Increased efficacy and safety in the treatment of experimental liver cancer with a novel adenovirus-alphavirus hybrid vector
An improved viral vector for cancer gene therapy should be capable of infecting tumors with high efficiency, inducing specific and high-level expression of transgene in the tumor and selectively destroying tumor cells. In the design of such a vector to treat hepatocellular carcinoma, we took advanta...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2006-02, Vol.66 (3), p.1620-1629 |
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| creator | MIN GUAN RODRIGUEZ-MADOZ, Juan R ALZUGUREN, Pilar GOMAR, Celia GABRIELA KRAMER, M KOCHANEK, Stefan PRIETO, Jesus SMERDOU, Cristian CHENG QIAN |
| description | An improved viral vector for cancer gene therapy should be capable of infecting tumors with high efficiency, inducing specific and high-level expression of transgene in the tumor and selectively destroying tumor cells. In the design of such a vector to treat hepatocellular carcinoma, we took advantage of (a) the high infectivity of adenoviruses for hepatic cells, (b) the high level of protein expression and proapoptotic properties that characterize Semliki Forest virus (SFV) replicon, and (c) tumor selectivity provided by alpha-fetoprotein (AFP) promoter. We constructed a hybrid viral vector composed of a helper-dependent adenovirus containing an SFV replicon under the transcriptional control of AFP promoter and a transgene driven by SFV subgenomic promoter. Hybrid vectors containing murine interleukin-12 (mIL-12) genes or reporter gene LacZ showed very specific and high-level expression of transgenes in AFP-expressing hepatocellular carcinoma cells, both in vitro and in an in vivo hepatocellular carcinoma animal model. Infected hepatocellular carcinoma cells were selectively eliminated due to the induction of apoptosis by SFV replication. In a rat orthotopic liver tumor model, treatment of established tumors with a hybrid vector carrying mIL-12 gene resulted in strong antitumoral activity without accompanying toxicity. This new type of hybrid vectors may provide a potent and safe tool for cancer gene therapy. |
| doi_str_mv | 10.1158/0008-5472.CAN-05-0877 |
| format | Article |
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In the design of such a vector to treat hepatocellular carcinoma, we took advantage of (a) the high infectivity of adenoviruses for hepatic cells, (b) the high level of protein expression and proapoptotic properties that characterize Semliki Forest virus (SFV) replicon, and (c) tumor selectivity provided by alpha-fetoprotein (AFP) promoter. We constructed a hybrid viral vector composed of a helper-dependent adenovirus containing an SFV replicon under the transcriptional control of AFP promoter and a transgene driven by SFV subgenomic promoter. Hybrid vectors containing murine interleukin-12 (mIL-12) genes or reporter gene LacZ showed very specific and high-level expression of transgenes in AFP-expressing hepatocellular carcinoma cells, both in vitro and in an in vivo hepatocellular carcinoma animal model. Infected hepatocellular carcinoma cells were selectively eliminated due to the induction of apoptosis by SFV replication. In a rat orthotopic liver tumor model, treatment of established tumors with a hybrid vector carrying mIL-12 gene resulted in strong antitumoral activity without accompanying toxicity. This new type of hybrid vectors may provide a potent and safe tool for cancer gene therapy.