Selection of genetically modified hematopoietic cells in vitro and in vivo using alkylating agent lysomustine
Efficient gene transfer into hematopoietic stem cells is vital for the success of gene therapy of hematopoietic and immune system disorders. An in vivo selection system based on a mutant form of the O 6-methylguanine-DNA-methyltransferase gene (MGMTm) is considered one of the more promising strategi...
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| Veröffentlicht in: | Analytical biochemistry 2010-09, Vol.404 (2), p.149-154 |
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| container_title | Analytical biochemistry |
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| creator | Rozov, F.N. Grinenko, T.S. Levit, G.L. Krasnov, V.P. Belyavsky, A.V. |
| description | Efficient gene transfer into hematopoietic stem cells is vital for the success of gene therapy of hematopoietic and immune system disorders. An in vivo selection system based on a mutant form of the
O
6-methylguanine-DNA-methyltransferase gene (MGMTm) is considered one of the more promising strategies for expansion of hematopoietic cells transduced with viral vectors. Here we demonstrate that MGMTm-expressing cells can be efficiently selected using lysomustine, a nitrosourea derivative of lysine. K562 and murine bone marrow cells expressing MGMTm are protected from the cytotoxic action of lysomustine in vitro. We also show in a murine model that MGMTm-transduced hematopoietic cells can be expanded in vivo on transplantation into sublethally irradiated recipients followed by lysomustine treatment. These results indicate that lysomustine can be used as a potent novel chemoselection drug applicable for gene therapy of hematopoietic and immune system disorders. |
| doi_str_mv | 10.1016/j.ab.2010.04.037 |
| format | Article |
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O
6-methylguanine-DNA-methyltransferase gene (MGMTm) is considered one of the more promising strategies for expansion of hematopoietic cells transduced with viral vectors. Here we demonstrate that MGMTm-expressing cells can be efficiently selected using lysomustine, a nitrosourea derivative of lysine. K562 and murine bone marrow cells expressing MGMTm are protected from the cytotoxic action of lysomustine in vitro. We also show in a murine model that MGMTm-transduced hematopoietic cells can be expanded in vivo on transplantation into sublethally irradiated recipients followed by lysomustine treatment. These results indicate that lysomustine can be used as a potent novel chemoselection drug applicable for gene therapy of hematopoietic and immune system disorders.</description><identifier>ISSN: 0003-2697</identifier><identifier>EISSN: 1096-0309</identifier><identifier>DOI: 10.1016/j.ab.2010.04.037</identifier><identifier>PMID: 20450874</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Alkylating Agents - chemistry ; Alkylating Agents - pharmacology ; Animals ; BCNU ; Bone Marrow Cells - metabolism ; Bone Marrow Transplantation ; Carmustine - chemistry ; Carmustine - pharmacology ; Cell Line, Tumor ; Female ; Gene therapy ; Genetic Vectors ; Hematopoiesis ; Humans ; Lentivirus - genetics ; Lysine - analogs & derivatives ; Lysine - chemistry ; Lysine - pharmacology ; Lysomustine ; Mice ; Mice, Inbred C57BL ; Nitrosourea Compounds - chemistry ; Nitrosourea Compounds - pharmacology ; O-Methylguanine-DNA Methyltransferase - genetics ; O6-Benzylguanine ; O6-Methylguanine-DNA methyltransferase ; Transfection</subject><ispartof>Analytical biochemistry, 2010-09, Vol.404 (2), p.149-154</ispartof><rights>2010 Elsevier Inc.</rights><rights>2010 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c381t-ad773783df910e272907c6cd7d9a4769f3ed7e749683d73b80b10efb889398923</citedby><cites>FETCH-LOGICAL-c381t-ad773783df910e272907c6cd7d9a4769f3ed7e749683d73b80b10efb889398923</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0003269710002897$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20450874$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rozov, F.N.