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Titolo:
Selection of drug-resistant transduced cells with cytosine nucleoside analogs using the human cytidine deaminase gene
Autore:
Beausejour, CM; Eliopoulos, N; Momparler, L; Le, NLO; Momparler, RL;
Indirizzi:
Univ Montreal, Hop St Justine, Ctr Rech Pediat, Dept Pharmacol, Montreal, PQ H3T 1C5, Canada Univ Montreal Montreal PQ Canada H3T 1C5 ol, Montreal, PQ H3T 1C5, Canada McGill Univ, Lady Davis Inst, Montreal, PQ, Canada McGill Univ Montreal PQ Canada iv, Lady Davis Inst, Montreal, PQ, Canada
Titolo Testata:
CANCER GENE THERAPY
fascicolo: 9, volume: 8, anno: 2001,
pagine: 669 - 676
SICI:
0929-1903(200109)8:9<669:SODTCW>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
IN-VIVO SELECTION; BONE-MARROW CELLS; HEMATOPOIETIC STEM-CELLS; LONG-TERM ENGRAFTMENT; DIHYDROFOLATE-REDUCTASE; BREAST-CANCER; RETROVIRAL TRANSFER; CONFERS RESISTANCE; PERIPHERAL-BLOOD; HUMAN MDR1;
Keywords:
cytidine deaminase; cytosine arabinoside; difluorodeoxycytidine; selection; drug resistance; retroviral vector;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Momparler, RL Hop St Justine, Ctr Rech, 3175 Cote Ste Catherine, Montreal,PQ H3T 1C5, Canada Hop St Justine 3175 Cote Ste Catherine Montreal PQ Canada H3T 1C5
Citazione:
C.M. Beausejour et al., "Selection of drug-resistant transduced cells with cytosine nucleoside analogs using the human cytidine deaminase gene", CANC GENE T, 8(9), 2001, pp. 669-676

Abstract

Hematopoietic toxicity produced by most anticancer drugs limits their potential for curative therapy. We have shown previously that the human cytidine deaminase (CID) gene can confer drug resistance in murine bone marrow cells (BMCs) to the nucleoside analog, cytosine arabinoside (ARA-C). In the present study, as the first objective we showed that the CID gene can also render-drug resistance in BMCs to related analogs, 2',2'-difluorodeoxycytidine (dFdC) and 5-azadeoxycytidine (5-AZA-CdR). As a second objective, we investigated the potential of ex vivo selection with cytosine nucleoside analogs of CD-transduced BMC. The goal of this approach was to enrich the fraction of CD-transduced BMCs so as to increase the transgene expression and [eve[ of drug resistance before transplantation. This strategy may have the potential to circumvent the problem in clinical gene therapy of low level of gene transfer and adequate long-term gene expression. Using a bicistronic retroviral vector containing the CD and the green fluorescent protein (CDiGFP), we transduced murine L1210 leukemic cells. All three analogs, ARA-C, dFdC, and 5-AZA-CdR were demonstrated in vitro to enrich ( >95%) the population of leukemic cells expressing the GFP transgene. However, with CD-transduced primary murine BMCs cultivated at high cell density we observed that in vitro selection with ARA-C was riot possible due to release of CID into theculture medium at amounts that were sufficient to inactivate the analog. The CD-containing medium produced a chemoprotective effect on mock BMCs as shown by lack of significant growth inhibition in the presence of ARA-C. However, at low cell density in a cell mixture containing CD-transduced cells,the mock BMCs showed marked drug sensitivity to ARA-C as determined by clonogenic assay. Selection with ARA-C was shown to significantly increase theCID enzyme activity in transduced BMC. These results suggest that CD gene has the potential to be a good selectable marker and a possible tool for chemoprotection in cancer gene therapy.

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Documento generato il 31/05/20 alle ore 22:45:07