title: Endogenous production of tumor necrosis factor in normal mice and human cancer patients by interferons and other cytokines combined with biological response modifiers of bacterial origin.
abstract: The priming effect of endogenous biological response modifiers (BRMs), interferons (IFNs), and interleukin-2 (IL2), and the triggering effect of BRMs of bacterial origin, OK-432 and Corynebacterium parvum, on endogenous production of the tumor necrosis factor (TNF) were investigated in mice. TNF activity in serum was measured by in vitro cytotoxicity assay with L-929 cells as a target. The i.v. injection of OK-432 (3KE per mouse) triggered TNF maximally (mean value: 30 U/ml) after 2 h, with a similar time course to that of triggering by lipopolysaccharide. The priming activities of IFNs and IL2 were examined in the system of TNF-triggering by OK-432. The i.v. injection of recombinant IFN-gamma (rIFN-gamma, 10(4) U per mouse) increased TNF production to 790 U/ml; this priming effect was observed just after its injection, was maximal after 2 to 6 h, and disappeared after 24 h. Other types of interferon, rIFN-alpha A/D(Bgl) (2 X 10(5) U per mouse), rIFN-beta (10(6) U per mouse), and natural IFN-alpha/beta (10(6) U per mouse) showed maximal priming activity 6 h after their injection (200 to 800 U/ml) but no effect just after their injection. Recombinant IL2 (10(6) U per mouse) had priming activity that showed a similar time course to that of interferons other than IFN-gamma (a maximal TNF production: 100 U/ml). The i.v. injection of C. parvum, like OK-432, triggered TNF production at doses of 0.06 and 0.3 mg per mouse 2 h after its injection and the triggered TNF activity was enhanced by rIFN-gamma. These findings suggest that combinations of the above endogenous BRMs as priming agents and OK-432 or C. parvum as a triggering agent could induce endogenous production of TNF even in human cancer patients. In fact, combined administration of rIFN-gamma and OK-432 produced TNF in human cancer patients. The advantage of this method for treatment of human cancer patients is discussed.
mesh_terms: D000818:Animals; D001688:Biological Products / Q000494:pharmacology*; D016207:Cytokines; D007372:Interferons / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009369:Neoplasms / Q000378:metabolism*; D010844:Picibanil / Q000494:pharmacology*; D011425:Propionibacterium acnes / Q000276:immunology*; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology
chemical_list: D001688:Biological Products; D016207:Cytokines; D007376:Interleukin-2; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D010844:Picibanil; D007372:Interferons