The effects of 1-µ-d-arabinofuranosylcytosine (ara-C) on the reduction of cytidine diphosphate (CDP) to deoxycytidine diphosphate (dCDP) and on the syntheses of RNA and DNA were studied in vitro with whole cells of human leukemic leukocytes. Uridine-3H was used as a radioactive precursor, and the results were compared with those of hydroxyurea. ara-C (20 µm) and hydroxyurea (0.01 m) inhibited DNA synthesis approximately 70% and 80% respectively without any inhibition of RNA synthesis. Under the same conditions, however, the levels of deoxycytidine phosphate-3H as well as cytidine phosphate-3H in the acid-soluble fraction, were not affected significantly by ara-C. In sharp contrast with ara-C, hydroxyurea markedly decreased the level of deoxycytidine phosphate-3H in the acid-soluble fraction without any effects on the level of cytidine phosphate-3H. These results suggest that the primary site of action of ara-C might not be at the level of reduction of CDP to dCDP in human leukemic leukocytes. Another site of action was therefore investigated, and it was shown that ara-C inhibited, to some extent, activities of crude DNA polymerases from both human leukemic leukocytes and Ehrlich ascites tumor cells. The 5′-triphosphate of ara-C showed marked inhibition of crude and partially purified DNA polymerases from Ehrlich ascites tumor cells.
This work was supported in part by a grant from the Ministry of Education of Japan.