Increased resistance to nitrogen mustards and antifolates following in vitro selection of murine fibroblasts and primary hematopoietic cells transduced with a bicistronic retroviral vector expressing the rat glutathione S-transferase A3 and a mutant dihydrofolate reductase
We have constructed a retroviral bicistronic vector, MFG/GID, that transduces the expression of both the A3 isoform of the rat glutathione S -transferase (GST A3), and the tyr-22 variant of the human dihydrofolate reductase (DHFR L22Y ). Transduction of murine 3T3 fibroblasts with this vector increa...
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| Veröffentlicht in: | Cancer gene therapy 2003-08, Vol.10 (8), p.637-646 |
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| creator | Belzile, Jean-Philippe Karatzas, Antonis Shiu, Hoi-Ying Létourneau, Sylvain Palerme, Jean-Sébastien Cournoyer, Denis |
| description | We have constructed a retroviral bicistronic vector, MFG/GID, that transduces the expression of both the A3 isoform of the rat glutathione
S
-transferase (GST A3), and the tyr-22 variant of the human dihydrofolate reductase (DHFR
L22Y
). Transduction of murine 3T3 fibroblasts with this vector increased their
in vitro
resistance to chlorambucil (1.8-fold) and trimetrexate (TMTX) (748-fold). TMTX selection of a mixed population of 20% GID-transduced NIH 3T3 cells and 80% control cells resulted in a marked increase in the GST peroxidase activity associated with the GST A3 isoform (17.7-fold). MFG/GID-transduced primary clonogenic murine hematopoietic progenitor cells were likewise more resistant to TMTX and chlorambucil than control
β
-gal-transduced cells. Selecting GID-transduced hematopoietic cells with a combination of TMTX and a nucleoside transport inhibitor resulted in a marked increase in resistance upon re-exposure to TMTX (99% survival). Similarly, GID-transduced hematopoietic cells selected with TMTX were more resistant to chlorambucil, with 40% survival at a drug concentration that killed practically all control cells. These results suggest that antifolate-mediated selection of MFG/GID-transduced hematopoietic cells could be used as a mean to enrich the population of transduced cells prior to or following transplantation, thus potentially conferring
in vivo
chemoprotection to nitrogen mustards and antifolates. |
| doi_str_mv | 10.1038/sj.cgt.7700619 |
| format | Article |
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S
-transferase (GST A3), and the tyr-22 variant of the human dihydrofolate reductase (DHFR
L22Y
). Transduction of murine 3T3 fibroblasts with this vector increased their
in vitro
resistance to chlorambucil (1.8-fold) and trimetrexate (TMTX) (748-fold). TMTX selection of a mixed population of 20% GID-transduced NIH 3T3 cells and 80% control cells resulted in a marked increase in the GST peroxidase activity associated with the GST A3 isoform (17.7-fold). MFG/GID-transduced primary clonogenic murine hematopoietic progenitor cells were likewise more resistant to TMTX and chlorambucil than control
β
-gal-transduced cells. Selecting GID-transduced hematopoietic cells with a combination of TMTX and a nucleoside transport inhibitor resulted in a marked increase in resistance upon re-exposure to TMTX (99% survival). Similarly, GID-transduced hematopoietic cells selected with TMTX were more resistant to chlorambucil, with 40% survival at a drug concentration that killed practically all control cells. These results suggest that antifolate-mediated selection of MFG/GID-transduced hematopoietic cells could be used as a mean to enrich the population of transduced cells prior to or following transplantation, thus potentially conferring
in vivo
