Antiangiogenic gene therapy with soluble VEGF‐receptors ‐1, ‐2 and ‐3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma
Identifieur interne : 005C54 ( Istex/Corpus ); précédent : 005C53; suivant : 005C55Antiangiogenic gene therapy with soluble VEGF‐receptors ‐1, ‐2 and ‐3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma
Auteurs : Minna Sopo ; Maarit Anttila ; Hanna Sallinen ; Laura Tuppurainen ; Anniina Laurema ; Svetlana Laidinen ; Kirsi Hamalainen ; Pasi Tuunanen ; Jonna K. Koponen ; Veli-Matti Kosma ; Seppo Heinonen ; Kari Alitalo ; Seppo Yla-HerttualaSource :
- International Journal of Cancer [ 0020-7136 ] ; 2012-11-15.
Abstract
We compared effects of antiangiogenic gene therapy with a combination of soluble sVEGFR‐1, sVEGFR‐2 and sVEGFR‐3 to chemotherapy with carboplatin and paclitaxel and to antiangiogenic monoclonal anti‐VEGF‐antibody bevacizumab in an intraperitoneal ovarian cancer xenograft model in mice (n = 80). Gene therapy was also combined with chemotherapy. Therapy was initiated when sizable tumors were confirmed in magnetic resonance imaging (MRI). Adenovirus‐mediated gene transfer was performed intravenously (2 × 109 pfu), while chemotherapy and monoclonal anti‐VEGF‐antibody were dosed intraperitoneally. The study groups were as follows: AdLacZ control (n = 21); combination of AdsVEGFR‐1, ‐2 and ‐3 (n = 21); combination of AdsVEGFR‐1, ‐2, ‐3 and paclitaxel (n = 9); bevacizumab (n = 14); paclitaxel (n = 9) and carboplatin (n = 5). Effectiveness was assessed by survival time and surrogate measures such as sequential MRI, immunohistochemistry, microvessel density and tumor growth. Antiangiogenic gene therapy combined with paclitaxel significantly prolonged the mean survival of mice (25 days) compared to the controls (15 days) and all other treatment groups (p = 0.001). Bevacizumab treatment did not have any significant effect on the survival. Tumors of the mice treated by gene therapy were significantly smaller than in the control group (p = 0.021). The mean vascular density and total vascular area were also significantly smaller in the tumors of the gene therapy group (p = 0.01). These results show potential of the antiangiogenic gene therapy to improve efficacy of chemotherapy with paclitaxel and support testing of this approach in a phase I clinical trial for the treatment of ovarian cancer.
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DOI: 10.1002/ijc.27495
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Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation></author><author><name sortKey="Koponen, Jonna K" sort="Koponen, Jonna K" uniqKey="Koponen J" first="Jonna K." last="Koponen">Jonna K. Koponen</name><affiliation><mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation></author><author><name sortKey="Kosma, Veli Atti" sort="Kosma, Veli Atti" uniqKey="Kosma V" first="Veli-Matti" last="Kosma">Veli-Matti Kosma</name><affiliation><mods:affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Pathology, Kuopio University Hospital, Kuopio, Finland</mods:affiliation></affiliation></author><author><name sortKey="Heinonen, Seppo" sort="Heinonen, Seppo" uniqKey="Heinonen S" first="Seppo" last="Heinonen">Seppo Heinonen</name><affiliation><mods:affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</mods:affiliation></affiliation></author><author><name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name><affiliation><mods:affiliation>Molecular/Cancer Biology, Laboratory Biomedicum Helsinki and Haartman Institute, University of Helsinki, Helsinki, Finland</mods:affiliation></affiliation></author><author><name sortKey="Yla Erttuala, Seppo" sort="Yla Erttuala, Seppo" uniqKey="Yla Erttuala S" first="Seppo" last="Yla-Herttuala">Seppo Yla-Herttuala</name><affiliation><mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation><affiliation><mods:affiliation>Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland</mods:affiliation></affiliation><affiliation><mods:affiliation>Professor of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, P.O. Box 1627, Kuopio, FIN‐70211 Finland</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:C56F58B9F19CB32F85C629ECF166F523ADBF02E5</idno><date when="2012" year="2012">2012</date><idno type="doi">10.1002/ijc.27495</idno><idno type="url">https://api.istex.fr/document/C56F58B9F19CB32F85C629ECF166F523ADBF02E5/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">005C54</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">005C54</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Antiangiogenic gene therapy with soluble VEGF‐receptors ‐1, ‐2 and ‐3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma</title><author><name sortKey="Sopo, Minna" sort="Sopo, Minna" uniqKey="Sopo M" first="Minna" last="Sopo">Minna Sopo</name><affiliation><mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</mods:affiliation></affiliation></author><author><name sortKey="Anttila, Maarit" sort="Anttila, Maarit" uniqKey="Anttila M" first="Maarit" last="Anttila">Maarit Anttila</name><affiliation><mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</mods:affiliation></affiliation></author><author><name sortKey="Sallinen, Hanna" sort="Sallinen, Hanna" uniqKey="Sallinen H" first="Hanna" last="Sallinen">Hanna Sallinen</name><affiliation><mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</mods:affiliation></affiliation></author><author><name