Systemic Delivery of Oncolytic Adenoviruses Targeting Transforming Growth Factor-β Inhibits Established Bone Metastasis in a Prostate Cancer Mouse Model
We have examined whether Ad.sTβRFc and TAd.sTβRFc, two oncolytic viruses expressing soluble transforming growth factor-β receptor II fused with human Fc (sTGFβRIIFc), can be developed to treat bone metastasis of prostate cancer. Incubation of PC-3 and DU-145 prostate tumor cells with Ad.sTβRFc and T...
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| Veröffentlicht in: | Human gene therapy 2012-08, Vol.23 (8), p.871-882 |
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| creator | ZEBIN HU GUPTA, Janhavi PIENTA, Kenneth J GUISE, Theresa LEE, Chung STERN, Paula H STOCK, Stuart SETH, Prem ZHENWEI ZHANG GERSENY, Helen BERG, Arthur YUN JU CHEN ZHILING ZHANG HONGYAN DU BRENDLER, Charles B XIANGHUI XIAO |
| description | We have examined whether Ad.sTβRFc and TAd.sTβRFc, two oncolytic viruses expressing soluble transforming growth factor-β receptor II fused with human Fc (sTGFβRIIFc), can be developed to treat bone metastasis of prostate cancer. Incubation of PC-3 and DU-145 prostate tumor cells with Ad.sTβRFc and TAd.sTβRFc produced sTGFβRIIFc and viral replication; sTGFβRIIFc caused inhibition of TGF-β-mediated SMAD2 and SMAD3 phosphorylation. Ad(E1-).sTβRFc, an E1(-) adenovirus, produced sTGFβRIIFc but failed to replicate in tumor cells. To examine the antitumor response of adenoviral vectors, PC-3-luc cells were injected into the left heart ventricle of nude mice. On day 9, mice were subjected to whole-body bioluminescence imaging (BLI). Mice bearing hind-limb tumors were administered viral vectors via the tail vein on days 10, 13, and 17 (2.5×10(10) viral particles per injection per mouse, each injection in a 0.1-ml volume), and subjected to BLI and X-ray radiography weekly until day 53. Ad.sTβRFc, TAd.sTβRFc, and Ad(E1-).sTβRFc caused significant inhibition of tumor growth; however, Ad.sTβRFc was the most effective among all the vectors. Only Ad.sTβRFc and TAd.sTβRFc inhibited tumor-induced hypercalcemia. Histomorphometric and synchrotron micro-computed tomographic analysis of isolated bones indicated that Ad.sTβRFc induced significant reduction in tumor burden, osteoclast number, and trabecular and cortical bone destruction. These studies suggest that Ad.sTβRFc and TAd.sTβRFc can be developed as potential new therapies for prostate cancer bone metastasis. |
| doi_str_mv | 10.1089/hum.2012.040 |
| format | Article |
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Incubation of PC-3 and DU-145 prostate tumor cells with Ad.sTβRFc and TAd.sTβRFc produced sTGFβRIIFc and viral replication; sTGFβRIIFc caused inhibition of TGF-β-mediated SMAD2 and SMAD3 phosphorylation. Ad(E1-).sTβRFc, an E1(-) adenovirus, produced sTGFβRIIFc but failed to replicate in tumor cells. To examine the antitumor response of adenoviral vectors, PC-3-luc cells were injected into the left heart ventricle of nude mice. On day 9, mice were subjected to whole-body bioluminescence imaging (BLI). Mice bearing hind-limb tumors were administered viral vectors via the tail vein on days 10, 13, and 17 (2.5×10(10) viral particles per injection per mouse, each injection in a 0.1-ml volume), and subjected to BLI and X-ray radiography weekly until day 53. Ad.sTβRFc, TAd.sTβRFc, and Ad(E1-).sTβRFc caused significant inhibition of tumor growth; however, Ad.sTβRFc was the most effective among all the vectors. Only Ad.sTβRFc and TAd.sTβRFc inhibited tumor-induced hypercalcemia. Histomorphometric and synchrotron micro-computed tomographic analysis of isolated bones indicated that Ad.sTβRFc induced significant reduction in tumor burden, osteoclast number, and trabecular and cortical bone destruction. These studies suggest that Ad.sTβRFc and TAd.sTβRFc can be developed as potential new therapies for prostate cancer bone metastasis.