Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization
Replication-competent adenoviruses may provide a highly efficient means of delivering therapeutic genes to tumors. Previously, we evaluated in vitro a replication-competent adenovirus (Ad5-CD/TKrep) containing a cytosine deaminase (CD)/herpes simplex type 1 thymidine kinase (HSV-1 TK) fusion gene th...
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| Veröffentlicht in: | Human gene therapy 2000, Vol.11 (1), p.67-76 |
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| creator | ROGULSKI, K. R WING, M. S PAIELLI, D. L GILBERT, J. D JAE HO KIM FREYTAG, S. O |
| description | Replication-competent adenoviruses may provide a highly efficient means of delivering therapeutic genes to tumors. Previously, we evaluated in vitro a replication-competent adenovirus (Ad5-CD/TKrep) containing a cytosine deaminase (CD)/herpes simplex type 1 thymidine kinase (HSV-1 TK) fusion gene that allows lytic viral therapy to be combined with double suicide gene therapy. Both the CD/5-FC and HSV-1 TK/GCV enzyme/prodrug systems enhanced the tumor cell-specific cytopathic effects of the Ad5-CD/TKrep virus in vitro and sensitized cells to radiation. To extend these in vitro findings in vivo, we evaluated the antitumor activity of the Ad5-CD/TKrep virus in combination with double prodrug therapy and radiation therapy. The Ad5-CD/TKrep virus independently demonstrated significant antitumor activity against C33A cervical carcinoma xenografts. Therapeutic outcome was dramatically improved with systemic administration of double, but not single, prodrug (5-FC + GCV) therapy. When used in a neoadjuvant setting, Ad5-CD/TKrep-mediated double suicide gene therapy dramatically potentiated the effectiveness of radiation therapy. The trimodal approach of Ad5-CD/TKrep viral, double suicide gene, and radiotherapies produced significant tumor regression and ultimately 100% tumor cure. The results demonstrate the high therapeutic potential of the trimodal approach and provide a solid foundation for future clinical trials. |
| doi_str_mv | 10.1089/10430340050016166 |
| format | Article |
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R ; WING, M. S ; PAIELLI, D. L ; GILBERT, J. D ; JAE HO KIM ; FREYTAG, S. O</creator><creatorcontrib>ROGULSKI, K. R ; WING, M. S ; PAIELLI, D. L ; GILBERT, J. D ; JAE HO KIM ; FREYTAG, S. O</creatorcontrib><description>Replication-competent adenoviruses may provide a highly efficient means of delivering therapeutic genes to tumors. Previously, we evaluated in vitro a replication-competent adenovirus (Ad5-CD/TKrep) containing a cytosine deaminase (CD)/herpes simplex type 1 thymidine kinase (HSV-1 TK) fusion gene that allows lytic viral therapy to be combined with double suicide gene therapy. Both the CD/5-FC and HSV-1 TK/GCV enzyme/prodrug systems enhanced the tumor cell-specific cytopathic effects of the Ad5-CD/TKrep virus in vitro and sensitized cells to radiation. To extend these in vitro findings in vivo, we evaluated the antitumor activity of the Ad5-CD/TKrep virus in combination with double prodrug therapy and radiation therapy. The Ad5-CD/TKrep virus independently demonstrated significant antitumor activity against C33A cervical carcinoma xenografts. Therapeutic outcome was dramatically improved with systemic administration of double, but not single, prodrug (5-FC + GCV) therapy. When used in a neoadjuvant setting, Ad5-CD/TKrep-mediated double suicide gene therapy dramatically potentiated the effectiveness of radiation therapy. The trimodal approach of Ad5-CD/TKrep viral, double suicide gene, and radiotherapies produced significant tumor regression and ultimately 100% tumor cure. The results demonstrate the high therapeutic potential of the trimodal approach and provide a solid foundation for future clinical trials.