Synthesis and large production of glucocorticoid action enhancers and development of new steroid therapy.

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Establishments of large production of glucocorticoid action enhancers from enteric bacteria and of the methods of chemical synthesis of them are focused in this research. In addition we tried to improve steroid therapy by using of these modulators. We found two kinds of the enhancers of glucocorticoid actions. One is glucocorticoid sensitivity amplifier (GSA) from enteric bacteria, which enhances sensitivity for glucocorticoid actions in target cells and the chemical structure of it was determied to be pseudouridiny1-N-oleoylphosphamate. The second is glucocorticoid potency amplifiers (GPAs), such as phorbol ester, epidermal growth factor and diacylglycerols, all of which activate protein kinase C directly and/or indirectly in vivo. On the other hand, inhibitors of protein kinase C supperssed glucocorticoid actions.In the research period, we improved culture conditions of p. mirabilis, one of the enteric bacteria, which produces GSA. High concentrations of histidine in mimimal essentia … More l medium induced GSA at late exponential phase of cell Growth. We also established enzymatical synthesis of pseudouridine 5'-phosphate in large scale but there are no way to bind NH_2-terminal position of oleamide to phosphate position of pseudouridine 5'-phosphate until now. We are continuing to condensation of them.In the studies of mechanism of glucocorticoid action, we found that inhibitor of protein kinase C, such as H-7, inhibited dissociation of glucocorticoid receptor and heat shock protein in cytosol, resuting in the inhibition of translocation of glucocorticoid receptor into nuclei and in the inhibition of glucocorticoid action in hepatocytes. From these results, we speculate that protein kinase C is essential in the glucocorticoid actions and activators of proteinkinase C enhance glucocorticoid actions. On the basis of these results, we are now using GPAs and GSA in the inhibition of growth of L5178Y and L1210 lymphatic leukemia cells in mice as one of the clinical use of steroid therapy. Less