Potential of Ribozymes against Deoxycytidine Kinase to Confer Drug Resistance to Cytosine Nucleoside Analogs

Hematopoietic toxicity is the dose-limiting side effect produced in cancer chemotherapy with deoxycytidine nucleoside analogs. Deletion of the deoxycytidine kinase (dCK), results in a drug resistance phenotype to these analogs. An interesting gene therapy strategy to confer drug resistance to cytosi...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2000-11, Vol.278 (3), p.569-575
Main Authors: Beauséjour, Christian M., Tremblay, Guy, Momparler, Richard L.
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Clone Cells
Cytarabine - toxicity
cytosine
cytosine arabinoside
deoxycytidine kinase
Deoxycytidine Kinase - genetics
Deoxycytidine Kinase - metabolism
DNA Primers
drug resistance
Drug Resistance, Neoplasm - genetics
Gene Expression Regulation, Enzymologic
gene transfer
Leukemia L1210
Mice
Molecular Sequence Data
Nucleic Acid Conformation
nucleoside analogs
Oligodeoxyribonucleotides, Antisense
ribozyme
RNA, Catalytic - chemistry
RNA, Catalytic - genetics
RNA, Catalytic - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Transcription, Genetic - drug effects
Transfection
Tumor Cells, Cultured
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Summary:Hematopoietic toxicity is the dose-limiting side effect produced in cancer chemotherapy with deoxycytidine nucleoside analogs. Deletion of the deoxycytidine kinase (dCK), results in a drug resistance phenotype to these analogs. An interesting gene therapy strategy to confer drug resistance to cytosine nucleoside analogs would be to specifically inactivate the dCK in normal hematopoietic stem cell. In this study, we designed hammerhead ribozymes that can specifically cut and downregulate the murine dCK mRNA. Three different ribozymes were identified and shown to cleave in vitro the dCK RNA. After introduction of ribozyme cDNA into murine L1210 leukemic cells by retroviral transfer, two of the ribozymes showed some capacity in reducing dCK activity. However, analysis of transduced L1210 clones showed that the significant reduction in the dCK mRNA was not sufficient to confer drug resistance to cytosine arabinoside. Nevertheless, these results provide a new avenue of modulating the dCK enzyme activity and with improved modifications may have the potential for use in gene therapy to confer drug resistance to deoxycytidine analogs.
ISSN:0006-291X
1090-2104
DOI:10.1006/bbrc.2000.3865