</creatorcontrib><creatorcontrib>Grinenko, T.S.</creatorcontrib><creatorcontrib>Levit, G.L.</creatorcontrib><creatorcontrib>Krasnov, V.P.</creatorcontrib><creatorcontrib>Belyavsky, A.V.</creatorcontrib><title>Selection of genetically modified hematopoietic cells in vitro and in vivo using alkylating agent lysomustine</title><title>Analytical biochemistry</title><addtitle>Anal Biochem</addtitle><description>Efficient gene transfer into hematopoietic stem cells is vital for the success of gene therapy of hematopoietic and immune system disorders. An in vivo selection system based on a mutant form of the
O
6-methylguanine-DNA-methyltransferase gene (MGMTm) is considered one of the more promising strategies for expansion of hematopoietic cells transduced with viral vectors. Here we demonstrate that MGMTm-expressing cells can be efficiently selected using lysomustine, a nitrosourea derivative of lysine. K562 and murine bone marrow cells expressing MGMTm are protected from the cytotoxic action of lysomustine in vitro. We also show in a murine model that MGMTm-transduced hematopoietic cells can be expanded in vivo on transplantation into sublethally irradiated recipients followed by lysomustine treatment. These results indicate that lysomustine can be used as a potent novel chemoselection drug applicable for gene therapy of hematopoietic and immune system disorders.</description><subject>Alkylating Agents - chemistry</subject><subject>Alkylating Agents - pharmacology</subject><subject>Animals</subject><subject>BCNU</subject><subject>Bone Marrow Cells - metabolism</subject><subject>Bone Marrow Transplantation</subject><subject>Carmustine - chemistry</subject><subject>Carmustine - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Female</subject><subject>Gene therapy</subject><subject>Genetic Vectors</subject><subject>Hematopoiesis</subject><subject>Humans</subject><subject>Lentivirus - genetics</subject><subject>Lysine - analogs & derivatives</subject><subject>Lysine - chemistry</subject><subject>Lysine - pharmacology</subject><subject>Lysomustine</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Nitrosourea Compounds - chemistry</subject><subject>Nitrosourea Compounds - pharmacology</subject><subject>O-Methylguanine-DNA Methyltransferase - genetics</subject><subject>O6-Benzylguanine</subject><subject>O6-Methylguanine-DNA methyltransferase</subject><subject>Transfection</subject><issn>0003-2697</issn><issn>1096-0309</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAQhi1ERZeWOyfkG6cs49ibibmhqnxIlTjQni3HnhQvTrzEyUr773HYwg1xmq9nXo3mZey1gK0A0bzbb223raGUoLYg8RnbCNBNBRL0c7YBAFnVjcZL9jLnPYAQate8YJc1qB20qDZs-EaR3BzSyFPPH2mkOTgb44kPyYc-kOffabBzOqSwjrijGDMPIz-GeUrcjv5cHBNfchgfuY0_TtHOv9OiN_N4ymlYcunQNbvobcz06ilesYePt_c3n6u7r5--3Hy4q5xsxVxZjyixlb7XAqjGWgO6xnn02ipsdC_JI6HSTWFQdi10heu7ttVSt7qWV-ztWfcwpZ8L5dkMIa-X25HSkg3u1E6iquH_pJQaW2xWEs6km1LOE_XmMIXBTicjwKxumL2xnVndMKBMcaOsvHkSX7qB_N-FP-8vwPszQOUZx0CTyS7Q6MiHqbhifAr_Vv8FZpiaZw</recordid><startdate>20100915</startdate><enddate>20100915</enddate><creator>Rozov, F.N.</creator><creator>Grinenko, T.S.</creator><creator>Levit, G.L.</creator><creator>Krasnov, V.P.</creator><creator>Belyavsky, A.V.</creator><general>Elsevier Inc</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>7X8</scope><scope>7QO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope></search><sort><creationdate>20100915</creationdate><title>Selection of genetically modified hematopoietic cells in vitro and in vivo using alkylating agent lysomustine</title><author>Rozov, F.N. ; Grinenko, T.S. ; Levit, G.L. ; Krasnov, V.P. ; Belyavsky, A.V.