ACTIVATION OF DEOXYCYTIDINE KINASE DURING INHIBITION OF DNA-SYNTHESISBY 2-CHLORO-2'-DEOXYADENOSINE (CLADRIBINE) IN HUMAN-LYMPHOCYTES

Deoxycytidine kinase (dCK, EC.2.1.1.74), a key enzyme in intracellular metabolism of many antileukemic drugs, was shown to be activated duri ng treatment: of lymphocytes by 2-chloro-2'-deoxyadenosine (Cl-dAdo, c ladribine), a potent inhibitor of DNA synthesis. While 5-[H-3]-thymidi ne (TdR) incorporation into DNA was decreased by 80-90%, dCK activity was doubled as a consequence of incubating the cells with 1 mu M 2-chl oro-2'-deoxyadenosine. Thymidine kinase (dTK, EC.2.7.1.21) activity wa s slightly decreased under the same conditions, similarly to 5-[H-3] t hymidine incorporation, dCK activation could not be prevented by cyclo heximide, and neither the amount of dCK protein nor its mRNA level was increased after 2-chloro-2'-deoxyadenosine treatment. These results s uggest a post-translational activation of dCK protein during inhibitio n of DNA synthesis. (C) 1998 Elsevier Science Inc.