During the initiation of cell growth there occurs an increase in the activity of ornithine decarboxylase and of the cellular polyamine content. In many cancer cells, these phenomena are exaggerated and/or ornithine decarboxylase and polyamine levels are permanently elevated. We are attempting to dissect the individual reactions that are involved in the regulation of the synthesis of polyamines and to understand their role in growth. We have found that ornithine decarboxylase of bacteria and of normal mammalian cells or of cancer cells is inhibited by low molecular weight proteins (antizymes), which although individually different, show a great degree of overlap in their properties. We now find that in the bacterial cells there may be more than one protein inhibitor (antizyme) of ornithine decarboxylase. However, these also inhibit arginine decarboxylase in bacteria, suggesting that they may control the complete pathway of polyamine biosynthesis in bacteria. We are purifying the various components of the reaction and determining their mode of interaction. We hope to be able to define the active sites of the reactants. It is anticipated that this work may lead to the development of effective noncompetitive inhibitors of ornithine decarboxylase. If such inhibitors are not competed for by ornithine, they may prove to be useful selective inhibitors of the growth of cancer cells. (B)
