Inhibition of deoxyribonucleic acid chain initiation: a new mode of action for 1-β-D-arabinofuranosylcytosine in human lymphoblasts

Abstract

A novel biochemical effect of 1-.beta.-D-arabinofuranosylcytosine (ara-C) on DNA replication in cultured human lymphoblasts is described. By incubating the cells with [3H]thymidine for 5 min and analyzing the nascent DNA by velocity sedimentation in alkaline sucrose gradients, it was possible to discern the initial effect of a very low concentration of drug (5 nM) on DNA replication. During the first 30 min of incubation, ara-C inhibited the initiation of new replicating units of DNA but did not affect the elongation of previously initiated units. A later effect was the reduction of the rate of DNA chain elongation. A model, based on the incorporation of ara-C into nascent DNA, is presented to account for a differential effect of the drug on DNA chain initiation and elongation in mammalian cells.