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Inhibition of Mammalian DNA Polymerase by the 5'-Triphosphate of 1-ß-D-Arabinofuranosylcytosine and the 5'-Triphosphate of 9-ß-D-Arabinofuranosyladenine¹

Department of Pathology and the Department of Therapeutic Research, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104

The 5'-triphosphate of 1-ß-D-arabinofuranosylcytosine (ara-CTP) was tested as a substrate or inhibitor of polynucleotide synthesis using mammalian polymerases. The compound did not replace deoxycytidine triphosphate (dCTP) as substrate for DNA polymerase and did not replace cytidine triphosphate as substrate for RNA polymerase. The compound was found to inhibit DNA synthesis catalyzed by DNA polymerase; the inhibition appeared to be competitive with dCTP. No inhibition of RNA polymerase was observed. Further studies indicate that the inhibition of mammalian DNA polymerase by the 5'-triphosphate of 9-ß-D-arabinofuranosyladenine (ara-ATP) is also competitive with the corresponding deoxytriphosphate.

The data on the mode of action of 1-ß-D-arabinofuranosylcytosine and of 9-ß-D-arabinofuranosyladenine have been summarized, and the present status of hypotheses on these mechanisms have been discussed. The data are consistent with the view that ara-CTP and ara-ATP act in animal cells via their respective triphosphates to inhibit the animal cell DNA polymerase, although ara-ATP, but not ara-CTP, may also act by inhibiting ribonucleotide reductase.

¹ This investigation was supported by USPHS Grants 7005 from the National Institute of Allergy and Infectious Disease and 10390 from the National Institute of General Medical Sciences.

² Research Career Development Awardee (GM-K3-12,888) of the USPHS.

Received 1/29/68. Accepted 6/26/68.

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