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-05-0877</identifier><identifier>PMID: 16452221</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Adenoviridae - genetics ; Adenovirus ; alpha-Fetoproteins - genetics ; Alphavirus ; Animals ; Antineoplastic agents ; Biological and medical sciences ; Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - therapy ; Carcinoma, Hepatocellular - virology ; Cell Line, Tumor ; Female ; Gastroenterology. Liver. Pancreas. Abdomen ; General aspects ; Genetic Therapy - adverse effects ; Genetic Therapy - methods ; Genetic Vectors - genetics ; Humans ; Interleukin-2 - genetics ; Liver Neoplasms - genetics ; Liver Neoplasms - therapy ; Liver Neoplasms - virology ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Male ; Medical sciences ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Pharmacology. 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In the design of such a vector to treat hepatocellular carcinoma, we took advantage of (a) the high infectivity of adenoviruses for hepatic cells, (b) the high level of protein expression and proapoptotic properties that characterize Semliki Forest virus (SFV) replicon, and (c) tumor selectivity provided by alpha-fetoprotein (AFP) promoter. We constructed a hybrid viral vector composed of a helper-dependent adenovirus containing an SFV replicon under the transcriptional control of AFP promoter and a transgene driven by SFV subgenomic promoter. Hybrid vectors containing murine interleukin-12 (mIL-12) genes or reporter gene LacZ showed very specific and high-level expression of transgenes in AFP-expressing hepatocellular carcinoma cells, both in vitro and in an in vivo hepatocellular carcinoma animal model. Infected hepatocellular carcinoma cells were selectively eliminated due to the induction of apoptosis by SFV replication. 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Abdomen</subject><subject>General aspects</subject><subject>Genetic Therapy - adverse effects</subject><subject>Genetic Therapy - methods</subject><subject>Genetic Vectors - genetics</subject><subject>Humans</subject><subject>Interleukin-2 - genetics</subject><subject>Liver Neoplasms - genetics</subject><subject>Liver Neoplasms - therapy</subject><subject>Liver Neoplasms - virology</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Pharmacology. Drug treatments</subject><subject>Promoter Regions, Genetic</subject><subject>Rats</subject><subject>Rats, Inbred BUF</subject><subject>Semliki Forest virus</subject><subject>Semliki forest virus - genetics</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkEtPwzAMgCMEYmPwE0C5wK2QtE2THaeJxyQEFzhHXupoQV07kmwwiR9PyiZ28kOfbfkj5JKzW86FumOMqUyUMr-dTl4yJjKmpDwiQy4KlcmyFMdk-M8MyFkIH6kUnIlTMuBVKfI850PyM2uNRwhYU7TWGTBbCm1NA1iMW-paGhdIY0LiEttIO0vxe4Xe9RU0tHEb9NRAa1L4cnFBgbbdBhsKNabE-XXIoFkt4C-li-3cu5pu0MTOn5MTC03Ai30ckfeH-7fpU_b8-jibTp4zU5YqZhxwjDmMFTNVej0HJarUKmsji5ybueWGYSGLQppiDAxlojmzTFZg5pLbYkRudntXvvtcY4h66YLBpoEWu3XQfCwrJRlLoNiBxncheLR6lT4Fv9Wc6V677pXqXqlO2jUTutee5q72B9bzJdaHqb3nBFzvAQgGGuuTMBcOnEygKFXxCxp1jVI</recordid><startdate>20060201</startdate><enddate>20060201</enddate><creator>MIN GUAN</creator><creator>RODRIGUEZ-MADOZ, Juan R</creator><creator>ALZUGUREN, Pilar</creator><creator>GOMAR, Celia</creator><creator>GABRIELA KRAMER, M</creator><creator>KOCHANEK, Stefan</creator><creator>PRIETO, Jesus</creator><creator>SMERDOU, Cristian</creator><creator>CHENG QIAN</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><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>7QO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20060201</creationdate><title>Increased efficacy and safety in the treatment of experimental liver cancer with a novel adenovirus-alphavirus hybrid vector</title><author>MIN GUAN ; RODRIGUEZ-MADOZ, Juan R ; ALZUGUREN, Pilar ; GOMAR, Celia ; GABRIELA KRAMER, M ; KOCHANEK, Stefan ; PRIETO, Jesus ; SMERDOU, Cristian ; CHENG QIAN</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c448t-1ae9e2a980c61582a856ae94dc7321cbf1c0e37337c39a0e79e210f076acb71f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Adenoviridae - genetics</topic><topic>Adenovirus</topic><topic>alpha-Fetoproteins - genetics</topic><topic>Alphavirus</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Carcinoma, Hepatocellular - genetics</topic><topic>Carcinoma, Hepatocellular - therapy</topic><topic>Carcinoma, Hepatocellular - virology</topic><topic>Cell Line, Tumor</topic><topic>Female</topic><topic>Gastroenterology. 