Conditionally replicating adenovirus expressing TIMP2 increases survival in a mouse model of disseminated ovarian cancer
Ovarian cancer remains difficult to treat mainly due to presentation of the disease at an advanced stage. Conditionally-replicating adenoviruses (CRAds) are promising anti-cancer agents that selectively kill the tumor cells. The present study evaluated the efficacy of a novel CRAd (Ad5/3-CXCR4-TIMP2...
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| creator | Yang, Sherry W Chanda, Diptiman Cody, James J Rivera, Angel A Waehler, Reinhard Siegal, Gene P Douglas, Joanne T Ponnazhagan, Selvarangan |
| description | Ovarian cancer remains difficult to treat mainly due to presentation of the disease at an advanced stage. Conditionally-replicating adenoviruses (CRAds) are promising anti-cancer agents that selectively kill the tumor cells. The present study evaluated the efficacy of a novel CRAd (Ad5/3-CXCR4-TIMP2) containing the CXCR4 promoter for selective viral replication in cancer cells together with TIMP2 as a therapeutic transgene, targeting the matrix metalloproteases (MMPs) in a murine orthotopic model of disseminated ovarian cancer. An orthotopic model of ovarian cancer was established in athymic nude mice by intraperitonal injection of the human ovarian cancer cell line, SKOV3-Luc, expressing luciferase. Upon confirmation of peritoneal dissemination of the cells by non-invasive imaging, mice were randomly divided into four treatment groups: PBS, Ad-ΔE1-TIMP2, Ad5/3-CXCR4, and Ad5/3-CXCR4-TIMP2. All mice were imaged weekly to monitor tumor growth and were sacrificed upon reaching any of the predefined endpoints, including high tumor burden and significant weight loss along with clinical evidence of pain and distress. Survival analysis was performed using the Log-rank test. The median survival for the PBS cohort was 33 days; for Ad-ΔE1-TIMP2, 39 days; for Ad5/3-CXCR4, 52.5 days; and for Ad5/3-CXCR4-TIMP2, 63 days. The TIMP2-armed CRAd delayed tumor growth and significantly increased survival when compared to the unarmed CRAd. This therapeutic effect was confirmed to be mediated through inhibition of MMP9. Results of the in vivo study support the translational potential of Ad5/3-CXCR4-TIMP2 for treatment of human patients with advanced ovarian cancer. |
| doi_str_mv | 10.1371/journal.pone.0025131 |
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Conditionally-replicating adenoviruses (CRAds) are promising anti-cancer agents that selectively kill the tumor cells. The present study evaluated the efficacy of a novel CRAd (Ad5/3-CXCR4-TIMP2) containing the CXCR4 promoter for selective viral replication in cancer cells together with TIMP2 as a therapeutic transgene, targeting the matrix metalloproteases (MMPs) in a murine orthotopic model of disseminated ovarian cancer. An orthotopic model of ovarian cancer was established in athymic nude mice by intraperitonal injection of the human ovarian cancer cell line, SKOV3-Luc, expressing luciferase. Upon confirmation of peritoneal dissemination of the cells by non-invasive imaging, mice were randomly divided into four treatment groups: PBS, Ad-ΔE1-TIMP2, Ad5/3-CXCR4, and Ad5/3-CXCR4-TIMP2. All mice were imaged weekly to monitor tumor growth and were sacrificed upon reaching any of the predefined endpoints, including high tumor burden and significant weight loss along with clinical evidence of pain and distress. Survival analysis was performed using the Log-rank test. The median survival for the PBS cohort was 33 days; for Ad-ΔE1-TIMP2, 39 days; for Ad5/3-CXCR4, 52.5 days; and for Ad5/3-CXCR4-TIMP2, 63 days. The TIMP2-armed CRAd delayed tumor growth and significantly increased survival when compared to the unarmed CRAd. This therapeutic effect was confirmed to be mediated through inhibition of MMP9. Results of the in vivo study support the translational potential of Ad5/3-CXCR4-TIMP2 for treatment of human patients with advanced ovarian cancer.