467
Green S, Dobransky A, Chiasson MA, Carswell EA, 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
Haranaka K, Satomi N, Sakurai A (1984) Differences in tumour necrosis factor productive ability among rodents. Br J Cancer 50: 471
Kiener PA, Marek F, Rodgers G, Lin P-F, Warr G, Desiderio J (1988) Induction of tumor necrosis factor, IFNγ, and acute lethality in mice by toxic and non-toxic forms of lipid A. J Immunol 141: 870
Moritz T, Niederle N, Baumann J, May D, Kurschel E, Osieka R, Kempeni J, Schlick E, Schmidt CG (1989) Phase I study of recombinant human tumour necrosis factor α in advanced malignant disease. Cancer Immunol Immunother 29: 144
Nawroth P, Stern DM (1986) Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 163: 740
Old LJ (1987) Tumour necrosis factor. Polypeptide mediator network. Nature 326: 330
Palladino MA, Shalaby MR, Kramer SM, Ferraiolo BL, Baughman RA, Deleo AB, Crase D, Marafino B, Aggarwal BB, Figari IS, Liggitt D, Patton JS (1987) Characterization of the antitumor activities of human tumor necrosis factor-α and the comparison with other cytokines: induction of tumor-specific immunity. J Immunol 138: 4023
Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino WJ, Kohr WJ, Aggarwal BB, Goeddel DV (1984) Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature 312: 724
Van de Wiel PA, Bloksma N, Kuper CF, Hofhuis FM, Willers JM (1989) Macroscopic and microscopic early effects of tumour necrosis factor on murine MethA sarcoma, and relation to curative activity. J Pathol 157: 65
Van de Wiel PA, Pieters RHH, Van der Pijl A, Bloksma N (1989) Synergic action between tumor necrosis factor and endotoxins or poly (A.U) on cultured bovine endothelial cells. Cancer Immunol Immunother 29: 23
Yamazaki S, Onishi E, Enami K, Natori K, Kohase M, Sakamoto H, Tanouchi M, Hayashi H (1986) Proposal of standardized methods and reference for assaying recombinant human tumor necrosis factor. Jpn J Med Sci Biol 39: 105
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
van de Wiel, P.A., van der Pijl, A. & Bloksma, N. Role of tumour necrosis factor in the tumour-necrotizing activity of agents with diverging toxicity. Cancer Immunol Immunother 33, 115–120 (1991). https://doi.org/10.1007/BF01742539
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01742539