</description><identifier>ISSN: 1043-0342</identifier><identifier>EISSN: 1557-7422</identifier><identifier>DOI: 10.1089/hum.2012.040</identifier><identifier>PMID: 22551458</identifier><identifier>CODEN: HGTHE3</identifier><language>eng</language><publisher>Larchmont, NY: Liebert</publisher><subject>Adenoviridae - genetics ; Adenovirus ; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy ; Animal models ; Animals ; Antitumor activity ; Applied cell therapy and gene therapy ; Biological and medical sciences ; Biotechnology ; Bone (trabecular) ; Bone cancer ; Bone growth ; Bone Neoplasms - secondary ; Bone Neoplasms - therapy ; Cell Line, Tumor ; Disease Models, Animal ; Fundamental and applied biological sciences. Psychology ; Gene therapy ; Genetic Vectors ; Health. Pharmaceutical industry ; HEK293 Cells ; Humans ; Hypercalcemia ; Industrial applications and implications. Economical aspects ; Male ; Medical sciences ; Metastases ; Mice ; Oncolysis ; Oncolytic Virotherapy ; Oncolytic Viruses - genetics ; Phosphorylation ; Prostate cancer ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - pathology ; Prostatic Neoplasms - therapy ; Radiography ; Smad2 protein ; Smad2 Protein - genetics ; Smad2 Protein - metabolism ; Smad3 Protein - genetics ; Smad3 Protein - metabolism ; Transforming Growth Factor beta - antagonists & inhibitors ; Transforming Growth Factor beta - genetics ; Transforming growth factor- beta ; transforming growth factor- beta receptors ; Transfusions. Complications. Transfusion reactions. Cell and gene therapy ; Tumor cells ; Tumors ; Veins ; Ventricle</subject><ispartof>Human gene therapy, 2012-08, Vol.23 (8), p.871-882</ispartof><rights>2015 INIST-CNRS</rights><rights>Copyright 2012, Mary Ann Liebert, Inc. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-44045408fb6a6336ae18f9a2373edd320ac6e3fac2b1c35c02c5b4d8e74e2cbe3</citedby><cites>FETCH-LOGICAL-c447t-44045408fb6a6336ae18f9a2373edd320ac6e3fac2b1c35c02c5b4d8e74e2cbe3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26259063$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22551458$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>ZEBIN HU</creatorcontrib><creatorcontrib>GUPTA, Janhavi</creatorcontrib><creatorcontrib>PIENTA, Kenneth J</creatorcontrib><creatorcontrib>GUISE, Theresa</creatorcontrib><creatorcontrib>LEE, Chung</creatorcontrib><creatorcontrib>STERN, Paula H</creatorcontrib><creatorcontrib>STOCK, Stuart</creatorcontrib><creatorcontrib>SETH, Prem</creatorcontrib><creatorcontrib>ZHENWEI ZHANG</creatorcontrib><creatorcontrib>GERSENY, Helen</creatorcontrib><creatorcontrib>BERG, Arthur</creatorcontrib><creatorcontrib>YUN JU CHEN</creatorcontrib><creatorcontrib>ZHILING ZHANG</creatorcontrib><creatorcontrib>HONGYAN DU</creatorcontrib><creatorcontrib>BRENDLER, Charles B</creatorcontrib><creatorcontrib>XIANGHUI XIAO</creatorcontrib><title>Systemic Delivery of Oncolytic Adenoviruses Targeting Transforming Growth Factor-β Inhibits Established Bone Metastasis in a Prostate Cancer Mouse Model</title><title>Human gene therapy</title><addtitle>Hum Gene Ther</addtitle><description>We have examined whether Ad.sTβRFc and TAd.sTβRFc, two oncolytic viruses expressing soluble transforming growth factor-β receptor II fused with human Fc (sTGFβRIIFc), can be developed to treat bone metastasis of prostate cancer. Incubation of PC-3 and DU-145 prostate tumor cells with Ad.sTβRFc and TAd.sTβRFc produced sTGFβRIIFc and viral replication; sTGFβRIIFc caused inhibition of TGF-β-mediated SMAD2 and SMAD3 phosphorylation. Ad(E1-).sTβRFc, an E1(-) adenovirus, produced sTGFβRIIFc but failed to replicate in tumor cells. To examine the antitumor response of adenoviral vectors, PC-3-luc cells were injected into the left heart ventricle of nude mice. On day 9, mice were subjected to whole-body bioluminescence imaging (BLI). Mice bearing hind-limb tumors were administered viral vectors via the tail vein on days 10, 13, and 17 (2.5×10(10) viral particles per injection per mouse, each injection in a 0.1-ml volume), and subjected to BLI and X-ray radiography weekly until day 53. Ad.sTβRFc, TAd.sTβRFc, and Ad(E1-).sTβRFc caused significant inhibition of tumor growth; however, Ad.sTβRFc was the most effective among all the vectors. Only Ad.sTβRFc and TAd.sTβRFc inhibited tumor-induced hypercalcemia. Histomorphometric and synchrotron micro-computed tomographic analysis of isolated bones indicated that Ad.sTβRFc induced significant reduction in tumor burden, osteoclast number, and trabecular and cortical bone destruction. These studies suggest that Ad.sTβRFc and TAd.sTβRFc can be developed as potential new therapies for prostate cancer bone metastasis.