PTERIDINE METABOLISM AND TRANSPORT IN MALIGNANT CELLS

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Clinical observations have linked altered pteridine metabolism and enhanced excretion of pteridines to diseases, which include malignancies, viral infections, generalized activation of the cellular immune system, and AIDS. In order to help understand these observations, this proposal seeks to investigate certain areas of pteridine biochemistry in human cell systems. In particular, it is intended to determine the pteridine content of cell extracts and culture media; to investigate the properties of the transport system which controls the influx and efflux of these derivatives; and to determine the relative roles played by dihydropteridine and dihydrofolate reductases in controlling pteridine metabolism. The investigations will be carried out using human lymphocytes and a variety of malignant cell lines of human origin including CEM, WIL2, HL60, and K562. The enzyme studies will employ the isolated proteins from rat liver and human sources. Of particular importance will be the identification of pteridines subject to modulated excretion. Radioactively labelled pteridines and folates will be employed to establish the origin of the secreted compounds since intermediates of both pteridine biosynthesis or folate degradation could be involved. The properties of the pteridine transport system will illustrate whether these provide a clearer picture of whether the pteridine excretion products of certain cell systems might be of regulatory significance by uptake or surface binding to other cell types. By these means, it is intended to expand the understanding of pteridine function in human cell systems and, thereby, determine whether previously documented clinical observations can be exploited either diagnostically or therapeutically. (A)