DNA Virus Inhibitory Activity of 1-β-D-Arabinofuranosylcytosine-3′,5′-cyclic Phosphate

Abstract

IT has been well established that the nucleoside analogue 1-β-D-arabinofuranosylcytosine (ara-C, arabinosylcytosine, cytarabine) has significant activity against DNA-containing viruses, in addition to its effects as an anticancer agent¹. Many studies have been aimed at the elucidation of the mechanisms by which these actions occur. Against leukaemia L-5178Y cells in culture, the inhibitory effect exerted by ara-C was due to the prevention of the conversion of cytidine nucleotides to deoxycytidine nucleotides^2,3. Inhibition of DNA synthesis by ara-C in a variety of cells was shown to occur at the level of DNA polymerization^4–7. The triphosphate of ara-C (ara-CTP) specifically inhibits⁸ DNA polymerase II, an ATP-depen-dent DNA polymerase from Escherichia coli which is responsible for DNA replication; ara-CTP does not affect the “repair” DNA polymerase I of E. coli³. Ara-C has been shown to be converted intracellularly to phosphate esters, mainly ara-CTP, in studies using sensitive tumour cells, whereas in the same study ara-C resistant cells were virtually incapable of phosphorylating the compound⁹. It thus appears certain that ara-C exerts intracellular activity through its phosphorylated derivatives.