Interferon and Cytotoxic Factor (Cytotoxin) Released in the Blood of Mice Infected with <i>Mycobacterium bovis</i> BĆG

The effect of alpha- and beta-adrenoceptor blocking agents on endotoxin-induced release of tumour necrosis factor (TNF), and of interferon in the circulation of Corynebacterium parvum-treated mice was the subject of this study. TNF was quantified after injection of TNF containing heated serum (TNS) into Meth A sarcoma-bearing mice by determining colour, extent, and incidence of haemorrhagic necrosis. The release of TNF was weakly inhibited by the competitive alpha-blocker phentolamine and the beta-blocker propranolol. The non-competitive alpha-blocker phenoxybenzamine inhibited to a higher degree. Endotoxin-induced elicitation of growth-inhibiting principles into TNS was antagonized by propranolol and phenoxybenzamine. Administration of adrenaline before endotoxin inhibited the elicitation of TNF and growth-inhibitory activities, which indicates tachyphylaxis. The release of interferon was effectively inhibited by both alpha-adrenoceptor blockers but not by propranolol. The interferon was heat-labile. The results indicate that endotoxin-induced TNF and interferon are separate factors, elicited in different ways. As both alpha-blockers do not only inhibit reactions at the alpha-adrenergic receptor but also reactions at the serotonin receptor and in the case of phenoxybenzamine also at the choline receptor, it is suggested that endotoxin-induced release of the anti-tumour factors is controlled by reactions mediated by one or more of these receptors. It is suggested that the inhibition of TNF release by propranolol may be due to the membrane-stabilizing activity of this agent.

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Endotoxin-induced release of tumour necrosis factor and interferon in vivo is inhibited by prior adrenoceptor blockade

Bloksma

Hofhuis

Benaissa-Trouw

et al. 1982

Cancer Immunol Immunother

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Role of histamine in the antitumour activity of endotoxin

Bloksma

Hofhuis

et al. 1984

Cancer Immunol Immunother

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The role of histamine in the antitumour activity of endotoxin against solid syngeneic Meth-A sarcoma in BALB/c mice was studied. Endotoxin induces haemorrhagic necrosis and regression of this tumour. Histamine and the selective H1 receptor agonist 2-pyridylethylamine mimicked the induction of necrosis but did not cause regression. The selective H2 receptor agonist dimaprit did not cause any tumour damage. The effect of histamine could be inhibited by the H1 receptor antagonists diphenhydramine and promethazine but not by the H2 receptor antagonist cimetidine. Endotoxin-induced necrosis was slightly affected by diphenhydramine, and the incidence of regression was reduced by both H1 antagonists. Cimetidine potentiated endotoxin-induced regression. Similar effects were observed concerning the effects of H-receptor antagonists on necrosis and regression induced by tumour necrosis serum (TNS). Histological examination revealed no marked additional effects of diphenhydramine or cimetidine on endotoxin-induced hyperaemia, haemorrhagic necrosis, and mitotic arrest of the tumour cells. Only cimetidine increased the extent of nonhaemorrhagic necrosis. The endotoxin-induced release of tumour necrosis factor and cytostatic activity in TNS was clearly reduced by diphenhydramine, but hardly affected by cimetidine. Data indicate that intact H1 receptors are required for the induction of tumour regression and antitumour factors by endotoxin. Concomitant H2 blockade may facilitate this by stimulating H1 receptor-mediated processes upon endotoxin-induced histamine release, although a cimetidine-induced inhibition of T-suppressor cell activation might also be involved.

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Synergistic action of human recombinant tumor necrosis factor with endotoxins or nontoxic poly A:U against solid Meth A tumors in mice

Bloksma

Hofhuis

1987

Cancer Immunol Immunother

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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 alpha/beta 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 alpha/beta as an induced synergistic factor is not likely. Muramyl dipeptide and TNF might share properties needed for synergy with endotoxins.

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Interferon and Cytotoxic Factor (Cytotoxin) Released in the Blood of Mice Infected with Mycobacterium bovis BĆG

Cited by 10 publications

References 24 publications

Endotoxin-induced release of tumour necrosis factor and interferon in vivo is inhibited by prior adrenoceptor blockade

Endotoxin-induced release of tumour necrosis factor and interferon in vivo is inhibited by prior adrenoceptor blockade

Role of histamine in the antitumour activity of endotoxin

Synergistic action of human recombinant tumor necrosis factor with endotoxins or nontoxic poly A:U against solid Meth A tumors in mice

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