A novel dual function retrovirus expressing multidrug resistance 1 and O6-alkylguanine-DNA-alkyltransferase for engineering resistance of haemopoietic progenitor cells to multiple chemotherapeutic agents.

2.50
Hdl Handle:
http://hdl.handle.net/10541/91413
Title:
A novel dual function retrovirus expressing multidrug resistance 1 and O6-alkylguanine-DNA-alkyltransferase for engineering resistance of haemopoietic progenitor cells to multiple chemotherapeutic agents.
Authors:
Jelinek, J; Rafferty, Joseph A; Cmejla, R; Hildinger, M; Chinnasamy, Dhanalakshmi; Lashford, Linda S; Ostertag, W; Margison, Geoffrey P; Dexter, T Michael; Fairbairn, Leslie J; Baum, Christopher
Abstract:
Following transduction with a retrovirus (SF1MIH) expressing both the multidrug resistance 1 (MDR1) and O6-alkylguanine-DNA-alkyltransferase (ATase) proteins, human erythroleukaemic progenitor (K562) cells were isolated which were resistant to killing by the MDR1 substrate, colchicine. In colony-forming survival assays, K562-SF1MIH cells exhibited resistance to colchicine and doxorubicin, as well as to the O6-alkylating agents N-Methyl-N-nitrosourea (MNU) and temozolomide. Furthermore, the resistance to doxorubicin was abolished by preincubation with the MDR1 inhibitor verapamil while resistance to MNU was ablated by the specific ATase inactivator, O6-benzylguanine (O6-beG) confirming that resistance to doxorubicin and MNU was conferred by MDR1 and ATase, respectively. When K562-SF1MIH were exposed to combinations of colchicine and MNU or doxorubicin and temozolomide, simultaneous resistance to these agents was observed. Thus, transduction of K562 with SF1MIH conferred dual resistance to these cells. These data offer the prospect of designing vectors that will confer resistance to entire regimens of chemotherapy rather than just to individual components of such drug cocktails, thereby substantially increasing the efficacy of therapy. Furthermore, the use of such dual expression constructs is likely to be highly informative for the design of effective in vivo selection protocols, an issue likely to make a major impact in a clinical context in gene therapy in the near future.
Affiliation:
Institute of Haematology and Blood Transfusion, Praha, Czech Republic.
Citation:
A novel dual function retrovirus expressing multidrug resistance 1 and O6-alkylguanine-DNA-alkyltransferase for engineering resistance of haemopoietic progenitor cells to multiple chemotherapeutic agents. 1999, 6 (8):1489-93 Gene Ther.
Journal:
Gene Therapy
Issue Date:
Aug-1999
URI:
http://hdl.handle.net/10541/91413
DOI:
10.1038/sj.gt.3300962
PubMed ID:
10467374
Type:
Article
Language:
en
ISSN:
0969-7128
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorJelinek, Jen
dc.contributor.authorRafferty, Joseph Aen
dc.contributor.authorCmejla, Ren
dc.contributor.authorHildinger, Men
dc.contributor.authorChinnasamy, Dhanalakshmien
dc.contributor.authorLashford, Linda Sen
dc.contributor.authorOstertag, Wen
dc.contributor.authorMargison, Geoffrey Pen
dc.contributor.authorDexter, T Michaelen
dc.contributor.authorFairbairn, Leslie Jen
dc.contributor.authorBaum, Christopheren
dc.date.accessioned2010-02-08T15:29:25Z-
dc.date.available2010-02-08T15:29:25Z-
dc.date.issued1999-08-
dc.identifier.citationA novel dual function retrovirus expressing multidrug resistance 1 and O6-alkylguanine-DNA-alkyltransferase for engineering resistance of haemopoietic progenitor cells to multiple chemotherapeutic agents. 1999, 6 (8):1489-93 Gene Ther.en
dc.identifier.issn0969-7128-
dc.identifier.pmid10467374-
dc.identifier.doi10.1038/sj.gt.3300962-
dc.identifier.urihttp://hdl.handle.net/10541/91413-
dc.description.abstractFollowing transduction with a retrovirus (SF1MIH) expressing both the multidrug resistance 1 (MDR1) and O6-alkylguanine-DNA-alkyltransferase (ATase) proteins, human erythroleukaemic progenitor (K562) cells were isolated which were resistant to killing by the MDR1 substrate, colchicine. In colony-forming survival assays, K562-SF1MIH cells exhibited resistance to colchicine and doxorubicin, as well as to the O6-alkylating agents N-Methyl-N-nitrosourea (MNU) and temozolomide. Furthermore, the resistance to doxorubicin was abolished by preincubation with the MDR1 inhibitor verapamil while resistance to MNU was ablated by the specific ATase inactivator, O6-benzylguanine (O6-beG) confirming that resistance to doxorubicin and MNU was conferred by MDR1 and ATase, respectively. When K562-SF1MIH were exposed to combinations of colchicine and MNU or doxorubicin and temozolomide, simultaneous resistance to these agents was observed. Thus, transduction of K562 with SF1MIH conferred dual resistance to these cells. These data offer the prospect of designing vectors that will confer resistance to entire regimens of chemotherapy rather than just to individual components of such drug cocktails, thereby substantially increasing the efficacy of therapy. Furthermore, the use of such dual expression constructs is likely to be highly informative for the design of effective in vivo selection protocols, an issue likely to make a major impact in a clinical context in gene therapy in the near future.en
dc.language.isoenen
dc.subjectCancer Drug Resistanceen
dc.subjectHaematopoietic Stem Cellsen
dc.subject.meshAntineoplastic Agents-
dc.subject.meshDrug Resistance, Multiple-
dc.subject.meshDrug Resistance, Neoplasm-
dc.subject.meshGenes, MDR-
dc.subject.meshGenetic Vectors-
dc.subject.meshHematopoietic Stem Cells-
dc.subject.meshHumans-
dc.subject.meshK562 Cells-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.subject.meshRetroviridae-
dc.subject.meshTransduction, Genetic-
dc.titleA novel dual function retrovirus expressing multidrug resistance 1 and O6-alkylguanine-DNA-alkyltransferase for engineering resistance of haemopoietic progenitor cells to multiple chemotherapeutic agents.en
dc.typeArticleen
dc.contributor.departmentInstitute of Haematology and Blood Transfusion, Praha, Czech Republic.en
dc.identifier.journalGene Therapyen
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