chemoprotection to nitrogen mustards and antifolates.</description><identifier>ISSN: 0929-1903</identifier><identifier>EISSN: 1476-5500</identifier><identifier>DOI: 10.1038/sj.cgt.7700619</identifier><identifier>PMID: 12872145</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Animals ; Antineoplastic Agents, Alkylating - pharmacology ; Biomedical and Life Sciences ; Biomedicine ; Cancer ; Care and treatment ; Chemoprotection ; Chemotherapy ; Chlorambucil ; Complications and side effects ; Dihydrofolate reductase ; Drug Resistance ; Fibroblasts ; Fibroblasts - drug effects ; Folic Acid Antagonists - adverse effects ; Folic Acid Antagonists - pharmacology ; Gene Expression ; Gene Therapy ; Gene Transfer Techniques ; Genetic Vectors ; Glutathione transferase ; Glutathione Transferase - genetics ; Glutathione Transferase - metabolism ; Health aspects ; Hematopoietic stem cells ; Hematopoietic Stem Cells - drug effects ; Humans ; Leukemia ; Mice ; NIH 3T3 Cells ; Nitrogen Mustard Compounds - adverse effects ; Nitrogen Mustard Compounds - pharmacology ; original-article ; Peroxidase ; Progenitor cells ; Protein Isoforms - chemistry ; Rats ; Retroviridae - genetics ; Risk factors ; Tetrahydrofolate Dehydrogenase - genetics ; Tetrahydrofolate Dehydrogenase - metabolism ; Transduction, Genetic ; Transplantation</subject><ispartof>Cancer gene therapy, 2003-08, Vol.10 (8), p.637-646</ispartof><rights>Springer Nature America, Inc. 2003</rights><rights>COPYRIGHT 2003 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Aug 2003</rights><rights>Nature Publishing Group 2003.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c484t-37b903bb8bb8bebb9c64a78c45f18ab695ec66414e767b052091d20a1462233f3</citedby><cites>FETCH-LOGICAL-c484t-37b903bb8bb8bebb9c64a78c45f18ab695ec66414e767b052091d20a1462233f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/sj.cgt.7700619$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/sj.cgt.7700619$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27923,27924,41487,42556,51318</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12872145$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Belzile, Jean-Philippe</creatorcontrib><creatorcontrib>Karatzas, Antonis</creatorcontrib><creatorcontrib>Shiu, Hoi-Ying</creatorcontrib><creatorcontrib>Létourneau, Sylvain</creatorcontrib><creatorcontrib>Palerme, Jean-Sébastien</creatorcontrib><creatorcontrib>Cournoyer, Denis</creatorcontrib><title>Increased resistance to nitrogen mustards and antifolates following in vitro selection of murine fibroblasts and primary hematopoietic cells transduced with a bicistronic retroviral vector expressing the rat glutathione S-transferase A3 and a mutant dihydrofolate reductase</title><title>Cancer gene therapy</title><addtitle>Cancer Gene Ther</addtitle><addtitle>Cancer Gene Ther</addtitle><description>We have constructed a retroviral bicistronic vector, MFG/GID, that transduces the expression of both the A3 isoform of the rat glutathione
S
-transferase (GST A3), and the tyr-22 variant of the human dihydrofolate reductase (DHFR
L22Y
). Transduction of murine 3T3 fibroblasts with this vector increased their
in vitro
resistance to chlorambucil (1.8-fold) and trimetrexate (TMTX) (748-fold). TMTX selection of a mixed population of 20% GID-transduced NIH 3T3 cells and 80% control cells resulted in a marked increase in the GST peroxidase activity associated with the GST A3 isoform (17.7-fold). MFG/GID-transduced primary clonogenic murine hematopoietic progenitor cells were likewise more resistant to TMTX and chlorambucil than control
β
-gal-transduced cells. Selecting GID-transduced hematopoietic cells with a combination of TMTX and a nucleoside transport inhibitor resulted in a marked increase in resistance upon re-exposure to TMTX (99% survival). Similarly, GID-transduced hematopoietic cells selected with TMTX were more resistant to chlorambucil, with 40% survival at a drug concentration that killed practically all control cells. These results suggest that antifolate-mediated selection of MFG/GID-transduced hematopoietic cells could be used as a mean to enrich the population of transduced cells prior to or following transplantation, thus potentially conferring
in vivo
chemoprotection to nitrogen mustards and antifolates.</description><subject>Animals</subject><subject>Antineoplastic Agents, Alkylating - pharmacology</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer</subject><subject>Care and treatment</subject><subject>Chemoprotection</subject><subject>Chemotherapy</subject><subject>Chlorambucil</subject><subject>Complications and side effects</subject><subject>Dihydrofolate reductase</subject><subject>Drug Resistance</subject><subject>Fibroblasts</subject><subject>Fibroblasts - drug effects</subject><subject>Folic Acid Antagonists - adverse effects</subject><subject>Folic Acid Antagonists - pharmacology</subject><subject>Gene Expression</subject><subject>Gene Therapy</subject><subject>Gene Transfer