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c381t-ad773783df910e272907c6cd7d9a4769f3ed7e749683d73b80b10efb889398923</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Alkylating Agents - chemistry</topic><topic>Alkylating Agents - pharmacology</topic><topic>Animals</topic><topic>BCNU</topic><topic>Bone Marrow Cells - metabolism</topic><topic>Bone Marrow Transplantation</topic><topic>Carmustine - chemistry</topic><topic>Carmustine - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Female</topic><topic>Gene therapy</topic><topic>Genetic Vectors</topic><topic>Hematopoiesis</topic><topic>Humans</topic><topic>Lentivirus - genetics</topic><topic>Lysine - analogs & derivatives</topic><topic>Lysine - chemistry</topic><topic>Lysine - pharmacology</topic><topic>Lysomustine</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Nitrosourea Compounds - chemistry</topic><topic>Nitrosourea Compounds - pharmacology</topic><topic>O-Methylguanine-DNA Methyltransferase - genetics</topic><topic>O6-Benzylguanine</topic><topic>O6-Methylguanine-DNA methyltransferase</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rozov, F.N.</creatorcontrib><creatorcontrib>Grinenko, T.S.</creatorcontrib><creatorcontrib>Levit, G.L.</creatorcontrib><creatorcontrib>Krasnov, V.P.</creatorcontrib><creatorcontrib>Belyavsky, A.V.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Analytical biochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rozov, F.N.</au><au>Grinenko, T.S.</au><au>Levit, G.L.</au><au>Krasnov, V.P.</au><au>Belyavsky, A.V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selection of genetically modified hematopoietic cells in vitro and in vivo using alkylating agent lysomustine</atitle><jtitle>Analytical biochemistry</jtitle><addtitle>Anal Biochem</addtitle><date>2010-09-15</date><risdate>2010</risdate><volume>404</volume><issue>2</issue><spage>149</spage><epage>154</epage><pages>149-154</pages><issn>0003-2697</issn><eissn>1096-0309</eissn><abstract>Efficient gene transfer into hematopoietic stem cells is vital for the success of gene therapy of hematopoietic and immune system disorders. An in vivo selection system based on a mutant form of the
O
6-methylguanine-DNA-methyltransferase gene (MGMTm) is considered one of the more promising strategies for expansion of hematopoietic cells transduced with viral vectors. Here we demonstrate that MGMTm-expressing cells can be efficiently selected using lysomustine, a nitrosourea derivative of lysine. K562 and murine bone marrow cells expressing MGMTm are protected from the cytotoxic action of lysomustine in vitro. We also show in a murine model that MGMTm-transduced hematopoietic cells can be expanded in vivo on transplantation into sublethally irradiated recipients followed by lysomustine treatment. These results indicate that lysomustine can be used as a potent novel chemoselection drug applicable for gene therapy of hematopoietic and immune system disorders.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>20450874</pmid><doi>10.1016/j.ab.2010.04.037</doi><tpages>6</tpages></addata></record> |
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| subjects | Alkylating Agents - chemistry Alkylating Agents - pharmacology Animals BCNU Bone Marrow Cells - metabolism Bone Marrow Transplantation Carmustine - chemistry Carmustine - pharmacology Cell Line, Tumor Female Gene therapy Genetic Vectors Hematopoiesis Humans Lentivirus - genetics Lysine - analogs & derivatives Lysine - chemistry Lysine - pharmacology Lysomustine Mice Mice, Inbred C57BL Nitrosourea Compounds - chemistry Nitrosourea Compounds - pharmacology O-Methylguanine-DNA Methyltransferase - genetics O6-Benzylguanine O6-Methylguanine-DNA methyltransferase Transfection |
| title | Selection of genetically modified hematopoietic cells in vitro and in vivo using alkylating agent lysomustine |
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