Double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus in combination with radiotherapy elicits an enhanced anti-tumor effect

Radiation therapy, a mainstay for anti-tumor therapeutic regimens for a variety of tumor types, triggers tumor cell apoptotic pathways by either directly eliciting DNA damage or indirectly inducing the formation of oxygen radicals. In an effort to augment radiation therapy, we generated a double E1B...

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Veröffentlicht in:Gene therapy 2009-09, Vol.16 (9), p.1111-1121
Hauptverfasser: Kim, J, Kim, P-H, Yoo, J Y, Yoon, A-R, Choi, H J, Seong, J, Kim, I-W, Kim, J-H, Yun, C-O
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container_end_page 1121
container_issue 9
container_start_page 1111
container_title Gene therapy
container_volume 16
creator Kim, J
Kim, P-H
Yoo, J Y
Yoon, A-R
Choi, H J
Seong, J
Kim, I-W
Kim, J-H
Yun, C-O
description Radiation therapy, a mainstay for anti-tumor therapeutic regimens for a variety of tumor types, triggers tumor cell apoptotic pathways by either directly eliciting DNA damage or indirectly inducing the formation of oxygen radicals. In an effort to augment radiation therapy, we generated a double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus (Ad−ΔE1B19/55). In combination with radiotherapy, greater cytotoxicity was observed for Ad−ΔE1B19/55 than for the single E1B 55 kDa-deleted oncolytic Ad (Ad−ΔE1B55). Consistent with this observation, higher levels of p53, phospho-p53, phospho-Chk1, phospho-Chk2, PI3K (phosphatidylinositol-3-kinase), phospho-AKT, cytochrome c, and cleavage of PARP (poly (ADP-ribose) polymerase) and caspase-3 were observed in cells treated with Ad−ΔE1B19/55 compared with those treated with Ad−ΔE1B55, indicating that the E1B 19 kDa present in Ad−ΔE1B55 may partially block radiation-induced apoptosis. A significant therapeutic benefit was also observed in vivo when oncolytic Ads and radiation were combined. Tumors treated with Ad−ΔE1B19/55 and radiation showed large areas of necrosis and apoptosis with the corresponding induction of p53. Finally, consistent with in vitro observations, the combination of Ad−ΔE1B19/55 and radiation was more efficacious than the combination of Ad−ΔE1B55 and radiation. Taken together, these results present a strong therapeutic rationale for combining radiation therapy with E1B 19 kDa-deleted oncolytic Ad.
doi_str_mv 10.1038/gt.2009.72
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Finally, consistent with in vitro observations, the combination of Ad−ΔE1B19/55 and radiation was more efficacious than the combination of Ad−ΔE1B55 and radiation. Taken together, these results present a strong therapeutic rationale for combining radiation therapy with E1B 19 kDa-deleted oncolytic Ad.</description><identifier>ISSN: 0969-7128</identifier><identifier>EISSN: 1476-5462</identifier><identifier>DOI: 10.1038/gt.2009.72</identifier><identifier>PMID: 19494843</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>1-Phosphatidylinositol 3-kinase ; Adenoviridae - genetics ; Adenovirus E1B Proteins - genetics ; Adenoviruses ; Ageing, cell death ; AKT protein ; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy ; Animals ; Apoptosis ; Apoptosis - genetics ; Applied cell therapy and gene therapy ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedicine ; Biotechnology ; Cancer ; Care and treatment ; Caspase-3 ; Cell Biology ; Cell physiology ; CHK1 protein ; Combined Modality Therapy ; Cytochrome c ; Cytotoxicity ; DNA damage ; Female ; Fundamental and applied biological sciences. Psychology ; Gene Expression ; Gene Therapy ; Genetic aspects ; Genetic vectors ; Health. Pharmaceutical industry ; Human Genetics ; Humans ; Industrial applications and implications. Economical aspects ; Male ; Medical sciences ; Methods ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Molecular and cellular biology ; Nanotechnology ; Oncolysis ; Oncolytic Virotherapy - methods ; Oncolytic Viruses - genetics ; original-article ; p53 Protein ; Patient outcomes ; Poly(ADP-ribose) polymerase ; Radiation therapy ; Radiotherapy ; Ribose ; Transfusions. Complications. 