Techniques</subject><subject>Genetic Vectors</subject><subject>Glutathione transferase</subject><subject>Glutathione Transferase - genetics</subject><subject>Glutathione Transferase - metabolism</subject><subject>Health aspects</subject><subject>Hematopoietic stem cells</subject><subject>Hematopoietic Stem Cells - drug effects</subject><subject>Humans</subject><subject>Leukemia</subject><subject>Mice</subject><subject>NIH 3T3 Cells</subject><subject>Nitrogen Mustard Compounds - adverse effects</subject><subject>Nitrogen Mustard Compounds - pharmacology</subject><subject>original-article</subject><subject>Peroxidase</subject><subject>Progenitor cells</subject><subject>Protein Isoforms - chemistry</subject><subject>Rats</subject><subject>Retroviridae - genetics</subject><subject>Risk factors</subject><subject>Tetrahydrofolate Dehydrogenase - genetics</subject><subject>Tetrahydrofolate Dehydrogenase - metabolism</subject><subject>Transduction, Genetic</subject><subject>Transplantation</subject><issn>0929-1903</issn><issn>1476-5500</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1Uk2P0zAQDQjEloUDF45oBBK3dO3EiZNjteJjpZU4AOfIcSaJq8QuttNl_z1TWqkg7SqJbNnvvXlvMknylrM1Z3l1FbZrPcS1lIyVvH6arLiQZVoUjD1LVqzO6pTXLL9IXoawZYwuZf4iueBZJTMuitWTNzdWe1QBO_AYTIjKaoTowJro3YAW5oUOfRdA2Y6-aHo3qYgBaJ3cnbEDGAv7AxwCTqijcRZcT0RvLEJvWu_aSYV4lNh5Myt_DyPOKrqdMxiNBo3TFCB6ZUO3aHJzZ-IIClqjyZR3ljAeabM3Xk2wpzLOA_7eketw8BBHBK8iDNMSVRzJA8L39K9gj54CwiY_RiBjlDJCZ8b7zrtjHBKnupFwr5LnvZoCvj6tl8nPz59-XH9Nb799ubne3KZaVCKmuWypsW1bHV5s21qXQslKi6LnlWrLukBdloILlKVsWZGxmncZU1yUWZbnfX6ZfDjq7rz7tWCIzdYt3lLJJiOeZEUhGKHeP4riUlRZwcRZalATNsb2jnLr2QTdbHiVyVIUvCDU-gEUPR3ORlO_ekPn_xE-_kMYUU1xDI76S80NDypr70Lw2Denn9xw1hzGtAnbhsa0OY0pEd6dUi3tjN0ZfppLAlwdAYGu7ID-HPsRyT9dP_k2</recordid><startdate>20030801</startdate><enddate>20030801</enddate><creator>Belzile, Jean-Philippe</creator><creator>Karatzas, Antonis</creator><creator>Shiu, Hoi-Ying</creator><creator>Létourneau, Sylvain</creator><creator>Palerme, Jean-Sébastien</creator><creator>Cournoyer, Denis</creator><general>Nature Publishing Group US</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope></search><sort><creationdate>20030801</creationdate><title>Increased resistance to nitrogen mustards and antifolates following in vitro selection of murine fibroblasts and primary hematopoietic cells transduced with a bicistronic retroviral vector expressing the rat glutathione S-transferase A3 and a mutant dihydrofolate reductase</title><author>Belzile, Jean-Philippe ; Karatzas, Antonis ; Shiu, Hoi-Ying ; Létourneau, Sylvain ; Palerme, Jean-Sébastien ; Cournoyer, Denis</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c484t-37b903bb8bb8bebb9c64a78c45f18ab695ec66414e767b052091d20a1462233f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Antineoplastic Agents, Alkylating - pharmacology</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer</topic><topic>Care and treatment</topic><topic>Chemoprotection</topic><topic>Chemotherapy</topic><topic>Chlorambucil</topic><topic>Complications and side effects</topic><topic>Dihydrofolate reductase</topic><topic>Drug Resistance</topic><topic>Fibroblasts</topic><topic>Fibroblasts - drug effects</topic><topic>Folic Acid Antagonists - adverse effects</topic><topic>Folic Acid Antagonists - pharmacology</topic><topic>Gene Expression</topic><topic>Gene Therapy</topic><topic>Gene Transfer Techniques</topic><topic>Genetic Vectors</topic><topic>Glutathione transferase</topic><topic>Glutathione Transferase - genetics</topic><topic>Glutathione Transferase - metabolism</topic><topic>Health aspects</topic><topic>Hematopoietic stem cells</topic><topic>Hematopoietic Stem Cells - drug effects</topic><topic>Humans</topic><topic>Leukemia</topic><topic>Mice</topic><topic>NIH 3T3 Cells</topic><topic>Nitrogen Mustard Compounds - adverse effects</topic><topic>Nitrogen Mustard Compounds - pharmacology</topic><topic>original-article</topic><topic>Peroxidase</topic><topic>Progenitor cells</topic><topic>Protein Isoforms - chemistry</topic><topic>Rats</topic><topic>Retroviridae - genetics</topic><topic>Risk factors</topic><topic>Tetrahydrofolate Dehydrogenase - genetics</topic><topic>Tetrahydrofolate Dehydrogenase - metabolism</topic><topic>Transduction, Genetic</topic><topic>Transplantation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Belzile, Jean-Philippe</creatorcontrib><creatorcontrib>Karatzas, Antonis</creatorcontrib><creatorcontrib>Shiu, Hoi-Ying</creatorcontrib><creatorcontrib>Létourneau, Sylvain</creatorcontrib><creatorcontrib>Palerme, Jean-Sébastien</creatorcontrib><creatorcontrib>Cournoyer, Denis</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><jtitle>Cancer gene therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Belzile, Jean-Philippe</au><au>Karatzas, Antonis</au><au>Shiu, Hoi-Ying</au><au>Létourneau, Sylvain</au><au>Palerme, Jean-Sébastien</au><au>Cournoyer, Denis</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increased resistance to nitrogen mustards and antifolates following in vitro selection of murine fibroblasts and primary hematopoietic cells transduced with a bicistronic retroviral vector expressing the rat glutathione S-transferase A3 and a mutant dihydrofolate reductase</atitle><jtitle>Cancer gene therapy</jtitle><stitle>Cancer Gene Ther</stitle><addtitle>Cancer Gene Ther</addtitle><date>2003-08-01</date><risdate>2003</risdate><volume>10</volume><issue>8</issue><spage>637</spage><epage>646</epage><pages>637-646</pages><issn>0929-1903</issn><eissn>1476-5500</eissn><abstract>We have constructed a retroviral bicistronic vector, MFG/GID, that transduces the expression of both the A3 isoform of the rat glutathione
S
-transferase (GST A3), and the tyr-22 variant of the human dihydrofolate reductase (DHFR
L22Y
). Transduction of murine 3T3 fibroblasts with this vector increased their
in vitro
resistance to chlorambucil (1.8-fold) and trimetrexate (TMTX) (748-fold). TMTX selection of a mixed population of 20% GID-transduced NIH 3T3 cells and 80% control cells resulted in a marked increase in the GST peroxidase activity associated with the GST A3 isoform (17.7-fold). MFG/GID-transduced primary clonogenic murine hematopoietic progenitor cells were likewise more resistant to TMTX and chlorambucil than control
β
-gal-transduced cells. Selecting GID-transduced hematopoietic cells with a combination of TMTX and a nucleoside transport inhibitor resulted in a marked increase in resistance upon re-exposure to TMTX (99% survival). Similarly, GID-transduced hematopoietic cells selected with TMTX were more resistant to chlorambucil, with 40% survival at a drug concentration that killed practically all control cells. These results suggest that antifolate-mediated selection of MFG/GID-transduced hematopoietic cells could be used as a mean to enrich the population of transduced cells prior to or following transplantation, thus potentially conferring
in vivo
chemoprotection to nitrogen mustards and antifolates.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>12872145</pmid><doi>10.1038/sj.cgt.7700619</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0929-1903 |
| ispartof | Cancer gene therapy, 2003-08, Vol.10 (8), p.637-646 |
| issn | 0929-1903 1476-5500 |
| language | eng |
| recordid | cdi_proquest_journals_2641705540 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; SpringerLink Journals - AutoHoldings |
| subjects | Animals Antineoplastic Agents, Alkylating - pharmacology Biomedical and Life Sciences Biomedicine Cancer Care and treatment Chemoprotection Chemotherapy Chlorambucil Complications and side effects Dihydrofolate reductase Drug Resistance Fibroblasts Fibroblasts - drug effects Folic Acid Antagonists - adverse effects Folic Acid Antagonists - pharmacology Gene Expression Gene Therapy Gene Transfer Techniques Genetic Vectors Glutathione transferase Glutathione Transferase - genetics Glutathione Transferase - metabolism Health aspects Hematopoietic stem cells Hematopoietic Stem Cells - drug effects Humans Leukemia Mice NIH 3T3 Cells Nitrogen Mustard Compounds - adverse effects Nitrogen Mustard Compounds - pharmacology original-article Peroxidase Progenitor cells Protein Isoforms - chemistry Rats Retroviridae - genetics Risk factors Tetrahydrofolate Dehydrogenase - genetics Tetrahydrofolate Dehydrogenase - metabolism Transduction, Genetic Transplantation |
| title | Increased resistance to nitrogen mustards and antifolates following in vitro selection of murine fibroblasts and primary hematopoietic cells transduced with a bicistronic retroviral vector expressing the rat glutathione S-transferase A3 and a mutant dihydrofolate reductase |
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