sortKey="Tuppurainen, Laura" sort="Tuppurainen, Laura" uniqKey="Tuppurainen L" first="Laura" last="Tuppurainen">Laura Tuppurainen</name><affiliation><mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation></author><author><name sortKey="Laurema, Anniina" sort="Laurema, Anniina" uniqKey="Laurema A" first="Anniina" last="Laurema">Anniina Laurema</name><affiliation><mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation></author><author><name sortKey="Laidinen, Svetlana" sort="Laidinen, Svetlana" uniqKey="Laidinen S" first="Svetlana" last="Laidinen">Svetlana Laidinen</name><affiliation><mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation></author><author><name sortKey="Hamalainen, Kirsi" sort="Hamalainen, Kirsi" uniqKey="Hamalainen K" first="Kirsi" last="Hamalainen">Kirsi Hamalainen</name><affiliation><mods:affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Pathology, Kuopio University Hospital, Kuopio, Finland</mods:affiliation></affiliation></author><author><name sortKey="Tuunanen, Pasi" sort="Tuunanen, Pasi" uniqKey="Tuunanen P" first="Pasi" last="Tuunanen">Pasi Tuunanen</name><affiliation><mods:affiliation>National BIO‐NMR Facility, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation></author><author><name sortKey="Koponen, Jonna K" sort="Koponen, Jonna K" uniqKey="Koponen J" first="Jonna K." last="Koponen">Jonna K. Koponen</name><affiliation><mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation></author><author><name sortKey="Kosma, Veli Atti" sort="Kosma, Veli Atti" uniqKey="Kosma V" first="Veli-Matti" last="Kosma">Veli-Matti Kosma</name><affiliation><mods:affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Pathology, Kuopio University Hospital, Kuopio, Finland</mods:affiliation></affiliation></author><author><name sortKey="Heinonen, Seppo" sort="Heinonen, Seppo" uniqKey="Heinonen S" first="Seppo" last="Heinonen">Seppo Heinonen</name><affiliation><mods:affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</mods:affiliation></affiliation></author><author><name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name><affiliation><mods:affiliation>Molecular/Cancer Biology, Laboratory Biomedicum Helsinki and Haartman Institute, University of Helsinki, Helsinki, Finland</mods:affiliation></affiliation></author><author><name sortKey="Yla Erttuala, Seppo" sort="Yla Erttuala, Seppo" uniqKey="Yla Erttuala S" first="Seppo" last="Yla-Herttuala">Seppo Yla-Herttuala</name><affiliation><mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation></affiliation><affiliation><mods:affiliation>Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland</mods:affiliation></affiliation><affiliation><mods:affiliation>Professor of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, P.O. Box 1627, Kuopio, FIN‐70211 Finland</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">International Journal of Cancer</title><title level="j" type="alt">INTERNATIONAL JOURNAL OF CANCER</title><idno type="ISSN">0020-7136</idno><idno type="eISSN">1097-0215</idno><imprint><biblScope unit="vol">131</biblScope><biblScope unit="issue">10</biblScope><biblScope unit="page" from="2394">2394</biblScope><biblScope unit="page" to="2401">2401</biblScope><biblScope unit="page-count">8</biblScope><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2012-11-15">2012-11-15</date></imprint><idno type="ISSN">0020-7136</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0020-7136</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We compared effects of antiangiogenic gene therapy with a combination of soluble sVEGFR‐1, sVEGFR‐2 and sVEGFR‐3 to chemotherapy with carboplatin and paclitaxel and to antiangiogenic monoclonal anti‐VEGF‐antibody bevacizumab in an intraperitoneal ovarian cancer xenograft model in mice (n = 80). Gene therapy was also combined with chemotherapy. Therapy was initiated when sizable tumors were confirmed in magnetic resonance imaging (MRI). Adenovirus‐mediated gene transfer was performed intravenously (2 × 109 pfu), while chemotherapy and monoclonal anti‐VEGF‐antibody were dosed intraperitoneally. The study groups were as follows: AdLacZ control (n = 21); combination of AdsVEGFR‐1, ‐2 and ‐3 (n = 21); combination of AdsVEGFR‐1, ‐2, ‐3 and paclitaxel (n = 9); bevacizumab (n = 14); paclitaxel (n = 9) and carboplatin (n = 5). Effectiveness was assessed by survival time and surrogate measures such as sequential MRI, immunohistochemistry, microvessel density and tumor growth. Antiangiogenic gene therapy combined with paclitaxel significantly prolonged the mean survival of mice (25 days) compared to the controls (15 days) and all other treatment groups (p = 0.001). Bevacizumab treatment did not have any significant effect on the survival. Tumors of the mice treated by gene therapy were significantly smaller than in the control group (p = 0.021). The mean vascular density and total vascular area were also significantly smaller in the tumors of the gene therapy group (p = 0.01). These results show potential of the antiangiogenic gene therapy to improve efficacy of chemotherapy with paclitaxel and support testing of this approach in a phase I clinical trial for the treatment of ovarian cancer.