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 ch emotherapeutic agent for treatment of leukemias and lymphomas, most su ccessfully used in hairy cell leukemia and B-cell chronic lymphocytic leukemia. CdA is phosphorylated intracellularly to its monophosphate d erivative by the enzymes deoxycytidine kinase and deoxyguanosine kinas e. Cell lines deficient in deoxycytidine kinase were shown to be resis tant to CdA and a high deoxycytidine kinase level in combination with low 5'-nucleotidase has been proposed to partly explain the selectivit y in CdA toxicity for lymphoid cells. In this report biochemical prope rties in CdA phosphorylation mediated by deoxycytidine kinase and deox yguanosine kinase are reviewed and discussed in relation to the furthe r metabolism of CdA 5'-monophosphate, the different possible mechanism s of action and the correlation with clinical response. It is conclude d 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.