Drug-Encoded Biomarkers for Monitoring Biological Therapies
Blood tests are necessary, easy-to-perform and low-cost alternatives for monitoring of oncolytic virotherapy and other biological therapies in translational research. Here we assessed three candidate proteins with the potential to be used as biomarkers in biological fluids: two glucuronidases from E...
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| creator | Tsoneva, Desislava Stritzker, Jochen Bedenk, Kristina Zhang, Qian Frentzen, Alexa Cappello, Joseph Fischer, Utz Szalay, Aladar A |
| description | Blood tests are necessary, easy-to-perform and low-cost alternatives for monitoring of oncolytic virotherapy and other biological therapies in translational research. Here we assessed three candidate proteins with the potential to be used as biomarkers in biological fluids: two glucuronidases from E. coli (GusA) and Staphylococcus sp. RLH1 (GusPlus), and the luciferase from Gaussia princeps (GLuc). The three genes encoding these proteins were inserted individually into vaccinia virus GLV-1h68 genome under the control of an identical promoter. The three resulting recombinant viruses were used to infect tumor cells in cultures and human tumor xenografts in nude mice. In contrast to the actively secreted GLuc, the cytoplasmic glucuronidases GusA and GusPlus were released into the supernatants only as a result of virus-mediated oncolysis. GusPlus resulted in the most sensitive detection of enzyme activity under controlled assay conditions in samples containing as little as 1 pg/ml of GusPlus, followed by GusA (25 pg/ml) and GLuc (≥375 pg/ml). Unexpectedly, even though GusA had a lower specific activity compared to GusPlus, the substrate conversion in the serum of tumor-bearing mice injected with the GusA-encoding virus strains was substantially higher than that of GusPlus. This was attributed to a 3.2 fold and 16.2 fold longer half-life of GusA in the blood stream compared to GusPlus and GLuc respectively, thus a more sensitive monitor of virus replication than the other two enzymes. Due to the good correlation between enzymatic activity of expressed marker gene and virus titer, we conclude that the amount of the biomarker protein in the body fluid semiquantitatively represents the amount of virus in the infected tumors which was confirmed by low light imaging. We found GusA to be the most reliable biomarker for monitoring oncolytic virotherapy among the three tested markers. |
| doi_str_mv | 10.1371/journal.pone.0137573 |
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Here we assessed three candidate proteins with the potential to be used as biomarkers in biological fluids: two glucuronidases from E. coli (GusA) and Staphylococcus sp. RLH1 (GusPlus), and the luciferase from Gaussia princeps (GLuc). The three genes encoding these proteins were inserted individually into vaccinia virus GLV-1h68 genome under the control of an identical promoter. The three resulting recombinant viruses were used to infect tumor cells in cultures and human tumor xenografts in nude mice. In contrast to the actively secreted GLuc, the cytoplasmic glucuronidases GusA and GusPlus were released into the supernatants only as a result of virus-mediated oncolysis. GusPlus resulted in the most sensitive detection of enzyme activity under controlled assay conditions in samples containing as little as 1 pg/ml of GusPlus, followed by GusA (25 pg/ml) and GLuc (≥375 pg/ml). Unexpectedly, even though GusA had a lower specific activity compared to GusPlus, the substrate conversion in the serum of tumor-bearing mice injected with the GusA-encoding virus strains was substantially higher than that of GusPlus. This was attributed to a 3.2 fold and 16.2 fold longer half-life of GusA in the blood stream compared to GusPlus and GLuc respectively, thus a more sensitive monitor of virus replication than the other two enzymes. Due to the good correlation between enzymatic activity of expressed marker gene and virus titer, we conclude that the amount of the biomarker protein in the body fluid semiquantitatively represents the amount of virus in the infected tumors which was confirmed by low light imaging. We found GusA to be the most reliable biomarker for monitoring oncolytic virotherapy among the three tested markers.