</div></front></TEI><istex><corpusName>wiley</corpusName><keywords><teeft><json:string>paclitaxel</json:string><json:string>ovarian</json:string><json:string>bevacizumab</json:string><json:string>gene therapy</json:string><json:string>chemotherapy</json:string><json:string>antiangiogenic</json:string><json:string>vegf</json:string><json:string>ovarian cancer</json:string><json:string>carboplatin</json:string><json:string>kuopio</json:string><json:string>receptor</json:string><json:string>antiangiogenic gene therapy</json:string><json:string>ascites</json:string><json:string>gene therapy group</json:string><json:string>gene transfer</json:string><json:string>svegfr</json:string><json:string>clin</json:string><json:string>angiogenesis</json:string><json:string>uicc</json:string><json:string>tumor growth</json:string><json:string>epithelial</json:string><json:string>intraperitoneal</json:string><json:string>tumor volume</json:string><json:string>ovarian carcinoma</json:string><json:string>oncol</json:string><json:string>tumor volumes</json:string><json:string>eastern finland</json:string><json:string>paclitaxel group</json:string><json:string>other treatment groups</json:string><json:string>control group</json:string><json:string>kuopio university hospital</json:string><json:string>growth factor</json:string><json:string>carcinoma</json:string><json:string>gene</json:string><json:string>liver samples</json:string><json:string>magnetic resonance imaging</json:string><json:string>tumor weights</json:string><json:string>paclitaxel groups</json:string><json:string>finland</json:string><json:string>therapy</json:string><json:string>ascites formation</json:string><json:string>study groups</json:string><json:string>plasma level</json:string><json:string>liver toxicity</json:string><json:string>microvessel measurements</json:string><json:string>virtanen institute</json:string><json:string>tumor tissue</json:string><json:string>soluble receptors</json:string><json:string>clin cancer</json:string><json:string>microvessel density</json:string><json:string>vascular</json:string><json:string>soluble</json:string><json:string>tumor</json:string><json:string>mouse</json:string><json:string>sizable tumors</json:string><json:string>plasma samples</json:string><json:string>tumor weight</json:string><json:string>vegf receptors</json:string><json:string>tumor masses</json:string><json:string>placental growth factor</json:string><json:string>nude mice</json:string><json:string>svegfr treatment</json:string><json:string>different treatment groups</json:string><json:string>control mice</json:string><json:string>treatment effect</json:string><json:string>molecular medicine</json:string><json:string>carboplatin group</json:string><json:string>smaller tumors</json:string><json:string>animal model</json:string><json:string>connective tissue</json:string><json:string>nude mouse</json:string><json:string>treatment groups</json:string><json:string>chemotherapy group</json:string><json:string>bevacizumab group</json:string><json:string>emil aaltonen foundation</json:string><json:string>regenerative changes</json:string><json:string>northern savo</json:string><json:string>survival advantage</json:string><json:string>lymhangiogenomics network</json:string><json:string>monoclonal bevacizumab</json:string><json:string>cell line</json:string><json:string>maintenance treatment</json:string><json:string>finnish academy</json:string><json:string>tumor progression</json:string><json:string>cancer therapy</json:string><json:string>tumor cells</json:string><json:string>growth factor receptor</json:string><json:string>ovarian carsinoma</json:string><json:string>transgenic mice</json:string><json:string>cancer model</json:string><json:string>cancer xenograft model</json:string></teeft></keywords><author><json:item><name>Minna Sopo</name><affiliations><json:string>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</json:string><json:string>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</json:string><json:string>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</json:string></affiliations></json:item><json:item><name>Maarit Anttila</name><affiliations><json:string>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</json:string><json:string>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</json:string><json:string>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</json:string></affiliations></json:item><json:item><name>Hanna Sallinen</name><affiliations><json:string>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</json:string><json:string>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</json:string><json:string>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</json:string></affiliations></json:item><json:item><name>Laura Tuppurainen</name><affiliations><json:string>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</json:string></affiliations></json:item><json:item><name>Anniina Laurema</name><affiliations><json:string>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</json:string></affiliations></json:item><json:item><name>Svetlana Laidinen</name><affiliations><json:string>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</json:string></affiliations></json:item><json:item><name>Kirsi Hamalainen</name><affiliations><json:string>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</json:string><json:string>Department of Pathology, Kuopio University Hospital, Kuopio, Finland</json:string></affiliations></json:item><json:item><name>Pasi Tuunanen</name><affiliations><json:string>National BIO‐NMR