Relationship of deoxycytidine kinase and cytoplasmic 5'-nucleotidase to the chemotherapeutic efficacy of 2-chlorodeoxyadenosine.
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.
Kawasaki
H
H
Department of Medicine, University of California San Diego, La Jolla 92093-0663.
Carrera
C J
CJ
Piro
L D
LD
Saven
A
A
Kipps
T J
TJ
Carson
D A
DA
D015720:5'-Nucleotidase / Q000097:blood / Q000378:metabolism*; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D017338:Cladribine; D003593:Cytoplasm / Q000201:enzymology; D003842:Deoxycytidine Kinase / Q000097:blood / Q000378:metabolism*; D005189:False Positive Reactions; D005260:Female; D006801:Humans; D007943:Leukemia, Hairy Cell / Q000145:classification / Q000188:drug therapy* / Q000201:enzymology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D017338:Cladribine; D003842:Deoxycytidine Kinase; D015720:5'-Nucleotidase