On the phosphorylation of 2-chlorodeoxyadenosine (CdA) and its correlation with clinical response in leukemia treatment.
The nucleoside analog 2-chlorodeoxyadenosine (CdA, Cladribine) is a chemotherapeutic agent for treatment of leukemias and lymphomas, most successfully used in hairy cell leukemia and B-cell chronic lymphocytic leukemia. CdA is phosphorylated intracellularly to its monophosphate derivative by the enzymes deoxycytidine kinase and deoxyguanosine kinase. Cell lines deficient in deoxycytidine kinase were shown to be resistant to CdA and a high deoxycytidine kinase level in combination with low 5'-nucleotidase has been proposed to partly explain the selectivity in CdA toxicity for lymphoid cells. In this report biochemical properties in CdA phosphorylation mediated by deoxycytidine kinase and deoxyguanosine kinase are reviewed and discussed in relation to the further metabolism of CdA 5'-monophosphate, the different possible mechanisms of action and the correlation with clinical response. It is concluded that much is known about the metabolism and mechanisms of action of CdA, but that the remarkable therapeutic effect in hairy cell leukemia has yet to be explicitly explained.
Arnér
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Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D017338:Cladribine / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism*; D010766:Phosphorylation
D000970:Antineoplastic Agents; D017338:Cladribine