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Cell therapy and gene therapy</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - genetics</subject><subject>Applied cell therapy and gene therapy</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Biotechnology</subject><subject>Cancer</subject><subject>Care and treatment</subject><subject>Caspase-3</subject><subject>Cell Biology</subject><subject>Cell physiology</subject><subject>CHK1 protein</subject><subject>Combined Modality Therapy</subject><subject>Cytochrome c</subject><subject>Cytotoxicity</subject><subject>DNA damage</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene Expression</subject><subject>Gene Therapy</subject><subject>Genetic aspects</subject><subject>Genetic vectors</subject><subject>Health. Pharmaceutical industry</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Industrial applications and implications. Economical aspects</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Methods</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Molecular and cellular biology</subject><subject>Nanotechnology</subject><subject>Oncolysis</subject><subject>Oncolytic Virotherapy - methods</subject><subject>Oncolytic Viruses - genetics</subject><subject>original-article</subject><subject>p53 Protein</subject><subject>Patient outcomes</subject><subject>Poly(ADP-ribose) polymerase</subject><subject>Radiation therapy</subject><subject>Radiotherapy</subject><subject>Ribose</subject><subject>Transfusions. Complications. Transfusion reactions. Cell and gene therapy</subject><subject>Tumors</subject><subject>Uterine Cervical Neoplasms - pathology</subject><subject>Uterine Cervical Neoplasms - radiotherapy</subject><subject>Uterine Cervical Neoplasms - therapy</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0969-7128</issn><issn>1476-5462</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp10s1u1DAQAOAIgWgpXHgAZIEAAcpix3YcH0tboFIlJH7Okdee7Lok9mI7wN649jV5Ehx2xbKoyAdLk88zsWeK4j7BM4Jp83KRZhXGciaqG8UhYaIuOaurm8UhlrUsBamag-JOjJcYYyaa6nZxQCSTrGH0sLg69eO8B3RGXiEif_64-nyqSqSc-R3hfBsx0EMCg7zTvl8nq5Ey4PxXG8aIrEPaD3PrVLLeoW82LVFQxvq0hKBWawS91TbFnBaBWyqncyblki3TOPiAoOtAp7vFrU71Ee5t96Pi0-uzjydvy4t3b85Pji9KzWqZ8nUMdITPqeZirgUzinBJeMdpI7UwFHClJaESAIxkhBnOa8a1IvMGa1CCHhVPN3lXwX8ZIaZ2sFFD3ysHfoytoJQJ3Eia5aN_5KUfg8s_11Y1YzWtG0GyevhfRRrBOBZ4l2qhemit63wKSk-F2-Mqt4k2dTUVnF2j8jIwWO0ddDbH9w482zuQTYLvaaHGGNvzD-_37ZO_7BJUn5bR9-PUs7gPn2-gDj7GAF27CnZQYd0S3E4D1y5SOw1cK6qMH2xvP84HMDu6nbAMHm-Bilr1Xcjtt_GPm55IUsGze7FxMX9yCwi7Z7ym7C_5QOi9</recordid><startdate>20090901</startdate><enddate>20090901</enddate><creator>Kim, J</creator><creator>Kim, P-H</creator><creator>Yoo, J Y</creator><creator>Yoon, A-R</creator><creator>Choi, H J</creator><creator>Seong, J</creator><creator>Kim, I-W</creator><creator>Kim, J-H</creator><creator>Yun, C-O</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>ISR</scope><scope>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</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>8G5</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>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20090901</creationdate><title>Double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus in combination with radiotherapy elicits an enhanced anti-tumor effect</title><author>Kim, J ; Kim, P-H ; Yoo, J Y ; Yoon, A-R ; Choi, H J ; Seong, J ; Kim, I-W ; Kim, J-H ; Yun, C-O</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c469t-71def15b3c57bc74da15915f5389c7d3e02c9139eeed9414d55645ca1b80cea73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>Adenoviridae - genetics</topic><topic>Adenovirus E1B Proteins - genetics</topic><topic>Adenoviruses</topic><topic>Ageing, cell death</topic><topic>AKT protein</topic><topic>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - genetics</topic><topic>Applied cell therapy and gene therapy</topic><topic>Biological and medical sciences</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Biotechnology</topic><topic>Cancer</topic><topic>Care and treatment</topic><topic>Caspase-3</topic><topic>Cell Biology</topic><topic>Cell physiology</topic><topic>CHK1 protein</topic><topic>Combined Modality Therapy</topic><topic>Cytochrome c</topic><topic>Cytotoxicity</topic><topic>DNA damage</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene Expression</topic><topic>Gene Therapy</topic><topic>Genetic aspects</topic><topic>Genetic vectors</topic><topic>Health. Pharmaceutical industry</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Industrial applications and implications. 