Gene amplification of human cytidine deaminase proviral cDNA and increased levels of its mRNA produces enhanced drug resistance to cytosine arabinoside in retroviral-transduced murine fibroblasts

Hematopoietic toxicity is one of the major problems that limits the effectiveness of many antineoplastic drugs. One approach to overcome this problem is to confer chemoresistance to the hematopoietic cells by gene transfer of drug resistance genes. Human cytidine deaminase (CD) inactivates the cytos...

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Bibliographic Details
Published in:Cancer letters 1999-01, Vol.135 (1), p.29-36
Main Authors: BEAUSEJOUR, C. M, MOMPARLER, R. L
Format: Article
Language:English
Subjects:
3T3 Cells - enzymology
3T3 Cells - virology
Animals
Antineoplastic agents
Biological and medical sciences
Cytarabine - pharmacology
Cytidine Deaminase - biosynthesis
Cytidine Deaminase - genetics
Drug Resistance
Gene Amplification - genetics
General aspects
Humans
Medical sciences
Mice
Pharmacology. Drug treatments
Proviruses - enzymology
Proviruses - genetics
Retroviridae - genetics
RNA, Messenger - biosynthesis
Transduction, Genetic
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Summary:Hematopoietic toxicity is one of the major problems that limits the effectiveness of many antineoplastic drugs. One approach to overcome this problem is to confer chemoresistance to the hematopoietic cells by gene transfer of drug resistance genes. Human cytidine deaminase (CD) inactivates the cytosine nucleoside analogues, such as cytosine arabinoside (ARA-C), by deamination. We have reported previously that retroviral-mediated gene transfer of CD conferred drug resistance to ARA-C in murine cells. One of the major problems in the use of these vectors is to obtain adequate and prolonged expression of the transferred gene to produce a therapeutic effect in the transduced cells. The objective of this investigation was to determine if it is possible to increase the expression of CD proviral DNA in transduced murine fibroblast cells. We observed that by the use of continuous exposure to increasing concentrations of ARA-C it was possible to enhance drug resistance in the transduced cells. This drug resistance was found to be associated with increases in CD enzyme activity and CD proviral mRNA and by amplification of the proviral CD gene.
ISSN:0304-3835
1872-7980