OXALINS AND CELL PROLIFERATION AND REGULATION

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Recent investigations in our laboratory have led to the discovery that several different oxalic acid derivatives (we propose the general term 'oxalins' to refer to these compounds) are probable animal metabolites, and that they may be involved in controlling cell proliferation, in regulating metabolism, and in possibly acting as part of the intracellular messenger system for various hormones. Direct evidence has been obtained that oxalyl thiolesters (S-oxalins) and N-oxalylcysteine are indeed animal metabolites, and that S-oxalins are probably important participants in the cell proliferation process. In fact our data suggest that S-oxalins are cell proliferatIon inhibitors. If oxalins are involved in such processes, then the significance of the proposed research to human health is evident. The work would thus be relevant to physiological processes such as the uncontrolled cell proliferation encountered in cancer and the rapid cell proliferation during the immune response. Given the devastation that cancer and immune diseases can cause to humans, it seems imperative to clarify further the role of these new metabolites (especially the S- oxalins) in the response of cells to hormones, and in the regulation of cell proliferation and metabolism. That is the broad long-term objective of the proposed research. Most of the research will be performed using bovine lymph node lymphocytes. The specific aims of the proposed research are the following: (a) develop a sensitive radioimmunoassay for S-oxalins, (b) clarify further what hormones and stimulants affect the intracellular concentrations of S-oxalins, and correlate any changes with the known metabolic effects of such stimulants (among the hormones and stimulants to be investigated are: plant lectins, phorbol esters, interleukins, calcium ionophores, prostaglandins, leukotrienes, etc.), (c) Investigate the effects on the S-oxalin concentration of specific enzyme inhibitors (or activators) that are known to affect the cellular response to the foregoing hormones and stimulants, or to interfere with their production, (d) Investigate the effects that chemical removal of S-oxalins from the cells have on processes that hormones and stimulants normally affect, or on the cellular response to hormones and stimulants, (e) Investigate the effects of added S-oxalins on cellular responses to hormones, stimulants and inhibitors, and (f) determine whether S-oxalins are inhibitors or activators of key enzymes thought to be involved in the cellular response to the hormones or stimulants listed above.