Activation of deoxycytidine kinase during inhibition of DNA synthesis by 2-chloro-2′-deoxyadenosine (cladribine) in human lymphocytes

Abstract

Deoxycytidine kinase (dCK, EC.2.7.1.74), a key enzyme in intracellular metabolism of many antileukemic drugs, was shown to be activated during treatment of lymphocytes by 2-chloro-2′-deoxyadenosine (Cl-dAdo, cladribine), a potent inhibitor of DNA synthesis. While 5-[ 3H]-thymidine (TdR) incorporation into DNA was decreased by 80–90%, dCK activity was doubled as a consequence of incubating the cells with 1 μM 2-chloro-2′-deoxyadenosine. Thymidine kinase (dTK, EC.2.7.1.21) activity was slightly decreased under the same conditions, similarly to 5-[ 3H]-thymidine incorporation. dCK activation could not be prevented by cycloheximide, and neither the amount of dCK protein nor its mRNA level was increased after 2-chloro-2′-deoxyadenosine treatment. These results suggest a post-translational activation of dCK protein during inhibition of DNA synthesis.