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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/Curation ); précédent : 005C53; suivant : 005C55

Antiangiogenic 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 :

RBID : ISTEX:C56F58B9F19CB32F85C629ECF166F523ADBF02E5

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.

Url:
DOI: 10.1002/ijc.27495

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ISTEX:C56F58B9F19CB32F85C629ECF166F523ADBF02E5

Le document en format XML

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<name sortKey="Yla Erttuala, Seppo" sort="Yla Erttuala, Seppo" uniqKey="Yla Erttuala S" first="Seppo" last="Yla-Herttuala">Seppo Yla-Herttuala</name>
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<mods:affiliation>Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland</mods:affiliation>
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<mods:affiliation>Professor of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, P.O. Box 1627, Kuopio, FIN‐70211 Finland</mods:affiliation>
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<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>
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<name sortKey="Sopo, Minna" sort="Sopo, Minna" uniqKey="Sopo M" first="Minna" last="Sopo">Minna Sopo</name>
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<mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation>
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<mods:affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</mods:affiliation>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Department of Gynaecology, Kuopio University Hospital, Kuopio</wicri:regionArea>
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<name sortKey="Anttila, Maarit" sort="Anttila, Maarit" uniqKey="Anttila M" first="Maarit" last="Anttila">Maarit Anttila</name>
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<mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio</wicri:regionArea>
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<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>
</affiliation>
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<mods:affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</mods:affiliation>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Department of Gynaecology, Kuopio University Hospital, Kuopio</wicri:regionArea>
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<name sortKey="Sallinen, Hanna" sort="Sallinen, Hanna" uniqKey="Sallinen H" first="Hanna" last="Sallinen">Hanna Sallinen</name>
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<mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation>
<country xml:lang="fr">Finlande</country>
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<wicri:regionArea>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio</wicri:regionArea>
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<mods:affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</mods:affiliation>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Department of Gynaecology, Kuopio University Hospital, Kuopio</wicri:regionArea>
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<name sortKey="Tuppurainen, Laura" sort="Tuppurainen, Laura" uniqKey="Tuppurainen L" first="Laura" last="Tuppurainen">Laura Tuppurainen</name>
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<name sortKey="Laurema, Anniina" sort="Laurema, Anniina" uniqKey="Laurema A" first="Anniina" last="Laurema">Anniina Laurema</name>
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<wicri:regionArea>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio</wicri:regionArea>
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<name sortKey="Laidinen, Svetlana" sort="Laidinen, Svetlana" uniqKey="Laidinen S" first="Svetlana" last="Laidinen">Svetlana Laidinen</name>
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<mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio</wicri:regionArea>
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<name sortKey="Hamalainen, Kirsi" sort="Hamalainen, Kirsi" uniqKey="Hamalainen K" first="Kirsi" last="Hamalainen">Kirsi Hamalainen</name>
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<wicri:regionArea>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio</wicri:regionArea>
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<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Department of Pathology, Kuopio University Hospital, Kuopio</wicri:regionArea>
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<name sortKey="Tuunanen, Pasi" sort="Tuunanen, Pasi" uniqKey="Tuunanen P" first="Pasi" last="Tuunanen">Pasi Tuunanen</name>
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<mods:affiliation>National BIO‐NMR Facility, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation>
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<wicri:regionArea>National BIO‐NMR Facility, A.I. Virtanen Institute, University of Eastern Finland, Kuopio</wicri:regionArea>
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<name sortKey="Koponen, Jonna K" sort="Koponen, Jonna K" uniqKey="Koponen J" first="Jonna K." last="Koponen">Jonna K. Koponen</name>
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<mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation>
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<wicri:regionArea>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio</wicri:regionArea>
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<name sortKey="Kosma, Veli Atti" sort="Kosma, Veli Atti" uniqKey="Kosma V" first="Veli-Matti" last="Kosma">Veli-Matti Kosma</name>
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<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>
</affiliation>
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<mods:affiliation>Department of Pathology, Kuopio University Hospital, Kuopio, Finland</mods:affiliation>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Department of Pathology, Kuopio University Hospital, Kuopio</wicri:regionArea>
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</author>
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<name sortKey="Heinonen, Seppo" sort="Heinonen, Seppo" uniqKey="Heinonen S" first="Seppo" last="Heinonen">Seppo Heinonen</name>
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<mods:affiliation>Institute of Clinical Medicine, Gynaecology, and Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</mods:affiliation>
<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>
</affiliation>
<affiliation wicri:level="1">
<mods:affiliation>Department of Gynaecology, Kuopio University Hospital, Kuopio, Finland</mods:affiliation>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Department of Gynaecology, Kuopio University Hospital, Kuopio</wicri:regionArea>
</affiliation>
</author>
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<name sortKey="Alitalo, Kari" sort="Alitalo, Kari" uniqKey="Alitalo K" first="Kari" last="Alitalo">Kari Alitalo</name>
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<mods:affiliation>Molecular/Cancer Biology, Laboratory Biomedicum Helsinki and Haartman Institute, University of Helsinki, Helsinki, Finland</mods:affiliation>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Molecular/Cancer Biology, Laboratory Biomedicum Helsinki and Haartman Institute, University of Helsinki, Helsinki</wicri:regionArea>
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</author>
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<name sortKey="Yla Erttuala, Seppo" sort="Yla Erttuala, Seppo" uniqKey="Yla Erttuala S" first="Seppo" last="Yla-Herttuala">Seppo Yla-Herttuala</name>
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<mods:affiliation>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland</mods:affiliation>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Department of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, Kuopio</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<mods:affiliation>Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland</mods:affiliation>
<country xml:lang="fr">Finlande</country>
<wicri:regionArea>Gene Therapy Unit, Kuopio University Hospital, Kuopio</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1">
<mods:affiliation>Professor of Molecular Medicine, A.I. Virtanen Institute, University of Eastern Finland, P.O. Box 1627, Kuopio, FIN‐70211 Finland</mods:affiliation>
<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>
</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>
</record>

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