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0025131</identifier><identifier>PMID: 22022379</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenoviridae - physiology ; Adenoviruses ; Angiogenesis ; Animals ; Anticancer properties ; Biology ; Cancer ; Cancer therapies ; Cancer treatment ; Cell Line, Tumor ; Cell Proliferation ; Cervical cancer ; Chemokines ; Chemotherapy ; CXCR4 protein ; Disease Models, Animal ; Female ; Gelatinase B ; Gynecology ; Health aspects ; Human papillomavirus ; Humans ; Imaging, Three-Dimensional ; Immunotherapy ; In vivo methods and tests ; Liver ; Luciferase ; Luminescent Measurements ; Matrix Metalloproteinase 9 - metabolism ; Medical prognosis ; Medicine ; Metastasis ; Mice ; Molecular biology ; Morphology ; Neovascularization, Pathologic - pathology ; Obstetrics ; Ovarian cancer ; Ovarian carcinoma ; Ovarian Neoplasms - blood supply ; Ovarian Neoplasms - enzymology ; Ovarian Neoplasms - pathology ; Pain ; Pathology ; Patients ; Peritoneum ; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism ; Proteins ; Replication ; Survival ; Survival Analysis ; Tissue inhibitor of metalloproteinase 2 ; Tissue Inhibitor of Metalloproteinase-2 - metabolism ; Tumor cells ; Tumors ; Virus Replication - physiology</subject><ispartof>PloS one, 2011-10, Vol.6 (10), p.e25131-e25131</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Yang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Yang et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c757t-8cd97f92575ca1b9bbff80fac7158e08c1b7fccd076d15d670a0edd6e0a8900d3</citedby><cites>FETCH-LOGICAL-c757t-8cd97f92575ca1b9bbff80fac7158e08c1b7fccd076d15d670a0edd6e0a8900d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192051/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192051/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22022379$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Sherry W</creatorcontrib><creatorcontrib>Chanda, Diptiman</creatorcontrib><creatorcontrib>Cody, James J</creatorcontrib><creatorcontrib>Rivera, Angel A</creatorcontrib><creatorcontrib>Waehler, Reinhard</creatorcontrib><creatorcontrib>Siegal, Gene P</creatorcontrib><creatorcontrib>Douglas, Joanne T</creatorcontrib><creatorcontrib>Ponnazhagan, Selvarangan</creatorcontrib><title>Conditionally replicating adenovirus expressing TIMP2 increases survival in a mouse model of disseminated ovarian cancer</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Ovarian cancer remains difficult to treat mainly due to presentation of the disease at an advanced stage. Conditionally-replicating adenoviruses (CRAds) are promising anti-cancer agents that selectively kill the tumor cells. The present study evaluated the efficacy of a novel CRAd (Ad5/3-CXCR4-TIMP2) containing the CXCR4 promoter for selective viral replication in cancer cells together with TIMP2 as a therapeutic transgene, targeting the matrix metalloproteases (MMPs) in a murine orthotopic model of disseminated ovarian cancer. An orthotopic model of ovarian cancer was established in athymic nude mice by intraperitonal injection of the human ovarian cancer cell line, SKOV3-Luc, expressing luciferase. Upon confirmation of peritoneal dissemination of the cells by non-invasive imaging, mice were randomly divided into four treatment groups: PBS, Ad-ΔE1-TIMP2, Ad5/3-CXCR4, and Ad5/3-CXCR4-TIMP2. All mice were imaged weekly to monitor tumor growth and were sacrificed upon reaching any of the predefined endpoints, including high tumor burden and significant weight loss along with clinical evidence of pain and distress. Survival analysis was performed using the Log-rank test. The median survival for the PBS cohort was 33 days; for Ad-ΔE1-TIMP2, 39 days; for Ad5/3-CXCR4, 52.5 days; and for Ad5/3-CXCR4-TIMP2, 63 days. The TIMP2-armed CRAd delayed tumor growth and significantly increased survival when compared to the unarmed CRAd. This therapeutic effect was confirmed to be mediated through inhibition of MMP9. Results of the in vivo study support the translational potential of Ad5/3-CXCR4-TIMP2 for treatment of human patients with advanced ovarian cancer.</description><subject>Adenoviridae - physiology</subject><subject>Adenoviruses</subject><subject>Angiogenesis</subject><subject>Animals</subject><subject>Anticancer properties</subject><subject>Biology</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cancer treatment</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cervical cancer</subject><subject>Chemokines</subject><subject>Chemotherapy</subject><subject>CXCR4 protein</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Gelatinase B</subject><subject>Gynecology</subject><subject>Health aspects</subject><subject>Human papillomavirus</subject><subject>Humans</subject><subject>Imaging, Three-Dimensional</subject><subject>Immunotherapy</subject><subject>In vivo methods and tests</subject><subject>Liver</subject><subject>Luciferase</subject><subject>Luminescent Measurements</subject><subject>Matrix Metalloproteinase 9 - metabolism</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Molecular