Inhibition of PVR with a tyrosine kinase inhibitor, dasatinib, in the swine
We tested the efficacy of dasatinib, a Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor, to prevent proliferative vitreoretinopathy (PVR). The effect of dasatinib on RPE sheet growth was determined by measuring enlargement of cultured RPE sheets in the presence or absence of das...
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| Veröffentlicht in: | Investigative ophthalmology & visual science 2013-02, Vol.54 (2), p.1150 |
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| creator | Umazume, Kazuhiko Liu, Lanhsin Scott, Patrick A de Castro, Juan P Fernandez McDonald, Kevin Kaplan, Henry J Tamiya, Shigeo |
| description | We tested the efficacy of dasatinib, a Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor, to prevent proliferative vitreoretinopathy (PVR).
The effect of dasatinib on RPE sheet growth was determined by measuring enlargement of cultured RPE sheets in the presence or absence of dasatinib. Epithelial-mesenchymal transition (EMT) of RPE cells was assessed by expression of S100A4. A scratch wound assay, cell number count, and type I collagen contraction assay were used to examine the effect of dasatinib on migration, proliferation, and extracellular matrix (ECM) contraction, respectively. Our swine model of experimental PVR with green fluorescent protein-positive (GFP+) RPE cells was used to assess the efficacy of dasatinib in preventing traction retinal detachment (TRD) caused by PVR. Full-field electroretinography and histologic examination were used to determine the retinal toxicity of dasatinib.
Dasatinib prevented RPE sheet growth, cell migration, proliferation, EMT, and ECM contraction in a concentration-dependent manner. 0.1 μM dasatinib inhibited nearly 80% of vitreous fluid-stimulated collagen gel contraction. Dasatinib also prevented TRD caused by PVR in vivo. Only 1/11 eyes had a TRD in the presence of dasatinib, while all 11 controls eyes had a TRD. Dasatinib did not cause any detectable toxicity of the retina.
Dasatinib significantly inhibited PVR-related RPE changes in vitro and prevented TRD in an experimental PVR model in the swine without any detectable toxicity. Our data suggested that dasatinib may be effective in the prevention of PVR. |
| doi_str_mv | 10.1167/iovs.12-10418 |
| format | Article |
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The effect of dasatinib on RPE sheet growth was determined by measuring enlargement of cultured RPE sheets in the presence or absence of dasatinib. Epithelial-mesenchymal transition (EMT) of RPE cells was assessed by expression of S100A4. A scratch wound assay, cell number count, and type I collagen contraction assay were used to examine the effect of dasatinib on migration, proliferation, and extracellular matrix (ECM) contraction, respectively. Our swine model of experimental PVR with green fluorescent protein-positive (GFP+) RPE cells was used to assess the efficacy of dasatinib in preventing traction retinal detachment (TRD) caused by PVR. Full-field electroretinography and histologic examination were used to determine the retinal toxicity of dasatinib.
Dasatinib prevented RPE sheet growth, cell migration, proliferation, EMT, and ECM contraction in a concentration-dependent manner. 0.1 μM dasatinib inhibited nearly 80% of vitreous fluid-stimulated collagen gel contraction. Dasatinib also prevented TRD caused by PVR in vivo. Only 1/11 eyes had a TRD in the presence of dasatinib, while all 11 controls eyes had a TRD. Dasatinib did not cause any detectable toxicity of the retina.
Dasatinib significantly inhibited PVR-related RPE changes in vitro and prevented TRD in an experimental PVR model in the swine without any detectable toxicity. Our data suggested that dasatinib may be effective in the prevention of PVR.</description><identifier>ISSN: 1552-5783</identifier><identifier>EISSN: 1552-5783</identifier><identifier>DOI: 10.1167/iovs.12-10418</identifier><identifier>PMID: 23341014</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Apoptosis - drug effects ; Cell Movement - drug effects ; Cell Proliferation - drug effects ; Cells, Cultured ; Dasatinib ; Disease Models, Animal ; Electroretinography - drug effects ; Female ; Fetus - cytology ; Pregnancy ; Protein Kinase Inhibitors - pharmacology ; Protein Kinase Inhibitors - toxicity ; Pyrimidines - pharmacology ; Pyrimidines - toxicity ; Retinal Detachment - drug therapy ; Retinal Detachment - prevention & control ; Retinal Pigment Epithelium - cytology ; Retinal Pigment Epithelium - drug effects ; Retinal Pigment Epithelium - enzymology ; Swine ; Thiazoles - pharmacology ; Thiazoles - toxicity ; Vitreoretinopathy, Proliferative - drug therapy ; Vitreoretinopathy, Proliferative - prevention & control ; Vitreous Body - cytology</subject><ispartof>Investigative ophthalmology & visual science, 2013-02, Vol.54 (2), p.1150</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c293t-26a48dfcfdaaa96cd90f3366e980951a96ddb9fec87f6d8e531eed0549e0f5dc3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23341014$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Umazume, Kazuhiko</creatorcontrib><creatorcontrib>Liu, Lanhsin</creatorcontrib><creatorcontrib>Scott, Patrick A</creatorcontrib><creatorcontrib>de Castro, Juan P Fernandez</creatorcontrib><creatorcontrib>McDonald, Kevin</creatorcontrib><creatorcontrib>Kaplan, Henry J</creatorcontrib><creatorcontrib>Tamiya, Shigeo</creatorcontrib><title>Inhibition of PVR with a tyrosine kinase inhibitor, dasatinib, in the swine</title><title>Investigative ophthalmology & visual science</title><addtitle>Invest Ophthalmol Vis Sci</addtitle><description>We tested the efficacy of dasatinib, a Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor, to prevent proliferative vitreoretinopathy (PVR).