Facility, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</json:string></affiliations></json:item><json:item><name>Jonna K. Koponen</name><affiliations><json:string>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</json:string></affiliations></json:item><json:item><name>Veli‐Matti Kosma</name><affiliations><json:string>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</json:string><json:string>Department of Pathology, Kuopio University Hospital, Kuopio, Finland</json:string></affiliations></json:item><json:item><name>Seppo Heinonen</name><affiliations><json:string>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</json:string><json:string>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</json:string></affiliations></json:item><json:item><name>Kari Alitalo</name><affiliations><json:string>Molecular/Cancer Biology, Laboratory Biomedicum Helsinki and Haartman Institute, University of Helsinki, Helsinki, Finland</json:string></affiliations></json:item><json:item><name>Seppo Yla‐Herttuala</name><affiliations><json:string>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</json:string><json:string>Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland</json:string><json:string>Professor of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, P.O. Box 1627, Kuopio, FIN‐70211 Finland</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>ovarian carcinoma</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>gene therapy</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>soluble VEGF‐receptors</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>paclitaxel</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>carboplatin</value></json:item></subject><articleId><json:string>IJC27495</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>We compared effects of antiangiogenic gene therapy with a combination of soluble sVEGFR‐1, sVEGFR‐2 and sVEGFR‐3 to chemotherapy with carboplatin and paclitaxel and to antiangiogenic monoclonal anti‐VEGF‐antibody bevacizumab in an intraperitoneal ovarian cancer xenograft model in mice (n = 80). Gene therapy was also combined with chemotherapy. Therapy was initiated when sizable tumors were confirmed in magnetic resonance imaging (MRI). Adenovirus‐mediated gene transfer was performed intravenously (2 × 109 pfu), while chemotherapy and monoclonal anti‐VEGF‐antibody were dosed intraperitoneally. The study groups were as follows: AdLacZ control (n = 21); combination of AdsVEGFR‐1, ‐2 and ‐3 (n = 21); combination of AdsVEGFR‐1, ‐2, ‐3 and paclitaxel (n = 9); bevacizumab (n = 14); paclitaxel (n = 9) and carboplatin (n = 5). Effectiveness was assessed by survival time and surrogate measures such as sequential MRI, immunohistochemistry, microvessel density and tumor growth. Antiangiogenic gene therapy combined with paclitaxel significantly prolonged the mean survival of mice (25 days) compared to the controls (15 days) and all other treatment groups (p = 0.001). Bevacizumab treatment did not have any significant effect on the survival. Tumors of the mice treated by gene therapy were significantly smaller than in the control group (p = 0.021). The mean vascular density and total vascular area were also significantly smaller in the tumors of the gene therapy group (p = 0.01). These results show potential of the antiangiogenic gene therapy to improve efficacy of chemotherapy with paclitaxel and support testing of this approach in a phase I clinical trial for the treatment of ovarian cancer.</abstract><qualityIndicators><score>8.5</score><pdfVersion>1.4</pdfVersion><pdfPageSize>612 x 810 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>1708</abstractCharCount><pdfWordCount>5356</pdfWordCount><pdfCharCount>33532</pdfCharCount><pdfPageCount>8</pdfPageCount><abstractWordCount>256</abstractWordCount></qualityIndicators><title>Antiangiogenic gene therapy with soluble VEGF‐receptors ‐1, ‐2 and ‐3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma</title><genre><json:string>article</json:string></genre><host><title>International Journal of Cancer</title><language><json:string>unknown</json:string></language><doi><json:string>10.1002/(ISSN)1097-0215</json:string></doi><issn><json:string>0020-7136</json:string></issn><eissn><json:string>1097-0215</json:string></eissn><publisherId><json:string>IJC</json:string></publisherId><volume>131</volume><issue>10</issue><pages><first>2394</first><last>2401</last><total>8</total></pages><genre><json:string>journal</json:string></genre><subject><json:item><value>Cancer Therapy</value></json:item></subject></host><categories><wos><json:string>science</json:string><json:string>oncology</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>clinical medicine</json:string><json:string>oncology & carcinogenesis</json:string></scienceMetrix><inist><json:string>sciences appliquees, technologies et medecines</json:string><json:string>sciences biologiques et medicales</json:string><json:string>sciences medicales</json:string></inist></categories><publicationDate>2012</publicationDate><copyrightDate>2012</copyrightDate><doi><json:string>10.1002/ijc.27495</json:string></doi><id>C56F58B9F19CB32F85C629ECF166F523ADBF02E5</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/C56F58B9F19CB32F85C629ECF166F523ADBF02E5/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/C56F58B9F19CB32F85C629ECF166F523ADBF02E5/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/C56F58B9F19CB32F85C629ECF166F523ADBF02E5/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Antiangiogenic