biology</subject><subject>Morphology</subject><subject>Neovascularization, Pathologic - pathology</subject><subject>Obstetrics</subject><subject>Ovarian cancer</subject><subject>Ovarian carcinoma</subject><subject>Ovarian Neoplasms - blood supply</subject><subject>Ovarian Neoplasms - enzymology</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Pain</subject><subject>Pathology</subject><subject>Patients</subject><subject>Peritoneum</subject><subject>Platelet Endothelial Cell Adhesion Molecule-1 - metabolism</subject><subject>Proteins</subject><subject>Replication</subject><subject>Survival</subject><subject>Survival Analysis</subject><subject>Tissue inhibitor of metalloproteinase 2</subject><subject>Tissue Inhibitor of Metalloproteinase-2 - metabolism</subject><subject>Tumor cells</subject><subject>Tumors</subject><subject>Virus Replication - 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Conditionally-replicating adenoviruses (CRAds) are promising anti-cancer agents that selectively kill the tumor cells. The present study evaluated the efficacy of a novel CRAd (Ad5/3-CXCR4-TIMP2) containing the CXCR4 promoter for selective viral replication in cancer cells together with TIMP2 as a therapeutic transgene, targeting the matrix metalloproteases (MMPs) in a murine orthotopic model of disseminated ovarian cancer. An orthotopic model of ovarian cancer was established in athymic nude mice by intraperitonal injection of the human ovarian cancer cell line, SKOV3-Luc, expressing luciferase. Upon confirmation of peritoneal dissemination of the cells by non-invasive imaging, mice were randomly divided into four treatment groups: PBS, Ad-ΔE1-TIMP2, Ad5/3-CXCR4, and Ad5/3-CXCR4-TIMP2. All mice were imaged weekly to monitor tumor growth and were sacrificed upon reaching any of the predefined endpoints, including high tumor burden and significant weight loss along with clinical evidence of pain and distress. Survival analysis was performed using the Log-rank test. The median survival for the PBS cohort was 33 days; for Ad-ΔE1-TIMP2, 39 days; for Ad5/3-CXCR4, 52.5 days; and for Ad5/3-CXCR4-TIMP2, 63 days. The TIMP2-armed CRAd delayed tumor growth and significantly increased survival when compared to the unarmed CRAd. This therapeutic effect was confirmed to be mediated through inhibition of MMP9. Results of the in vivo study support the translational potential of Ad5/3-CXCR4-TIMP2 for treatment of human patients with advanced ovarian cancer.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22022379</pmid><doi>10.1371/journal.pone.0025131</doi><tpages>e25131</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1309827239 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adenoviridae - physiology Adenoviruses Angiogenesis Animals Anticancer properties Biology Cancer Cancer therapies Cancer treatment Cell Line, Tumor Cell Proliferation Cervical cancer Chemokines Chemotherapy CXCR4 protein Disease Models, Animal Female Gelatinase B Gynecology Health aspects Human papillomavirus Humans Imaging, Three-Dimensional Immunotherapy In vivo methods and tests Liver Luciferase Luminescent Measurements Matrix Metalloproteinase 9 - metabolism Medical prognosis Medicine Metastasis Mice Molecular biology Morphology Neovascularization, Pathologic - pathology Obstetrics Ovarian cancer Ovarian carcinoma Ovarian Neoplasms - blood supply Ovarian Neoplasms - enzymology Ovarian Neoplasms - pathology Pain Pathology Patients Peritoneum Platelet Endothelial Cell Adhesion Molecule-1 - metabolism Proteins Replication Survival Survival Analysis Tissue inhibitor of metalloproteinase 2 Tissue Inhibitor of Metalloproteinase-2 - metabolism Tumor cells Tumors Virus Replication - physiology |
| title | Conditionally replicating adenovirus expressing TIMP2 increases survival in a mouse model of disseminated ovarian cancer |
| 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%3A32%3A43IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Conditionally%20replicating%20adenovirus%20expressing%20TIMP2%20increases%20survival%20in%20a%20mouse%20model%20of%20disseminated%20ovarian%20cancer&rft.jtitle=PloS%20one&rft.au=Yang,%20Sherry%20W&rft.date=2011-10-12&rft.volume=6&rft.issue=10&rft.spage=e25131&rft.epage=e25131&rft.pages=e25131-e25131&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0025131&rft_dat=%3Cgale_plos_%3EA476868781%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1309827239&rft_id=info:pmid/22022379&rft_galeid=A476868781&rft_doaj_id=oai_doaj_org_article_a89e8f6556d14978a92b7d720dbc70b6&rfr_iscdi=true |