The effect of dasatinib on RPE sheet growth was determined by measuring enlargement of cultured RPE sheets in the presence or absence of dasatinib. Epithelial-mesenchymal transition (EMT) of RPE cells was assessed by expression of S100A4. A scratch wound assay, cell number count, and type I collagen contraction assay were used to examine the effect of dasatinib on migration, proliferation, and extracellular matrix (ECM) contraction, respectively. Our swine model of experimental PVR with green fluorescent protein-positive (GFP+) RPE cells was used to assess the efficacy of dasatinib in preventing traction retinal detachment (TRD) caused by PVR. Full-field electroretinography and histologic examination were used to determine the retinal toxicity of dasatinib.
Dasatinib prevented RPE sheet growth, cell migration, proliferation, EMT, and ECM contraction in a concentration-dependent manner. 0.1 μM dasatinib inhibited nearly 80% of vitreous fluid-stimulated collagen gel contraction. Dasatinib also prevented TRD caused by PVR in vivo. Only 1/11 eyes had a TRD in the presence of dasatinib, while all 11 controls eyes had a TRD. Dasatinib did not cause any detectable toxicity of the retina.
Dasatinib significantly inhibited PVR-related RPE changes in vitro and prevented TRD in an experimental PVR model in the swine without any detectable toxicity. Our data suggested that dasatinib may be effective in the prevention of PVR.</description><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Cell Movement - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Cells, Cultured</subject><subject>Dasatinib</subject><subject>Disease Models, Animal</subject><subject>Electroretinography - drug effects</subject><subject>Female</subject><subject>Fetus - cytology</subject><subject>Pregnancy</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Kinase Inhibitors - toxicity</subject><subject>Pyrimidines - pharmacology</subject><subject>Pyrimidines - toxicity</subject><subject>Retinal Detachment - drug therapy</subject><subject>Retinal Detachment - prevention & control</subject><subject>Retinal Pigment Epithelium - cytology</subject><subject>Retinal Pigment Epithelium - drug effects</subject><subject>Retinal Pigment Epithelium - enzymology</subject><subject>Swine</subject><subject>Thiazoles - pharmacology</subject><subject>Thiazoles - toxicity</subject><subject>Vitreoretinopathy, Proliferative - drug therapy</subject><subject>Vitreoretinopathy, Proliferative - prevention & control</subject><subject>Vitreous Body - cytology</subject><issn>1552-5783</issn><issn>1552-5783</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkFFLwzAUhYMobk4ffZX8gGXmJk2aPMpwOhwoor6GtElo1LWjqY79ezur4tO5HD4uhw-hc6AzAJlfxuYzzYARoBmoAzQGIRgRueKH_-4ROknplVIGwOgxGjHOM6CQjdHdsq5iEbvY1LgJ-OHlEW9jV2GLu13bpFh7_BZrmzyOA9i0U-xssl2sYzHtW9xVHqdtT56io2Dfkz_7yQl6Xlw_zW_J6v5mOb9akZJp3hEmbaZcKIOz1mpZOk0D51J6ragW0FfOFTr4UuVBOuUFB-8dFZn2NAhX8gkiw9-yX5haH8ymjWvb7gxQs5di9lIMMPMtpecvBn7zUay9-6N_LfAvlT5elQ</recordid><startdate>20130201</startdate><enddate>20130201</enddate><creator>Umazume, Kazuhiko</creator><creator>Liu, Lanhsin</creator><creator>Scott, Patrick A</creator><creator>de Castro, Juan P Fernandez</creator><creator>McDonald, Kevin</creator><creator>Kaplan, Henry J</creator><creator>Tamiya, Shigeo</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20130201</creationdate><title>Inhibition of PVR with a tyrosine kinase inhibitor, dasatinib, in the swine</title><author>Umazume, Kazuhiko ; Liu, Lanhsin ; Scott, Patrick A ; de Castro, Juan P Fernandez ; McDonald, Kevin ; Kaplan, Henry J ; Tamiya, Shigeo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c293t-26a48dfcfdaaa96cd90f3366e980951a96ddb9fec87f6d8e531eed0549e0f5dc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Apoptosis - drug effects</topic><topic>Cell Movement - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>Cells, Cultured</topic><topic>Dasatinib</topic><topic>Disease Models, Animal</topic><topic>Electroretinography - drug effects</topic><topic>Female</topic><topic>Fetus - cytology</topic><topic>Pregnancy</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Kinase Inhibitors - toxicity</topic><topic>Pyrimidines - pharmacology</topic><topic>Pyrimidines - toxicity</topic><topic>Retinal Detachment - drug therapy</topic><topic>Retinal Detachment - prevention & control</topic><topic>Retinal Pigment Epithelium - cytology</topic><topic>Retinal Pigment Epithelium - drug effects</topic><topic>Retinal Pigment Epithelium - enzymology</topic><topic>Swine</topic><topic>Thiazoles - pharmacology</topic><topic>Thiazoles - toxicity</topic><topic>Vitreoretinopathy, Proliferative - drug therapy</topic><topic>Vitreoretinopathy, Proliferative - prevention & control</topic><topic>Vitreous Body - cytology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Umazume, Kazuhiko</creatorcontrib><creatorcontrib>Liu, Lanhsin</creatorcontrib><creatorcontrib>Scott, Patrick A</creatorcontrib><creatorcontrib>de Castro, Juan P Fernandez</creatorcontrib><creatorcontrib>McDonald, Kevin</creatorcontrib><creatorcontrib>Kaplan, Henry J</creatorcontrib><creatorcontrib>Tamiya, Shigeo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Investigative ophthalmology & visual science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Umazume, Kazuhiko</au><au>Liu, Lanhsin</au><au>Scott, Patrick A</au><au>de Castro, Juan P Fernandez</au><au>McDonald, Kevin</au><au>Kaplan, Henry J</au><au>Tamiya, Shigeo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of PVR with a tyrosine kinase inhibitor, dasatinib, in the swine</atitle><jtitle>Investigative ophthalmology & visual science</jtitle><addtitle>Invest Ophthalmol Vis Sci</addtitle><date>2013-02-01</date><risdate>2013</risdate><volume>54</volume><issue>2</issue><spage>1150</spage><pages>1150-</pages><issn>1552-5783</issn><eissn>1552-5783</eissn><abstract>We tested the efficacy of dasatinib, a Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor, to prevent proliferative vitreoretinopathy (PVR).
The effect of dasatinib on RPE sheet growth was determined by measuring enlargement of cultured RPE sheets in the presence or absence of dasatinib. Epithelial-mesenchymal transition (EMT) of RPE cells was assessed by expression of S100A4. A scratch wound assay, cell number count, and type I collagen contraction assay were used to examine the effect of dasatinib on migration, proliferation, and extracellular matrix (ECM) contraction, respectively. Our swine model of experimental PVR with green fluorescent protein-positive (GFP+) RPE cells was used to assess the efficacy of dasatinib in preventing traction retinal detachment (TRD) caused by PVR. Full-field electroretinography and histologic examination were used to determine the retinal toxicity of dasatinib.
Dasatinib prevented RPE sheet growth, cell migration, proliferation, EMT, and ECM contraction in a concentration-dependent manner. 0.1 μM dasatinib inhibited nearly 80% of vitreous fluid-stimulated collagen gel contraction. Dasatinib also prevented TRD caused by PVR in vivo. Only 1/11 eyes had a TRD in the presence of dasatinib, while all 11 controls eyes had a TRD. Dasatinib did not cause any detectable toxicity of the retina.
Dasatinib significantly inhibited PVR-related RPE changes in vitro and prevented TRD in an experimental PVR model in the swine without any detectable toxicity. Our data suggested that dasatinib may be effective in the prevention of PVR.</abstract><cop>United States</cop><pmid>23341014</pmid><doi>10.1167/iovs.12-10418</doi></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Animals Apoptosis - drug effects Cell Movement - drug effects Cell Proliferation - drug effects Cells, Cultured Dasatinib Disease Models, Animal Electroretinography - drug effects Female Fetus - cytology Pregnancy Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - toxicity Pyrimidines - pharmacology Pyrimidines - toxicity Retinal Detachment - drug therapy Retinal Detachment - prevention & control Retinal Pigment Epithelium - cytology Retinal Pigment Epithelium - drug effects Retinal Pigment Epithelium - enzymology Swine Thiazoles - pharmacology Thiazoles - toxicity Vitreoretinopathy, Proliferative - drug therapy Vitreoretinopathy, Proliferative - prevention & control Vitreous Body - cytology |
| title | Inhibition of PVR with a tyrosine kinase inhibitor, dasatinib, in the swine |
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