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Drug treatments</topic><topic>Promoter Regions, Genetic</topic><topic>Rats</topic><topic>Rats, Inbred BUF</topic><topic>Semliki Forest virus</topic><topic>Semliki forest virus - genetics</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MIN GUAN</creatorcontrib><creatorcontrib>RODRIGUEZ-MADOZ, Juan R</creatorcontrib><creatorcontrib>ALZUGUREN, Pilar</creatorcontrib><creatorcontrib>GOMAR, Celia</creatorcontrib><creatorcontrib>GABRIELA KRAMER, M</creatorcontrib><creatorcontrib>KOCHANEK, Stefan</creatorcontrib><creatorcontrib>PRIETO, Jesus</creatorcontrib><creatorcontrib>SMERDOU, Cristian</creatorcontrib><creatorcontrib>CHENG QIAN</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</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><collection>Genetics Abstracts</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MIN GUAN</au><au>RODRIGUEZ-MADOZ, Juan R</au><au>ALZUGUREN, Pilar</au><au>GOMAR, Celia</au><au>GABRIELA KRAMER, M</au><au>KOCHANEK, Stefan</au><au>PRIETO, Jesus</au><au>SMERDOU, Cristian</au><au>CHENG QIAN</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increased efficacy and safety in the treatment of experimental liver cancer with a novel adenovirus-alphavirus hybrid vector</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2006-02-01</date><risdate>2006</risdate><volume>66</volume><issue>3</issue><spage>1620</spage><epage>1629</epage><pages>1620-1629</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>An improved viral vector for cancer gene therapy should be capable of infecting tumors with high efficiency, inducing specific and high-level expression of transgene in the tumor and selectively destroying tumor cells. In the design of such a vector to treat hepatocellular carcinoma, we took advantage of (a) the high infectivity of adenoviruses for hepatic cells, (b) the high level of protein expression and proapoptotic properties that characterize Semliki Forest virus (SFV) replicon, and (c) tumor selectivity provided by alpha-fetoprotein (AFP) promoter. We constructed a hybrid viral vector composed of a helper-dependent adenovirus containing an SFV replicon under the transcriptional control of AFP promoter and a transgene driven by SFV subgenomic promoter. Hybrid vectors containing murine interleukin-12 (mIL-12) genes or reporter gene LacZ showed very specific and high-level expression of transgenes in AFP-expressing hepatocellular carcinoma cells, both in vitro and in an in vivo hepatocellular carcinoma animal model. Infected hepatocellular carcinoma cells were selectively eliminated due to the induction of apoptosis by SFV replication. 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| subjects | Adenoviridae - genetics Adenovirus alpha-Fetoproteins - genetics Alphavirus Animals Antineoplastic agents Biological and medical sciences Carcinoma, Hepatocellular - genetics Carcinoma, Hepatocellular - therapy Carcinoma, Hepatocellular - virology Cell Line, Tumor Female Gastroenterology. Liver. Pancreas. Abdomen General aspects Genetic Therapy - adverse effects Genetic Therapy - methods Genetic Vectors - genetics Humans Interleukin-2 - genetics Liver Neoplasms - genetics Liver Neoplasms - therapy Liver Neoplasms - virology Liver. Biliary tract. Portal circulation. Exocrine pancreas Male Medical sciences Mice Mice, Inbred BALB C Mice, Nude Pharmacology. Drug treatments Promoter Regions, Genetic Rats Rats, Inbred BUF Semliki Forest virus Semliki forest virus - genetics Tumors |
| title | Increased efficacy and safety in the treatment of experimental liver cancer with a novel adenovirus-alphavirus hybrid vector |
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