Molecular Pharmacology, Vol 4, 131-138, Copyright © 1968 by the American Society for Pharmacology and Experimental Therapeutics

Effect of 1,--D-Arabinofuranosylcytosine on DNA Synthesis

I. In Normal Rabbit Kidney Cell Cultures

¹ Department of Microbiology, Research Laboratories, Albert Einstein Medical Center, Philadelphia, Pennsylvania 19141

Low concentrations of 1--D-arabinofuranosylcytosine (Ara-C) inhibit the incorporation of cytidine aimd thymidine but stimulate the incorporation of deoxycytidine into the DNA of rabbit kidney cells. This stimulation is correlated with an increase in the level of activity of deoxycytidine kinase and with a consequent increase in the intracellular pool of phosphorylated deoxycytidine derived from the nucleoside in the medium.

Ara-C does not prevent the reduction of cytidine diphosphate to deoxycytidine diphosphate in rabbit kidney cells incubated in medium free of deoxycytidine. However, when small amounts of deoxycytidine are supplied to these cells, the drug is effective in inhibiting this reduction, probably as a result of an increase in the intracellular pool of deoxycytidine triphosphate and an ensuing negative feedback inhibition.

In agreement with observations made with other systems, in rabbit kidney cells the inhibition of DNA synthesis by the drug can be overcome by deoxycytidine. This reversal is due primarily to a successful competition of deoxycytidine with Ara-C at the level of phosphorylation, thereby preventing the accumulation of the effective inhibitor of DNA synthesis.

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ACKNOWLEDGMENTS This investigation was supported by grants from the National Institutes of Health (AI-03362) and from the National Science Foundation (GB-4995), and by a U.S. Public Health Research Career Program Award (5-K3-AI-19,335) from the National Institute of Allergy and Infectious Diseases.