gene therapy with soluble VEGF‐receptors ‐1, ‐2 and ‐3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma</title></titleStmt><publicationStmt><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><licence>Copyright © 2012 UICC</licence></availability><date type="published" when="2012-11-15"></date></publicationStmt><notesStmt><note type="content-type" subtype="article" source="article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</note><note type="publication-type" subtype="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="article"><analytic><title level="a" type="main" xml:lang="en">Antiangiogenic gene therapy with soluble VEGF‐receptors ‐1, ‐2 and ‐3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma</title><title level="a" type="short" xml:lang="en">Antiangiogenic Gene Therapy for Ovarian Cancer</title><author xml:id="author-0000"><persName><forename type="first">Minna</forename><surname>Sopo</surname></persName><affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland<address><country key="FI"></country></address></affiliation><affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland<address><country key="FI"></country></address></affiliation><affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland<address><country key="FI"></country></address></affiliation></author><author xml:id="author-0001"><persName><forename type="first">Maarit</forename><surname>Anttila</surname></persName><affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland<address><country key="FI"></country></address></affiliation><affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland<address><country key="FI"></country></address></affiliation><affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland<address><country key="FI"></country></address></affiliation></author><author xml:id="author-0002"><persName><forename type="first">Hanna</forename><surname>Sallinen</surname></persName><affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland<address><country key="FI"></country></address></affiliation><affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland<address><country key="FI"></country></address></affiliation><affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland<address><country key="FI"></country></address></affiliation></author><author xml:id="author-0003"><persName><forename type="first">Laura</forename><surname>Tuppurainen</surname></persName><affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland<address><country key="FI"></country></address></affiliation></author><author xml:id="author-0004"><persName><forename type="first">Anniina</forename><surname>Laurema</surname></persName><affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland<address><country key="FI"></country></address></affiliation></author><author xml:id="author-0005"><persName><forename type="first">Svetlana</forename><surname>Laidinen</surname></persName><affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland<address><country key="FI"></country></address></affiliation></author><author xml:id="author-0006"><persName><forename type="first">Kirsi</forename><surname>Hamalainen</surname></persName><affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland<address><country key="FI"></country></address></affiliation><affiliation>Department of Pathology, Kuopio University Hospital, Kuopio, Finland<address><country key="FI"></country></address></affiliation></author><author xml:id="author-0007"><persName><forename type="first">Pasi</forename><surname>Tuunanen</surname></persName><affiliation>National BIO‐NMR Facility, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland<address><country key="FI"></country></address></affiliation></author><author xml:id="author-0008"><persName><forename type="first">Jonna K.</forename><surname>Koponen</surname></persName><affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland<address><country key="FI"></country></address></affiliation></author><author xml:id="author-0009"><persName><forename type="first">Veli‐Matti</forename><surname>Kosma</surname></persName><affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland<address><country key="FI"></country></address></affiliation><affiliation>Department of Pathology, Kuopio University Hospital, Kuopio, Finland<address><country key="FI"></country></address></affiliation></author><author xml:id="author-0010"><persName><forename type="first">Seppo</forename><surname>Heinonen</surname></persName><affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland<address><country key="FI"></country></address></affiliation><affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland<address><country key="FI"></country></address></affiliation></author><author xml:id="author-0011"><persName><forename type="first">Kari</forename><surname>Alitalo</surname></persName><affiliation>Molecular/Cancer Biology, Laboratory Biomedicum Helsinki and Haartman Institute, University of Helsinki, Helsinki, Finland<address><country key="FI"></country></address></affiliation></author><author xml:id="author-0012" role="corresp"><persName><forename type="first">Seppo</forename><surname>Yla‐Herttuala</surname></persName><email>seppo.ylaherttuala@uef.fi</email><affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland<address><country