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In an effort to augment radiation therapy, we generated a double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus (Ad−ΔE1B19/55). In combination with radiotherapy, greater cytotoxicity was observed for Ad−ΔE1B19/55 than for the single E1B 55 kDa-deleted oncolytic Ad (Ad−ΔE1B55). Consistent with this observation, higher levels of p53, phospho-p53, phospho-Chk1, phospho-Chk2, PI3K (phosphatidylinositol-3-kinase), phospho-AKT, cytochrome c, and cleavage of PARP (poly (ADP-ribose) polymerase) and caspase-3 were observed in cells treated with Ad−ΔE1B19/55 compared with those treated with Ad−ΔE1B55, indicating that the E1B 19 kDa present in Ad−ΔE1B55 may partially block radiation-induced apoptosis. A significant therapeutic benefit was also observed in vivo when oncolytic Ads and radiation were combined. Tumors treated with Ad−ΔE1B19/55 and radiation showed large areas of necrosis and apoptosis with the corresponding induction of p53. Finally, consistent with in vitro observations, the combination of Ad−ΔE1B19/55 and radiation was more efficacious than the combination of Ad−ΔE1B55 and radiation. Taken together, these results present a strong therapeutic rationale for combining radiation therapy with E1B 19 kDa-deleted oncolytic Ad.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>19494843</pmid><doi>10.1038/gt.2009.72</doi><tpages>11</tpages></addata></record>
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identifier ISSN: 0969-7128
ispartof Gene therapy, 2009-09, Vol.16 (9), p.1111-1121
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1476-5462
language eng
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source MEDLINE; SpringerLink Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
subjects 1-Phosphatidylinositol 3-kinase
Adenoviridae - genetics
Adenovirus E1B Proteins - genetics
Adenoviruses
Ageing, cell death
AKT protein
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Animals
Apoptosis
Apoptosis - genetics
Applied cell therapy and gene therapy
Biological and medical sciences
Biomedical and Life Sciences
Biomedicine
Biotechnology
Cancer
Care and treatment
Caspase-3
Cell Biology
Cell physiology
CHK1 protein
Combined Modality Therapy
Cytochrome c
Cytotoxicity
DNA damage
Female
Fundamental and applied biological sciences. Psychology
Gene Expression
Gene Therapy
Genetic aspects
Genetic vectors
Health. Pharmaceutical industry
Human Genetics
Humans
Industrial applications and implications. Economical aspects
Male
Medical sciences
Methods
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular and cellular biology
Nanotechnology
Oncolysis
Oncolytic Virotherapy - methods
Oncolytic Viruses - genetics
original-article
p53 Protein
Patient outcomes
Poly(ADP-ribose) polymerase
Radiation therapy
Radiotherapy
Ribose
Transfusions. Complications. Transfusion reactions. Cell and gene therapy
Tumors
Uterine Cervical Neoplasms - pathology
Uterine Cervical Neoplasms - radiotherapy
Uterine Cervical Neoplasms - therapy
Xenograft Model Antitumor Assays
title Double E1B 19 kDa- and E1B 55 kDa-deleted oncolytic adenovirus in combination with radiotherapy elicits an enhanced anti-tumor effect
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-13T04%3A19%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Double%20E1B%2019%E2%80%89kDa-%20and%20E1B%2055%E2%80%89kDa-deleted%20oncolytic%20adenovirus%20in%20combination%20with%20radiotherapy%20elicits%20an%20enhanced%20anti-tumor%20effect&rft.jtitle=Gene%20therapy&rft.au=Kim,%20J&rft.date=2009-09-01&rft.volume=16&rft.issue=9&rft.spage=1111&rft.epage=1121&rft.pages=1111-1121&rft.issn=0969-7128&rft.eissn=1476-5462&rft_id=info:doi/10.1038/gt.2009.72&rft_dat=%3Cgale_proqu%3EA209638623%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=218745070&rft_id=info:pmid/19494843&rft_galeid=A209638623&rfr_iscdi=true