INHIBITORS OF POLYAMINE BIOSYNTHESIS BLOCK TUMOR NECROSIS FACTOR-INDUCED ACTIVATION OF MACROPHAGES

The activation of polyamine biosynthesis, dependent on increased gene expression of ornithine decarboxylase, has been found to play an impor tant role in the control of cell proliferation and differentiation. In this report it has been found that accumulation of ornithine decarbox ylase MRNA also follows stimulation of human monocytes/macrophages by tumor necrosis factor. Human recombinant tumor necrosis factor (100 un its/ml) also evoked an enhanced respiratory burst of macrophages. The respiratory burst response was inhibited in a dose-dependent manner wi th difluoromethylornithine, an inhibitor of ornithine decarboxylase, a nd methylglyoxal-bis(guanylhydrazone), an inhibitor of the formation o f spermidine and spermine. The data presented in this paper suggest th at polyamines may play a functional role in tumor necrosis factor-driv en macrophage activation, and they are discussed in the context of the ir possible use as inhibitors of polyamine metabolism in tumor chemoth erapy.