Study of the efficacy of a pronucleotide of 2-chloro-2'-deoxyadenosine in deoxycytidine kinase-deficient lymphoma cells.
2-Chloro-2 '-deoxyadenosine (CdA, cladribine) is a nucleoside analogue (NA) used for the treatment of lymphoproliferative disorders. Phosphorylation of the drug to CdAMP by deoxycytidine kinase (dCK) and its subsequent conversion to CdATP is essential for its efficacy. DCK deficiency is a common mechanism of resistance to NA, which could be overcome by the pronucleotide approach. The latter consists of using the nucleoside monophosphate conjugated to a lipophilic group enabling CdAMP to enter the cells by passive diffusion. In this study, we show that cycloSaligenyl-2-chloro-2 '-deoxyadenosine monophosphate (cycloSal-CdAMP) is 10-fold more potent that CdA in a dCK-deficient lymphoma cell line. These results suggest that the use of cycloSal-nucleotides could be a strategy to counteract resistance caused by dCK deficiency.
Bontemps
F
F
Laboratory of Physiological Chemistry, ICP and UCL, Brussels, Belgium. bontemps@bchm.ucl.ac.be
Meier
C
C
Delacauw
A
A
Balzarini
J
J
Galmarini
C
C
van den Neste
E
E
D045744:Cell Line, Tumor; D002470:Cell Survival; D017338:Cladribine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D003842:Deoxycytidine Kinase / Q000235:genetics* / Q000502:physiology*; D004058:Diffusion; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006868:Hydrolysis; D008223:Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D008956:Models, Chemical; D009711:Nucleotides / Q000494:pharmacology*; D010766:Phosphorylation
D009711:Nucleotides; D017338:Cladribine; D000242:Cyclic AMP; D003842:Deoxycytidine Kinase