Inhibition of DNA Synthesis by 1-β-D-Arabinofuranosylcytosine: Differential Effect on Chain Initiation and Elongation in Human Lymphoblasts

Abstract

1-β-D-Arabinofuranosylcystosine (ara-c) is a potent inhibitor of DNA replication in various organisms, such as bacteria (1), DNA viruses (2) and animal cells (3). In humans, ara-c has been quite effective in the treatment of acute granulocytic leukemia (4,5). Two of the possible hypotheses for its inhibitory effect on DNA synthesis center on the replicative DNA polymerase. In the first model, the triphosphate form of ara-C inhibits competitively the utilization of deoxycytidine triphosphate during the elongation of DNA chains (6–8). In the second model, ara-CTP is incorporated into the growing DNA chain and this incorporation now prevents further chain-elongation by the polymerase (9–11). Although both of these effects have been demonstrated in vitro the mechanism of action for this drug has not been clearly established in vivo (3).