Activation of deoxycytidine kinase during inhibition of DNA synthesis by 2-chloro-2'-deoxyadenosine (Cladribine) in human lymphocytes.
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 microM 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.
Sasvári-Székely
M
M
Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis Medical University, Budapest, Hungary.
Spasokoukotskaja
T
T
Szóke
M
M
Csapó
Z
Z
Turi
A
A
Szántó
I
I
Eriksson
S
S
Staub
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D017338:Cladribine / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis*; D003842:Deoxycytidine Kinase / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology
D000970:Antineoplastic Agents; D017338:Cladribine; D004247:DNA; D003842:Deoxycytidine Kinase