</description><subject>Adenoviridae - genetics</subject><subject>Adenovirus</subject><subject>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antitumor activity</subject><subject>Applied cell therapy and gene therapy</subject><subject>Biological and medical sciences</subject><subject>Biotechnology</subject><subject>Bone (trabecular)</subject><subject>Bone cancer</subject><subject>Bone growth</subject><subject>Bone Neoplasms - secondary</subject><subject>Bone Neoplasms - therapy</subject><subject>Cell Line, Tumor</subject><subject>Disease Models, Animal</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene therapy</subject><subject>Genetic Vectors</subject><subject>Health. Pharmaceutical industry</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Hypercalcemia</subject><subject>Industrial applications and implications. Economical aspects</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metastases</subject><subject>Mice</subject><subject>Oncolysis</subject><subject>Oncolytic Virotherapy</subject><subject>Oncolytic Viruses - genetics</subject><subject>Phosphorylation</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Prostatic Neoplasms - therapy</subject><subject>Radiography</subject><subject>Smad2 protein</subject><subject>Smad2 Protein - genetics</subject><subject>Smad2 Protein - metabolism</subject><subject>Smad3 Protein - genetics</subject><subject>Smad3 Protein - metabolism</subject><subject>Transforming Growth Factor beta - antagonists & inhibitors</subject><subject>Transforming Growth Factor beta - genetics</subject><subject>Transforming growth factor- beta</subject><subject>transforming growth factor- beta receptors</subject><subject>Transfusions. Complications. Transfusion reactions. Cell and gene therapy</subject><subject>Tumor cells</subject><subject>Tumors</subject><subject>Veins</subject><subject>Ventricle</subject><issn>1043-0342</issn><issn>1557-7422</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1u1DAQgCMEoqVw44x8QeJAFv_m54JUlrZUalUklrM1cSYbo8QutnfRPgqvwYPwTHjVpcCNi-0Zfxp75iuK54wuGG3aN-NmXnDK-IJK-qA4ZkrVZS05f5jPVIqSCsmPiicxfqGUCVXVj4sjzpViUjXHxfdPu5hwtoa8x8luMeyIH8iNM37apZw97dH5rQ2biJGsIKwxWbcmqwAuDj7M--Ai-G9pJOdgkg_lzx_k0o22symSs5igm2wcsSfvvENyjQlyLtpIrCNAPgafw4RkCc5gINc-P5TXHqenxaMBpojPDvtJ8fn8bLX8UF7dXFwuT69KI2WdSimpVJI2Q1dBJUQFyJqhBS5qgX0vOAVToRjA8I4ZoQzlRnWyb7CWyE2H4qR4e1f3dtPN2Bt0KcCkb4OdIey0B6v_vXF21Gu_1UIy0bRtLvDqUCD4rxuMSc82GpwmcJjb0YxWLaeCVvV_oEJmMbKpMvr6DjV5RDHgcP8jRvVevM7i9V68zuIz_uLvLu7h36Yz8PIAQDQwDVmgsfEPV3HV0jzAX8L6ut4</recordid><startdate>20120801</startdate><enddate>20120801</enddate><creator>ZEBIN HU</creator><creator>GUPTA, Janhavi</creator><creator>PIENTA, Kenneth J</creator><creator>GUISE, Theresa</creator><creator>LEE, Chung</creator><creator>STERN, Paula H</creator><creator>STOCK, Stuart</creator><creator>SETH, Prem</creator><creator>ZHENWEI ZHANG</creator><creator>GERSENY, Helen</creator><creator>BERG, Arthur</creator><creator>YUN JU CHEN</creator><creator>ZHILING ZHANG</creator><creator>HONGYAN DU</creator><creator>BRENDLER, Charles B</creator><creator>XIANGHUI XIAO</creator><general>Liebert</general><general>Mary Ann Liebert, Inc</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7QO</scope><scope>7QP</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20120801</creationdate><title>Systemic Delivery of Oncolytic Adenoviruses Targeting Transforming Growth Factor-β Inhibits Established Bone Metastasis in a Prostate Cancer Mouse Model</title><author>ZEBIN HU ; GUPTA, Janhavi ; PIENTA, Kenneth J ; GUISE, Theresa ; LEE, Chung ; STERN, Paula H ; STOCK, Stuart ; SETH, Prem ; ZHENWEI ZHANG ; GERSENY, Helen ; BERG, Arthur ; YUN JU CHEN ; ZHILING ZHANG ; HONGYAN DU ; BRENDLER, Charles B ; XIANGHUI XIAO</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-44045408fb6a6336ae18f9a2373edd320ac6e3fac2b1c35c02c5b4d8e74e2cbe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adenoviridae - genetics</topic><topic>Adenovirus</topic><topic>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</topic><topic>Animal models</topic><topic>Animals</topic><topic>Antitumor activity</topic><topic>Applied cell therapy and gene therapy</topic><topic>Biological and medical sciences</topic><topic>Biotechnology</topic><topic>Bone (trabecular)</topic><topic>Bone cancer</topic><topic>Bone growth</topic><topic>Bone Neoplasms - secondary</topic><topic>Bone Neoplasms - therapy</topic><topic>Cell