</description><identifier>ISSN: 1043-0342</identifier><identifier>EISSN: 1557-7422</identifier><identifier>DOI: 10.1089/10430340050016166</identifier><identifier>PMID: 10646640</identifier><identifier>CODEN: HGTHE3</identifier><language>eng</language><publisher>Larchmont, NY: Liebert</publisher><subject>Adenoviridae - enzymology ; Adenoviridae - genetics ; Adenoviridae - physiology ; Adenovirus ; Animals ; Artificial Gene Fusion ; Biological and medical sciences ; Biotechnology ; Cell Survival ; Combined Modality Therapy ; Cytosine Deaminase ; Female ; Fundamental and applied biological sciences. Psychology ; Gene therapy ; Genetic Therapy ; Genetic Vectors ; Health. Pharmaceutical industry ; herpes simplex 1 ; Herpesvirus 1, Human - enzymology ; Industrial applications and implications. Economical aspects ; Injections, Intralesional ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Neoplasms, Experimental - radiotherapy ; Neoplasms, Experimental - therapy ; Nucleoside Deaminases - genetics ; Radiation Tolerance ; Thymidine Kinase - genetics ; Virus Replication</subject><ispartof>Human gene therapy, 2000, Vol.11 (1), p.67-76</ispartof><rights>2000 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c423t-f91089704e9cddc99db65745df59f17b976e186623eb116763d9ecd26ffa7a703</citedby><cites>FETCH-LOGICAL-c423t-f91089704e9cddc99db65745df59f17b976e186623eb116763d9ecd26ffa7a703</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3042,4024,27923,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1250514$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10646640$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>ROGULSKI, K. R</creatorcontrib><creatorcontrib>WING, M. S</creatorcontrib><creatorcontrib>PAIELLI, D. L</creatorcontrib><creatorcontrib>GILBERT, J. D</creatorcontrib><creatorcontrib>JAE HO KIM</creatorcontrib><creatorcontrib>FREYTAG, S. O</creatorcontrib><title>Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization</title><title>Human gene therapy</title><addtitle>Hum Gene Ther</addtitle><description>Replication-competent adenoviruses may provide a highly efficient means of delivering therapeutic genes to tumors. Previously, we evaluated in vitro a replication-competent adenovirus (Ad5-CD/TKrep) containing a cytosine deaminase (CD)/herpes simplex type 1 thymidine kinase (HSV-1 TK) fusion gene that allows lytic viral therapy to be combined with double suicide gene therapy. Both the CD/5-FC and HSV-1 TK/GCV enzyme/prodrug systems enhanced the tumor cell-specific cytopathic effects of the Ad5-CD/TKrep virus in vitro and sensitized cells to radiation. To extend these in vitro findings in vivo, we evaluated the antitumor activity of the Ad5-CD/TKrep virus in combination with double prodrug therapy and radiation therapy. The Ad5-CD/TKrep virus independently demonstrated significant antitumor activity against C33A cervical carcinoma xenografts. Therapeutic outcome was dramatically improved with systemic administration of double, but not single, prodrug (5-FC + GCV) therapy. When used in a neoadjuvant setting, Ad5-CD/TKrep-mediated double suicide gene therapy dramatically potentiated the effectiveness of radiation therapy. The trimodal approach of Ad5-CD/TKrep viral, double suicide gene, and radiotherapies produced significant tumor regression and ultimately 100% tumor cure. The results demonstrate the high therapeutic potential of the trimodal approach and provide a solid foundation for future clinical trials.</description><subject>Adenoviridae - enzymology</subject><subject>Adenoviridae - genetics</subject><subject>Adenoviridae - physiology</subject><subject>Adenovirus</subject><subject>Animals</subject><subject>Artificial Gene Fusion</subject><subject>Biological and medical sciences</subject><subject>Biotechnology</subject><subject>Cell Survival</subject><subject>Combined Modality Therapy</subject><subject>Cytosine Deaminase</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene therapy</subject><subject>Genetic Therapy</subject><subject>Genetic Vectors</subject><subject>Health. Pharmaceutical industry</subject><subject>herpes simplex 1</subject><subject>Herpesvirus 1, Human - enzymology</subject><subject>Industrial applications and implications. Economical aspects</subject><subject>Injections, Intralesional</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Neoplasm Transplantation</subject><subject>Neoplasms, Experimental - radiotherapy</subject><subject>Neoplasms, Experimental - therapy</subject><subject>Nucleoside Deaminases - genetics</subject><subject>Radiation Tolerance</subject><subject>Thymidine Kinase - genetics</subject><subject>Virus Replication</subject><issn>1043-0342</issn><issn>1557-7422</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcmO1DAQhi0EYhZ4AC7IB8QtYCdekiMaVmmkucycI8cudxsldvAymvAsPOy46ZZA4sDJlv39X5WqEHpFyTtK-uE9JawjHSOEE0IFFeIJOqecy0aytn1a7_W_qUB7hi5S-l6hjgv5HJ1RIpgQjJyjXx9DmWbAqTjtDOAdeMB5D1GtG1Zlt4DP6fCAlc8ulyVErHR29y5vOFiscIR1dlplF3yjw7JCrhE8b9lprAz4cO9iOShiKLs9Br9XXoPBesshh4datpqUNzgq40ICn1x2P3_7XqBnVs0JXp7OS3T3-dPt1dfm-ubLt6sP141mbZcbOxymIQmDQRujh8FMgkvGjeWDpXIapADaC9F2MFEqpOjMANq0wlollSTdJXp79K4x_CiQ8ri4pGGelYdQ0ihJL_ueif-CVDLRMtZXkB5BHUNKEey4RreouI2UjIdux392VzOvT_IyLWD-ShyXVYE3J0AlrWYb6yBd-sO1nHDKukdjkqVF</recordid><startdate>2000</startdate><enddate>2000</enddate><creator>ROGULSKI, K. 