Antiangiogenic gene therapy with soluble VEGF‐receptors ‐1, ‐2 and ‐3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma
Identifieur interne : 004852 ( Main/Exploration ); précédent : 004851; suivant : 004853Antiangiogenic gene therapy with soluble VEGF‐receptors ‐1, ‐2 and ‐3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma
Auteurs : Minna Sopo [Finlande] ; Maarit Anttila [Finlande] ; Hanna Sallinen [Finlande] ; Laura Tuppurainen [Finlande] ; Anniina Laurema [Finlande] ; Svetlana Laidinen [Finlande] ; Kirsi Hamalainen [Finlande] ; Pasi Tuunanen [Finlande] ; Jonna K. Koponen [Finlande] ; Veli-Matti Kosma [Finlande] ; Seppo Heinonen [Finlande] ; Kari Alitalo [Finlande] ; Seppo Yla-Herttuala [Finlande]Source :
- 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
Affiliations:
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Virtanen Institute, University of Eastern Finland, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Gynaecology, Kuopio University Hospital, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation></author><author><name sortKey="Anttila, Maarit" sort="Anttila, Maarit" uniqKey="Anttila M" first="Maarit" last="Anttila">Maarit Anttila</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Molecular Medicine, A.I. 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Virtanen Institute, University of Eastern Finland, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation></author><author><name sortKey="Laurema, Anniina" sort="Laurema, Anniina" uniqKey="Laurema A" first="Anniina" last="Laurema">Anniina Laurema</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation></author><author><name sortKey="Laidinen, Svetlana" sort="Laidinen, Svetlana" uniqKey="Laidinen S" first="Svetlana" last="Laidinen">Svetlana Laidinen</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation></author><author><name sortKey="Hamalainen, Kirsi" sort="Hamalainen, Kirsi" uniqKey="Hamalainen K" first="Kirsi" last="Hamalainen">Kirsi Hamalainen</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Pathology, Kuopio University Hospital, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation></author><author><name sortKey="Tuunanen, Pasi" sort="Tuunanen, Pasi" uniqKey="Tuunanen P" first="Pasi" last="Tuunanen">Pasi Tuunanen</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>National BIO‐NMR Facility, A.I. Virtanen Institute, University of Eastern Finland, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></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 wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></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 wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Pathology, Kuopio University Hospital, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation></author><author><name sortKey="Heinonen, Seppo" sort="Heinonen, Seppo" uniqKey="Heinonen S" first="Seppo" last="Heinonen">Seppo Heinonen</name><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Gynaecology, Kuopio University Hospital, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation></author><author><name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name><affiliation wicri:level="4"><country xml:lang="fr">Finlande</country><wicri:regionArea>Molecular/Cancer Biology, Laboratory Biomedicum Helsinki and Haartman Institute, University of Helsinki, Helsinki</wicri:regionArea><orgName type="university">Université d'Helsinki</orgName><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName><placeName><settlement type="city">Helsinki</settlement><region type="région" nuts="2">Uusimaa</region></placeName><orgName type="university">Université d'Helsinki</orgName></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 wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Gene Therapy Unit, Kuopio University Hospital, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Finlande</country><wicri:regionArea>Professor of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, P.O. Box 1627, Kuopio</wicri:regionArea><wicri:noRegion>Kuopio</wicri:noRegion></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><affiliations><list><country><li>Finlande</li></country><region><li>Uusimaa</li></region><settlement><li>Helsinki</li></settlement><orgName><li>Université d'Helsinki</li></orgName></list><tree><country name="Finlande"><noRegion><name sortKey="Sopo, Minna" sort="Sopo, Minna" uniqKey="Sopo M" first="Minna" last="Sopo">Minna Sopo</name></noRegion><name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name><name sortKey="Anttila, Maarit" sort="Anttila, Maarit" uniqKey="Anttila M" first="Maarit" last="Anttila">Maarit Anttila</name><name sortKey="Anttila, Maarit" sort="Anttila, Maarit" uniqKey="Anttila M" first="Maarit" last="Anttila">Maarit Anttila</name><name sortKey="Anttila, Maarit" sort="Anttila, Maarit" uniqKey="Anttila M" first="Maarit" last="Anttila">Maarit Anttila</name><name sortKey="Hamalainen, Kirsi" sort="Hamalainen, Kirsi" uniqKey="Hamalainen K" first="Kirsi" last="Hamalainen">Kirsi Hamalainen</name><name sortKey="Hamalainen, Kirsi" sort="Hamalainen, Kirsi" uniqKey="Hamalainen K" first="Kirsi" last="Hamalainen">Kirsi Hamalainen</name><name sortKey="Heinonen, Seppo" sort="Heinonen, Seppo" uniqKey="Heinonen S" first="Seppo" last="Heinonen">Seppo Heinonen</name><name sortKey="Heinonen, Seppo" sort="Heinonen, Seppo" uniqKey="Heinonen S" first="Seppo" last="Heinonen">Seppo Heinonen</name><name sortKey="Koponen, Jonna K" sort="Koponen, Jonna K" uniqKey="Koponen J" first="Jonna K." last="Koponen">Jonna K. Koponen</name><name sortKey="Kosma, Veli Atti" sort="Kosma, Veli Atti" uniqKey="Kosma V" first="Veli-Matti" last="Kosma">Veli-Matti Kosma</name><name sortKey="Kosma, Veli Atti" sort="Kosma, Veli Atti" uniqKey="Kosma V" first="Veli-Matti" last="Kosma">Veli-Matti Kosma</name><name sortKey="Laidinen, Svetlana" sort="Laidinen, Svetlana" uniqKey="Laidinen S" first="Svetlana" last="Laidinen">Svetlana Laidinen</name><name sortKey="Laurema, Anniina" sort="Laurema, Anniina" uniqKey="Laurema A" first="Anniina" last="Laurema">Anniina Laurema</name><name sortKey="Sallinen, Hanna" sort="Sallinen, Hanna" uniqKey="Sallinen H" first="Hanna" last="Sallinen">Hanna Sallinen</name><name sortKey="Sallinen, Hanna" sort="Sallinen, Hanna" uniqKey="Sallinen H" first="Hanna" last="Sallinen">Hanna Sallinen</name><name sortKey="Sallinen, Hanna" sort="Sallinen, Hanna" uniqKey="Sallinen H" first="Hanna" last="Sallinen">Hanna Sallinen</name><name sortKey="Sopo, Minna" sort="Sopo, Minna" uniqKey="Sopo M" first="Minna" last="Sopo">Minna Sopo</name><name sortKey="Sopo, Minna" sort="Sopo, Minna" uniqKey="Sopo M" first="Minna" last="Sopo">Minna Sopo</name><name sortKey="Tuppurainen, Laura" sort="Tuppurainen, Laura" uniqKey="Tuppurainen L" first="Laura" last="Tuppurainen">Laura Tuppurainen</name><name sortKey="Tuunanen, Pasi" sort="Tuunanen, Pasi" uniqKey="Tuunanen P" first="Pasi" last="Tuunanen">Pasi Tuunanen</name><name sortKey="Yla Erttuala, Seppo" sort="Yla Erttuala, Seppo" uniqKey="Yla Erttuala S" first="Seppo" last="Yla-Herttuala">Seppo Yla-Herttuala</name><name sortKey="Yla Erttuala, Seppo" sort="Yla Erttuala, Seppo" uniqKey="Yla Erttuala S" first="Seppo" last="Yla-Herttuala">Seppo Yla-Herttuala</name><name sortKey="Yla Erttuala, Seppo" sort="Yla Erttuala, Seppo" uniqKey="Yla Erttuala S" first="Seppo" last="Yla-Herttuala">Seppo Yla-Herttuala</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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