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Study of the efficacy of a pronucleotide of 2-chloro-2'-deoxyadenosine in deoxycytidine kinase-deficient lymphoma cells.

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Bontemps, Françoise [UCL] Meier, C Delacauw, A Balzarini, Jan [KUL] Galmarini, C Van Den Neste, Eric [UCL]

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.

Document type Article de périodique (Journal article) – Journal Article, Research Support, Non-U.S. Gov't
Access type Accès restreint
Publication date 2006
Journal information "Nucleosides, nucleotides & nucleic acids" - Vol. 25, no. 9-11, p. 997-1000 (2006)
Peer reviewed yes
issn 1525-7770
Publication status Publié
Affiliations UCL - MD/MINT - Département de médecine interne
UCL - MD/BICL - Département de biochimie et de biologie cellulaire
UCL - MD/FSIO - Département de physiologie et pharmacologie
UCL - (SLuc) Service d'hématologie
MESH Subject Cell Line, Tumor ; Cell Survival ; Cladribine - pharmacology ; Cyclic AMP - metabolism ; Deoxycytidine Kinase - genetics - physiology ; Diffusion ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm ; Humans ; Hydrolysis ; Lymphoma - drug therapy - enzymology - genetics ; Models, Chemical ; Nucleotides - pharmacology ; Phosphorylation
Links
  1. Van Den Neste E, Int. J. Oncol., 27, 1113 (2005)
  2. Galmarini C M, Mackey J R, Dumontet C, Nucleoside analogues: mechanisms of drug resistance and reversal strategies, 10.1038/sj.leu.2402114
  3. Wagner Carston R., Iyer Vidhya V., McIntee Edward J., Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides, 10.1002/1098-1128(200011)20:6<417::aid-med1>3.0.co;2-z
  4. Meier Chris, Cyclosal-pronucleotides - development of first and second generation chemical trojan horses for antiviral chemotherapy, 10.2741/1283
  5. Galmarini Carlos Mar�a, Clarke Marilyn L., Santos Cheryl L., Jordheim Lars, Perigaud Christian, Gosselin Gilles, Cros Emeline, Mackey John R., Dumontet Charles, Sensitization of ara-C-resistant lymphoma cells by a pronucleotide analogue, 10.1002/ijc.11339
Bibliographic reference Bontemps, Françoise ; Meier, C ; Delacauw, A ; Balzarini, Jan ; Galmarini, C ; et. al. Study of the efficacy of a pronucleotide of 2-chloro-2'-deoxyadenosine in deoxycytidine kinase-deficient lymphoma cells.. In: Nucleosides, nucleotides & nucleic acids, Vol. 25, no. 9-11, p. 997-1000 (2006)
Permanent URL http://hdl.handle.net/2078.1/29457