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1-ß-D-Arabinofuranosylcytosine Nucleotide Inhibition of Sialic Acid Metabolism in WI-38 Cells¹

Department of Pharmacology and Toxicology and University of Rochester Cancer Center, University of Rochester, Rochester, New York 14642

Because cytidine nucleotides have been demonstrated to affect activity of sialyltransferases of both normal and malignant cells, we have investigated the effects of nucleotides of 1-ß-D-arabinofuranosylcytosine (ara-C) [1-ß-D-arabinofuranosylcytosine 5'-monophosphate and 1-ß-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP)] on synthesis of sialoglycoproteins. Normal human diploid fibroblasts (WI-38 cells) were used in culture at confluency, when fewer than 1% of the cells were synthesizing DNA. 1-ß-D-Arabinofuranosylcytosine 5'-monophosphate was inhibitory to both sialyltransferase activity of the intact cell and total cell homogenate transferase activity. The enzymes which synthesize and degrade the substrate of sialyltransferases, cytidine 5'-monophosphate-N-acetylneuraminic acid (CMP-AcNeu), were also tested for inhibition by nucleotides of ara-C. Synthesis of CMP-AcNeu was competitively inhibited by ara-CTP; however, formation of CMP-AcNeu when ara-CTP was supplied as substrate could not be detected. Hydrolysis of CMP-AcNeu was inhibited more severely by cytidine 5'-triphosphate than by ara-CTP or 1-ß-D-arabinofuranosylcytosine 5'-monophosphate. Confluent cultures of WI-38 cells exposed to ara-C have decreased amounts of glycoprotein sialic acid, suggesting that ara-C nucleotides may reach sufficient intracellular concentrations to affect the enzyme systems described.

¹ Supported in part by the University of Rochester Cancer Center Core Support Grant, 5-P30-CA 11198-11.

² Recipient of a Research Starter Grant from the Pharmaceutical Manufacturers Association. To whom requests for reprints should be addressed.

Received 11/ 5/79. Accepted 2/27/80.