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O</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c423t-f91089704e9cddc99db65745df59f17b976e186623eb116763d9ecd26ffa7a703</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Adenoviridae - enzymology</topic><topic>Adenoviridae - genetics</topic><topic>Adenoviridae - physiology</topic><topic>Adenovirus</topic><topic>Animals</topic><topic>Artificial Gene Fusion</topic><topic>Biological and medical sciences</topic><topic>Biotechnology</topic><topic>Cell Survival</topic><topic>Combined Modality Therapy</topic><topic>Cytosine Deaminase</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene therapy</topic><topic>Genetic Therapy</topic><topic>Genetic Vectors</topic><topic>Health. Pharmaceutical industry</topic><topic>herpes simplex 1</topic><topic>Herpesvirus 1, Human - enzymology</topic><topic>Industrial applications and implications. Economical aspects</topic><topic>Injections, Intralesional</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Neoplasm Transplantation</topic><topic>Neoplasms, Experimental - radiotherapy</topic><topic>Neoplasms, Experimental - therapy</topic><topic>Nucleoside Deaminases - genetics</topic><topic>Radiation Tolerance</topic><topic>Thymidine Kinase - genetics</topic><topic>Virus Replication</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>ROGULSKI, K. R</creatorcontrib><creatorcontrib>WING, M. S</creatorcontrib><creatorcontrib>PAIELLI, D. L</creatorcontrib><creatorcontrib>GILBERT, J. D</creatorcontrib><creatorcontrib>JAE HO KIM</creatorcontrib><creatorcontrib>FREYTAG, S. 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O</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization</atitle><jtitle>Human gene therapy</jtitle><addtitle>Hum Gene Ther</addtitle><date>2000</date><risdate>2000</risdate><volume>11</volume><issue>1</issue><spage>67</spage><epage>76</epage><pages>67-76</pages><issn>1043-0342</issn><eissn>1557-7422</eissn><coden>HGTHE3</coden><abstract>Replication-competent adenoviruses may provide a highly efficient means of delivering therapeutic genes to tumors. Previously, we evaluated in vitro a replication-competent adenovirus (Ad5-CD/TKrep) containing a cytosine deaminase (CD)/herpes simplex type 1 thymidine kinase (HSV-1 TK) fusion gene that allows lytic viral therapy to be combined with double suicide gene therapy. Both the CD/5-FC and HSV-1 TK/GCV enzyme/prodrug systems enhanced the tumor cell-specific cytopathic effects of the Ad5-CD/TKrep virus in vitro and sensitized cells to radiation. To extend these in vitro findings in vivo, we evaluated the antitumor activity of the Ad5-CD/TKrep virus in combination with double prodrug therapy and radiation therapy. The Ad5-CD/TKrep virus independently demonstrated significant antitumor activity against C33A cervical carcinoma xenografts. Therapeutic outcome was dramatically improved with systemic administration of double, but not single, prodrug (5-FC + GCV) therapy. When used in a neoadjuvant setting, Ad5-CD/TKrep-mediated double suicide gene therapy dramatically potentiated the effectiveness of radiation therapy. The trimodal approach of Ad5-CD/TKrep viral, double suicide gene, and radiotherapies produced significant tumor regression and ultimately 100% tumor cure. 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| ispartof | Human gene therapy, 2000, Vol.11 (1), p.67-76 |
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| source | Mary Ann Liebert Online Subscription; MEDLINE |
| subjects | Adenoviridae - enzymology Adenoviridae - genetics Adenoviridae - physiology Adenovirus Animals Artificial Gene Fusion Biological and medical sciences Biotechnology Cell Survival Combined Modality Therapy Cytosine Deaminase Female Fundamental and applied biological sciences. Psychology Gene therapy Genetic Therapy Genetic Vectors Health. Pharmaceutical industry herpes simplex 1 Herpesvirus 1, Human - enzymology Industrial applications and implications. Economical aspects Injections, Intralesional Mice Mice, Nude Neoplasm Transplantation Neoplasms, Experimental - radiotherapy Neoplasms, Experimental - therapy Nucleoside Deaminases - genetics Radiation Tolerance Thymidine Kinase - genetics Virus Replication |
| title | Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization |
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