key="FI"></country></address></affiliation><affiliation>Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland<address><country key="FI"></country></address></affiliation><note type="foot">Tel.: +358‐17‐16‐3075, Fax: +358‐17‐16‐3751</note><affiliation>Professor of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, P.O. Box 1627, Kuopio, FIN‐70211 Finland</affiliation></author><idno type="istex">C56F58B9F19CB32F85C629ECF166F523ADBF02E5</idno><idno type="DOI">10.1002/ijc.27495</idno><idno type="unit">IJC27495</idno><idno type="toTypesetVersion">file:IJC.IJC27495.pdf</idno></analytic><monogr><title level="j" type="main">International Journal of Cancer</title><title level="j" type="alt">INTERNATIONAL JOURNAL OF CANCER</title><idno type="pISSN">0020-7136</idno><idno type="eISSN">1097-0215</idno><idno type="book-DOI">10.1002/(ISSN)1097-0215</idno><idno type="book-part-DOI">10.1002/ijc.v131.10</idno><idno type="product">IJC</idno><imprint><biblScope unit="vol">131</biblScope><biblScope unit="issue">10</biblScope><biblScope unit="page" from="2394">2394</biblScope><biblScope unit="page" to="2401">2401</biblScope><biblScope unit="page-count">8</biblScope><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2012-11-15"></date></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><abstract xml:lang="en" style="main"><head>Abstract</head><p>We compared effects of antiangiogenic gene therapy with a combination of soluble sVEGFR‐1, sVEGFR‐2 and sVEGFR‐3 to chemotherapy with carboplatin and paclitaxel and to antiangiogenic monoclonal anti‐VEGF‐antibody bevacizumab in an intraperitoneal ovarian cancer xenograft model in mice (<hi rend="italic">n</hi> = 80). Gene therapy was also combined with chemotherapy. Therapy was initiated when sizable tumors were confirmed in magnetic resonance imaging (MRI). Adenovirus‐mediated gene transfer was performed intravenously (2 × 109 pfu), while chemotherapy and monoclonal anti‐VEGF‐antibody were dosed intraperitoneally. The study groups were as follows: AdLacZ control (<hi rend="italic">n</hi> = 21); combination of AdsVEGFR‐1, ‐2 and ‐3 (<hi rend="italic">n</hi> = 21); combination of AdsVEGFR‐1, ‐2, ‐3 and paclitaxel (<hi rend="italic">n</hi> = 9); bevacizumab (<hi rend="italic">n</hi> = 14); paclitaxel (<hi rend="italic">n</hi> = 9) and carboplatin (<hi rend="italic">n</hi> = 5). Effectiveness was assessed by survival time and surrogate measures such as sequential MRI, immunohistochemistry, microvessel density and tumor growth. Antiangiogenic gene therapy combined with paclitaxel significantly prolonged the mean survival of mice (25 days) compared to the controls (15 days) and all other treatment groups (<hi rend="italic">p</hi> = 0.001). Bevacizumab treatment did not have any significant effect on the survival. Tumors of the mice treated by gene therapy were significantly smaller than in the control group (<hi rend="italic">p</hi> = 0.021). The mean vascular density and total vascular area were also significantly smaller in the tumors of the gene therapy group (<hi rend="italic">p</hi> = 0.01). These results show potential of the antiangiogenic gene therapy to improve efficacy of chemotherapy with paclitaxel and support testing of this approach in a phase I clinical trial for the treatment of ovarian cancer.</p></abstract><textClass><keywords xml:lang="en"><term xml:id="kwd1">ovarian carcinoma</term><term xml:id="kwd2">gene therapy</term><term xml:id="kwd3">soluble VEGF‐receptors</term><term xml:id="kwd4">paclitaxel</term><term xml:id="kwd5">carboplatin</term></keywords><classCode scheme="articleCategory">Cancer Therapy</classCode><classCode scheme="tocHeading1">Cancer Therapy</classCode></textClass><langUsage><language ident="EN"></language></langUsage></profileDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/C56F58B9F19CB32F85C629ECF166F523ADBF02E5/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Wiley Subscription Services, Inc., A Wiley Company</publisherName><publisherLoc>Hoboken</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1097-0215</doi><issn type="print">0020-7136</issn><issn type="electronic">1097-0215</issn><idGroup><id type="product" value="IJC"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="INTERNATIONAL JOURNAL OF CANCER">International Journal of Cancer</title><title type="short">Int. 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Virtanen Institute, University of Eastern Finland, P.O. Box 1627, Kuopio, FIN‐70211 Finland</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:IJC.IJC27495.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="4"></count><count type="tableTotal" number="2"></count><count type="referenceTotal" number="37"></count><count type="wordTotal" number="6676"></count></countGroup><titleGroup><title type="main" xml:lang="en">Antiangiogenic gene therapy with soluble VEGF‐receptors ‐1, ‐2 and ‐3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma</title><title type="short" xml:lang="en">Antiangiogenic Gene Therapy for Ovarian Cancer</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af3 #af4"><personName><givenNames>Minna</givenNames><familyName>Sopo</familyName></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1 #af3 #af4"><personName><givenNames>Maarit</givenNames><familyName>Anttila</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1 #af3 #af4"><personName><givenNames>Hanna</givenNames><familyName>Sallinen</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Laura</givenNames><familyName>Tuppurainen</familyName></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Anniina</givenNames><familyName>Laurema</familyName></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Svetlana</givenNames><familyName>Laidinen</familyName></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af3 #af5"><personName><givenNames>Kirsi</givenNames><familyName>Hamalainen</familyName></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af2"><personName><givenNames>Pasi</givenNames><familyName>Tuunanen</familyName></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Jonna K.