Studies on the mechanism of action of cytosine arabinoside.

We have demonstrated that Ara-C incorporates in leukemic cell DNA and that the extent of this incorporation correlates significantly with loss of clonogenic survival. This relationship between formation of (Ara-C)DNA and cytotoxicity is also obtained in the presence of modulating agents such as thymidine. Further, the (Ara-C)DNA is structurally abnormal and undergoes strand scission upon exposure to alkali. We have also demonstrated that the incorporated Ara-C residue serves as a poor primer terminus for further chain elongation and thereby results in inhibition of DNA synthesis. These findings provide new insights into the mechanism of action of the most effective agent in the treatment of acute myelogenous leukemia. These findings have also been extended to demonstrate that Ara-C results in the induction of leukemic cell differentiation as well as lethal cellular events.