Line, Tumor</topic><topic>Disease Models, Animal</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene therapy</topic><topic>Genetic Vectors</topic><topic>Health. Pharmaceutical industry</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Hypercalcemia</topic><topic>Industrial applications and implications. Economical aspects</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metastases</topic><topic>Mice</topic><topic>Oncolysis</topic><topic>Oncolytic Virotherapy</topic><topic>Oncolytic Viruses - genetics</topic><topic>Phosphorylation</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms - genetics</topic><topic>Prostatic Neoplasms - pathology</topic><topic>Prostatic Neoplasms - therapy</topic><topic>Radiography</topic><topic>Smad2 protein</topic><topic>Smad2 Protein - genetics</topic><topic>Smad2 Protein - metabolism</topic><topic>Smad3 Protein - genetics</topic><topic>Smad3 Protein - metabolism</topic><topic>Transforming Growth Factor beta - antagonists & inhibitors</topic><topic>Transforming Growth Factor beta - genetics</topic><topic>Transforming growth factor- beta</topic><topic>transforming growth factor- beta receptors</topic><topic>Transfusions. Complications. Transfusion reactions. 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Incubation of PC-3 and DU-145 prostate tumor cells with Ad.sTβRFc and TAd.sTβRFc produced sTGFβRIIFc and viral replication; sTGFβRIIFc caused inhibition of TGF-β-mediated SMAD2 and SMAD3 phosphorylation. Ad(E1-).sTβRFc, an E1(-) adenovirus, produced sTGFβRIIFc but failed to replicate in tumor cells. To examine the antitumor response of adenoviral vectors, PC-3-luc cells were injected into the left heart ventricle of nude mice. On day 9, mice were subjected to whole-body bioluminescence imaging (BLI). Mice bearing hind-limb tumors were administered viral vectors via the tail vein on days 10, 13, and 17 (2.5×10(10) viral particles per injection per mouse, each injection in a 0.1-ml volume), and subjected to BLI and X-ray radiography weekly until day 53. Ad.sTβRFc, TAd.sTβRFc, and Ad(E1-).sTβRFc caused significant inhibition of tumor growth; however, Ad.sTβRFc was the most effective among all the vectors. Only Ad.sTβRFc and TAd.sTβRFc inhibited tumor-induced hypercalcemia. Histomorphometric and synchrotron micro-computed tomographic analysis of isolated bones indicated that Ad.sTβRFc induced significant reduction in tumor burden, osteoclast number, and trabecular and cortical bone destruction. These studies suggest that Ad.sTβRFc and TAd.sTβRFc can be developed as potential new therapies for prostate cancer bone metastasis.</abstract><cop>Larchmont, NY</cop><pub>Liebert</pub><pmid>22551458</pmid><doi>10.1089/hum.2012.040</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Human gene therapy, 2012-08, Vol.23 (8), p.871-882 |
| issn | 1043-0342 1557-7422 |
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| subjects | Adenoviridae - genetics Adenovirus Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Animal models Animals Antitumor activity Applied cell therapy and gene therapy Biological and medical sciences Biotechnology Bone (trabecular) Bone cancer Bone growth Bone Neoplasms - secondary Bone Neoplasms - therapy Cell Line, Tumor Disease Models, Animal Fundamental and applied biological sciences. Psychology Gene therapy Genetic Vectors Health. Pharmaceutical industry HEK293 Cells Humans Hypercalcemia Industrial applications and implications. Economical aspects Male Medical sciences Metastases Mice Oncolysis Oncolytic Virotherapy Oncolytic Viruses - genetics Phosphorylation Prostate cancer Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Prostatic Neoplasms - therapy Radiography Smad2 protein Smad2 Protein - genetics Smad2 Protein - metabolism Smad3 Protein - genetics Smad3 Protein - metabolism Transforming Growth Factor beta - antagonists & inhibitors Transforming Growth Factor beta - genetics Transforming growth factor- beta transforming growth factor- beta receptors Transfusions. Complications. Transfusion reactions. Cell and gene therapy Tumor cells Tumors Veins Ventricle |
| title | Systemic Delivery of Oncolytic Adenoviruses Targeting Transforming Growth Factor-β Inhibits Established Bone Metastasis in a Prostate Cancer Mouse Model |
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