</givenNames><familyName>Koponen</familyName></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af3 #af5"><personName><givenNames>Veli‐Matti</givenNames><familyName>Kosma</familyName></personName></creator><creator xml:id="au11" creatorRole="author" affiliationRef="#af3 #af4"><personName><givenNames>Seppo</givenNames><familyName>Heinonen</familyName></personName></creator><creator xml:id="au12" creatorRole="author" affiliationRef="#af6"><personName><givenNames>Kari</givenNames><familyName>Alitalo</familyName></personName></creator><creator xml:id="au13" creatorRole="author" affiliationRef="#af1 #af7" corresponding="yes" noteRef="#fn1"><personName><givenNames>Seppo</givenNames><familyName>Yla‐Herttuala</familyName></personName><contactDetails><email>seppo.ylaherttuala@uef.fi</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="FI" type="organization"><unparsedAffiliation>Department of Molecular Medicine, A.I. 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Additional Supporting Information may be found in the online version of this article.
</p><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:00207136:media:ijc27495:IJC_27495_sm_SuppInfo"></mediaResource><caption>Supporting Information</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>We compared effects of antiangiogenic gene therapy with a combination of soluble sVEGFR‐1, sVEGFR‐2 and sVEGFR‐3 to chemotherapy with carboplatin and paclitaxel and to antiangiogenic monoclonal anti‐VEGF‐antibody bevacizumab in an intraperitoneal ovarian cancer xenograft model in mice (<i>n</i> = 80). Gene therapy was also combined with chemotherapy. Therapy was initiated when sizable tumors were confirmed in magnetic resonance imaging (MRI). Adenovirus‐mediated gene transfer was performed intravenously (2 × 109 pfu), while chemotherapy and monoclonal anti‐VEGF‐antibody were dosed intraperitoneally. The study groups were as follows: AdLacZ control (<i>n</i> = 21); combination of AdsVEGFR‐1, ‐2 and ‐3 (<i>n</i> = 21); combination of AdsVEGFR‐1, ‐2, ‐3 and paclitaxel (<i>n</i> = 9); bevacizumab (<i>n</i> = 14); paclitaxel (<i>n</i> = 9) and carboplatin (<i>n</i> = 5). Effectiveness was assessed by survival time and surrogate measures such as sequential MRI, immunohistochemistry, microvessel density and tumor growth. Antiangiogenic gene therapy combined with paclitaxel significantly prolonged the mean survival of mice (25 days) compared to the controls (15 days) and all other treatment groups (<i>p</i> = 0.001). Bevacizumab treatment did not have any significant effect on the survival. Tumors of the mice treated by gene therapy were significantly smaller than in the control group (<i>p</i> = 0.021). The mean vascular density and total vascular area were also significantly smaller in the tumors of the gene therapy group (<i>p</i> = 0.01). These results show potential of the antiangiogenic gene therapy to improve efficacy of chemotherapy with paclitaxel and support testing of this approach in a phase I clinical trial for the treatment of ovarian cancer.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><p>Tel.: +358‐17‐16‐3075, Fax: +358‐17‐16‐3751</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Antiangiogenic gene therapy with soluble VEGF‐receptors ‐1, ‐2 and ‐3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Antiangiogenic Gene Therapy for Ovarian Cancer</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Antiangiogenic gene therapy with soluble VEGF‐receptors ‐1, ‐2 and ‐3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma</title></titleInfo><name type="personal"><namePart type="given">Minna</namePart><namePart type="family">Sopo</namePart><affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</affiliation><affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</affiliation><affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Maarit</namePart><namePart type="family">Anttila</namePart><affiliation>Department of Molecular Medicine, A.I. 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Virtanen Institute, University of Eastern Finland, Kuopio, Finland</affiliation><affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</affiliation><affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Laura</namePart><namePart type="family">Tuppurainen</namePart><affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Anniina</namePart><namePart type="family">Laurema</namePart><affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Svetlana</namePart><namePart type="family">Laidinen</namePart><affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kirsi</namePart><namePart type="family">Hamalainen</namePart><affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</affiliation><affiliation>Department of Pathology, Kuopio University Hospital, Kuopio, Finland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Pasi</namePart><namePart type="family">Tuunanen</namePart><affiliation>National BIO‐NMR Facility, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jonna K.