Relationship of deoxycytidine kinase and cytoplasmic 5'-nucleotidase to the chemotherapeutic efficacy of 2-chlorodeoxyadenosine

Abstract

Abstract The agent 2-chlorodeoxyadenosine (2-CdA) has chemotherapeutic activity in hairy cell leukemia (HCL) and in refractory chronic lymphocytic leukemia (CLL). The cytotoxic activity of 2-CdA requires the intracellular accumulation of 2-CdA nucleotides. Deoxycytidine kinase (dCK) and cytoplasmic 5′-nucleotidase (5′-NT) are the principal enzymes that phosphorylate 2-CdA and dephosphorylate 2-CdA 5′-monophosphate, respectively. The net accumulation of 2-CdA nucleotides may therefore depend on both dCK and 5′-NT. The purpose of the present experiments was to determine if there is a relationship between pretreatment levels of dCK and 5′-NT in HCL and in CLL cells, and the clinical outcome of 2- CdA treatment. As measured by a direct immunoassay for dCK in 25 CLL patients, and by a 5′-NT activity assay in 23 patients, mean dCK levels were significantly higher in 2-CdA responders than in nonresponders (P < .01), whereas mean 5′-NT levels were significantly lower in 2-CdA responders than in nonresponders (P < .05). Mean dCK levels were higher in six HCL 2-CdA responders than in one nonresponder, whereas mean 5′- NT levels were lower in the 2-CdA responders than in the nonresponder. These results suggest that both dCK and 5′-NT are determinants of 2-CdA responsiveness.