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0137573</identifier><identifier>PMID: 26348361</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Biochemistry ; Bioindicators ; Biological markers ; Biomarkers ; Biomarkers, Tumor - genetics ; Biomonitoring ; Blood ; Body fluids ; Cancer therapies ; Cancer treatment ; Cell culture ; Cell Line, Tumor ; E coli ; Enzymatic activity ; Enzyme activity ; Enzymes ; Escherichia coli ; Escherichia coli - enzymology ; Gaussia ; Genes ; Genomes ; Glucuronidase - biosynthesis ; Glucuronidase - genetics ; Humans ; Immunotherapy ; Luciferases - biosynthesis ; Luciferases - genetics ; Medical screening ; Methods ; Mice ; Neoplasms - genetics ; Neoplasms - therapy ; Neoplasms - virology ; Oncolysis ; Oncolytic Virotherapy ; Oncolytic Viruses - genetics ; Proteins ; Radioactive half-life ; Staphylococcus ; Staphylococcus - enzymology ; Substrates ; Tumor cells ; Tumors ; Vaccinia virus - genetics ; Viruses ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>PloS one, 2015-09, Vol.10 (9), p.e0137573-e0137573</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Tsoneva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://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>2015 Tsoneva et al 2015 Tsoneva et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-4dea78b722513a93be922b9c4e38bd517aba092eab4e7239799c35fbae2154c93</citedby><cites>FETCH-LOGICAL-c692t-4dea78b722513a93be922b9c4e38bd517aba092eab4e7239799c35fbae2154c93</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/PMC4562523/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562523/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26348361$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ulasov, Ilya</contributor><creatorcontrib>Tsoneva, Desislava</creatorcontrib><creatorcontrib>Stritzker, Jochen</creatorcontrib><creatorcontrib>Bedenk, Kristina</creatorcontrib><creatorcontrib>Zhang, Qian</creatorcontrib><creatorcontrib>Frentzen, Alexa</creatorcontrib><creatorcontrib>Cappello, Joseph</creatorcontrib><creatorcontrib>Fischer, Utz</creatorcontrib><creatorcontrib>Szalay, Aladar A</creatorcontrib><title>Drug-Encoded Biomarkers for Monitoring Biological Therapies</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Blood tests are necessary, easy-to-perform and low-cost alternatives for monitoring of oncolytic virotherapy and other biological therapies in translational research. 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Unexpectedly, even though GusA had a lower specific activity compared to GusPlus, the substrate conversion in the serum of tumor-bearing mice injected with the GusA-encoding virus strains was substantially higher than that of GusPlus. This was attributed to a 3.2 fold and 16.2 fold longer half-life of GusA in the blood stream compared to GusPlus and GLuc respectively, thus a more sensitive monitor of virus replication than the other two enzymes. Due to the good correlation between enzymatic activity of expressed marker gene and virus titer, we conclude that the amount of the biomarker protein in the body fluid semiquantitatively represents the amount of virus in the infected tumors which was confirmed by low light imaging. We found GusA to be the most reliable biomarker for monitoring oncolytic virotherapy among the three tested markers.</description><subject>Animals</subject><subject>Biochemistry</subject><subject>Bioindicators</subject><subject>Biological markers</subject><subject>Biomarkers</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomonitoring</subject><subject>Blood</subject><subject>Body fluids</subject><subject>Cancer therapies</subject><subject>Cancer treatment</subject><subject>Cell culture</subject><subject>Cell Line, Tumor</subject><subject>E coli</subject><subject>Enzymatic activity</subject><subject>Enzyme activity</subject><subject>Enzymes</subject><subject>Escherichia coli</subject><subject>Escherichia coli - enzymology</subject><subject>Gaussia</subject><subject>Genes</subject><subject>Genomes</subject><subject>Glucuronidase - biosynthesis</subject><subject>Glucuronidase - genetics</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>Luciferases - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tsoneva, Desislava</au><au>Stritzker, Jochen</au><au>Bedenk, Kristina</au><au>Zhang, Qian</au><au>Frentzen, Alexa</au><au>Cappello, Joseph</au><au>Fischer, Utz</au><au>Szalay, Aladar A</au><au>Ulasov, Ilya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Drug-Encoded Biomarkers for Monitoring Biological Therapies</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-09-08</date><risdate>2015</risdate><volume>10</volume><issue>9</issue><spage>e0137573</spage><epage>e0137573</epage><pages>e0137573-e0137573</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Blood tests are necessary, easy-to-perform and low-cost alternatives for monitoring of oncolytic virotherapy and other biological therapies in translational research. Here we assessed three candidate proteins with the potential to be used as biomarkers in biological fluids: two glucuronidases from E. coli (GusA) and Staphylococcus sp. RLH1 (GusPlus), and the luciferase from Gaussia princeps (GLuc). The three genes encoding these proteins were inserted individually into vaccinia virus GLV-1h68 genome under the control of an identical promoter. The three resulting recombinant viruses were used to infect tumor cells in cultures and human tumor xenografts in nude mice. In contrast to the actively secreted GLuc, the cytoplasmic glucuronidases GusA and GusPlus were released into the supernatants only as a result of virus-mediated oncolysis. GusPlus resulted in the most sensitive detection of enzyme activity under controlled assay conditions in samples containing as little as 1 pg/ml of GusPlus, followed by GusA (25 pg/ml) and GLuc (≥375 pg/ml). Unexpectedly, even though GusA had a lower specific activity compared to GusPlus, the substrate conversion in the serum of tumor-bearing mice injected with the GusA-encoding virus strains was substantially higher than that of GusPlus. This was attributed to a 3.2 fold and 16.2 fold longer half-life of GusA in the blood stream compared to GusPlus and GLuc respectively, thus a more sensitive monitor of virus replication than the other two enzymes. Due to the good correlation between enzymatic activity of expressed marker gene and virus titer, we conclude that the amount of the biomarker protein in the body fluid semiquantitatively represents the amount of virus in the infected tumors which was confirmed by low light imaging. We found GusA to be the most reliable biomarker for monitoring oncolytic virotherapy among the three tested markers.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26348361</pmid><doi>10.1371/journal.pone.0137573</doi><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-09, Vol.10 (9), p.e0137573-e0137573 |
| issn | 1932-6203 1932-6203 |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Biochemistry Bioindicators Biological markers Biomarkers Biomarkers, Tumor - genetics Biomonitoring Blood Body fluids Cancer therapies Cancer treatment Cell culture Cell Line, Tumor E coli Enzymatic activity Enzyme activity Enzymes Escherichia coli Escherichia coli - enzymology Gaussia Genes Genomes Glucuronidase - biosynthesis Glucuronidase - genetics Humans Immunotherapy Luciferases - biosynthesis Luciferases - genetics Medical screening Methods Mice Neoplasms - genetics Neoplasms - therapy Neoplasms - virology Oncolysis Oncolytic Virotherapy Oncolytic Viruses - genetics Proteins Radioactive half-life Staphylococcus Staphylococcus - enzymology Substrates Tumor cells Tumors Vaccinia virus - genetics Viruses Xenograft Model Antitumor Assays Xenografts |
| title | Drug-Encoded Biomarkers for Monitoring Biological Therapies |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-18T11%3A18%3A00IST&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=Drug-Encoded%20Biomarkers%20for%20Monitoring%20Biological%20Therapies&rft.jtitle=PloS%20one&rft.au=Tsoneva,%20Desislava&rft.date=2015-09-08&rft.volume=10&rft.issue=9&rft.spage=e0137573&rft.epage=e0137573&rft.pages=e0137573-e0137573&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0137573&rft_dat=%3Cgale_plos_%3EA428061003%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=1710982823&rft_id=info:pmid/26348361&rft_galeid=A428061003&rft_doaj_id=oai_doaj_org_article_39eaf199de544a3d95e81dd80153bae9&rfr_iscdi=true |