</namePart><namePart type="family">Koponen</namePart><affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Veli‐Matti</namePart><namePart type="family">Kosma</namePart><affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</affiliation><affiliation>Department of Pathology, Kuopio University Hospital, Kuopio, Finland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Seppo</namePart><namePart type="family">Heinonen</namePart><affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</affiliation><affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kari</namePart><namePart type="family">Alitalo</namePart><affiliation>Molecular/Cancer Biology, Laboratory Biomedicum Helsinki and Haartman Institute, University of Helsinki, Helsinki, Finland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Seppo</namePart><namePart type="family">Yla‐Herttuala</namePart><affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</affiliation><affiliation>Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland</affiliation><description>Tel.: +358‐17‐16‐3075, Fax: +358‐17‐16‐3751</description><affiliation>Professor of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, P.O. Box 1627, Kuopio, FIN‐70211 Finland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2012-11-15</dateIssued><dateCaptured encoding="w3cdtf">2011-09-06</dateCaptured><dateValid encoding="w3cdtf">2012-02-02</dateValid><copyrightDate encoding="w3cdtf">2012</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">4</extent><extent unit="tables">2</extent><extent unit="references">37</extent><extent unit="words">6676</extent></physicalDescription><abstract lang="en">We compared effects of antiangiogenic gene therapy with a combination of soluble sVEGFR‐1, sVEGFR‐2 and sVEGFR‐3 to chemotherapy with carboplatin and paclitaxel and to antiangiogenic monoclonal anti‐VEGF‐antibody bevacizumab in an intraperitoneal ovarian cancer xenograft model in mice (n = 80). Gene therapy was also combined with chemotherapy. Therapy was initiated when sizable tumors were confirmed in magnetic resonance imaging (MRI). Adenovirus‐mediated gene transfer was performed intravenously (2 × 109 pfu), while chemotherapy and monoclonal anti‐VEGF‐antibody were dosed intraperitoneally. The study groups were as follows: AdLacZ control (n = 21); combination of AdsVEGFR‐1, ‐2 and ‐3 (n = 21); combination of AdsVEGFR‐1, ‐2, ‐3 and paclitaxel (n = 9); bevacizumab (n = 14); paclitaxel (n = 9) and carboplatin (n = 5). Effectiveness was assessed by survival time and surrogate measures such as sequential MRI, immunohistochemistry, microvessel density and tumor growth. Antiangiogenic gene therapy combined with paclitaxel significantly prolonged the mean survival of mice (25 days) compared to the controls (15 days) and all other treatment groups (p = 0.001). Bevacizumab treatment did not have any significant effect on the survival. Tumors of the mice treated by gene therapy were significantly smaller than in the control group (p = 0.021). The mean vascular density and total vascular area were also significantly smaller in the tumors of the gene therapy group (p = 0.01). These results show potential of the antiangiogenic gene therapy to improve efficacy of chemotherapy with paclitaxel and support testing of this approach in a phase I clinical trial for the treatment of ovarian cancer.</abstract><note type="funding">Finnish Academy</note><note type="funding">EU Lymhangiogenomics Network</note><note type="funding">ERC Advanced Grant</note><note type="funding">Kuopio University Hospital EVO grant</note><note type="funding">The Finnish Cultural Foundation of Northern Savo and The Emil Aaltonen Foundation</note><subject lang="en"><genre>keywords</genre><topic>ovarian carcinoma</topic><topic>gene therapy</topic><topic>soluble VEGF‐receptors</topic><topic>paclitaxel</topic><topic>carboplatin</topic></subject><relatedItem type="host"><titleInfo><title>International Journal of Cancer</title></titleInfo><titleInfo type="abbreviated"><title>Int. J. Cancer</title></titleInfo><genre type="journal">journal</genre><note type="content"> Additional Supporting Information may be found in the online version of this article.Supporting Info Item: Supporting Information - </note><subject><genre>article-category</genre><topic>Cancer Therapy</topic></subject><identifier type="ISSN">0020-7136</identifier><identifier type="eISSN">1097-0215</identifier><identifier type="DOI">10.1002/(ISSN)1097-0215</identifier><identifier type="PublisherID">IJC</identifier><part><date>2012</date><detail type="volume"><caption>vol.</caption><number>131</number></detail><detail type="issue"><caption>no.</caption><number>10</number></detail><extent unit="pages"><start>2394</start><end>2401</end><total>8</total></extent></part></relatedItem><identifier type="istex">C56F58B9F19CB32F85C629ECF166F523ADBF02E5</identifier><identifier type="DOI">10.1002/ijc.27495</identifier><identifier type="ArticleID">IJC27495</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2012 UICC</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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