DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy
Key biologic effects of the alpha-particle emitter Actinium-225 in comparison to the beta-particle emitter Lutetium-177 labeled somatostatin-analogue DOTATOC in vitro and in vivo were studied to evaluate the significance of γH2AX-foci formation. To determine the relative biological effectiveness (RB...
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| Veröffentlicht in: | PloS one 2014-02, Vol.9 (2), p.e88239 |
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| creator | Graf, Franziska Fahrer, Jörg Maus, Stephan Morgenstern, Alfred Bruchertseifer, Frank Venkatachalam, Senthil Fottner, Christian Weber, Matthias M Huelsenbeck, Johannes Schreckenberger, Mathias Kaina, Bernd Miederer, Matthias |
| description | Key biologic effects of the alpha-particle emitter Actinium-225 in comparison to the beta-particle emitter Lutetium-177 labeled somatostatin-analogue DOTATOC in vitro and in vivo were studied to evaluate the significance of γH2AX-foci formation.
To determine the relative biological effectiveness (RBE) between the two isotopes (as - biological consequence of different ionisation-densities along a particle-track), somatostatin expressing AR42J cells were incubated with Ac-225-DOTATOC and Lu-177-DOTATOC up to 48 h and viability was analyzed using the MTT assay. DNA double strand breaks (DSB) were quantified by immunofluorescence staining of γH2AX-foci. Cell cycle was analyzed by flow cytometry. In vivo uptake of both radiolabeled somatostatin-analogues into subcutaneously growing AR42J tumors and the number of cells displaying γH2AX-foci were measured. Therapeutic efficacy was assayed by monitoring tumor growth after treatment with activities estimated from in vitro cytotoxicity.
Ac-225-DOTATOC resulted in ED50 values of 14 kBq/ml after 48 h, whereas Lu-177-DOTATOC displayed ED50 values of 10 MBq/ml. The number of DSB grew with increasing concentration of Ac-225-DOTATOC and similarly with Lu-177-DOTATOC when applying a factor of 700-fold higher activity compared to Ac-225. Already 24 h after incubation with 2.5-10 kBq/ml, Ac-225-DOTATOC cell-cycle studies showed up to a 60% increase in the percentage of tumor cells in G2/M phase. After 72 h an apoptotic subG1 peak was also detectable. Tumor uptake for both radio peptides at 48 h was identical (7.5%ID/g), though the overall number of cells with γH2AX-foci was higher in tumors treated with 48 kBq Ac-225-DOTATOC compared to tumors treated with 30 MBq Lu-177-DOTATOC (35% vs. 21%). Tumors with a volume of 0.34 ml reached delayed exponential tumor growth after 25 days (44 kBq Ac-225-DOTATOC) and after 21 days (34 MBq Lu-177-DOTATOC).
γH2AX-foci formation, triggered by beta- and alpha-irradiation, is an early key parameter in predicting response to internal radiotherapy. |
| doi_str_mv | 10.1371/journal.pone.0088239 |
| format | Article |
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To determine the relative biological effectiveness (RBE) between the two isotopes (as - biological consequence of different ionisation-densities along a particle-track), somatostatin expressing AR42J cells were incubated with Ac-225-DOTATOC and Lu-177-DOTATOC up to 48 h and viability was analyzed using the MTT assay. DNA double strand breaks (DSB) were quantified by immunofluorescence staining of γH2AX-foci. Cell cycle was analyzed by flow cytometry. In vivo uptake of both radiolabeled somatostatin-analogues into subcutaneously growing AR42J tumors and the number of cells displaying γH2AX-foci were measured. Therapeutic efficacy was assayed by monitoring tumor growth after treatment with activities estimated from in vitro cytotoxicity.
Ac-225-DOTATOC resulted in ED50 values of 14 kBq/ml after 48 h, whereas Lu-177-DOTATOC displayed ED50 values of 10 MBq/ml. The number of DSB grew with increasing concentration of Ac-225-DOTATOC and similarly with Lu-177-DOTATOC when applying a factor of 700-fold higher activity compared to Ac-225. Already 24 h after incubation with 2.5-10 kBq/ml, Ac-225-DOTATOC cell-cycle studies showed up to a 60% increase in the percentage of tumor cells in G2/M phase. After 72 h an apoptotic subG1 peak was also detectable. Tumor uptake for both radio peptides at 48 h was identical (7.5%ID/g), though the overall number of cells with γH2AX-foci was higher in tumors treated with 48 kBq Ac-225-DOTATOC compared to tumors treated with 30 MBq Lu-177-DOTATOC (35% vs. 21%). Tumors with a volume of 0.34 ml reached delayed exponential tumor growth after 25 days (44 kBq Ac-225-DOTATOC) and after 21 days (34 MBq Lu-177-DOTATOC).
γH2AX-foci formation, triggered by beta- and alpha-irradiation, is an early key parameter in predicting response to internal radiotherapy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0088239</identifier><identifier>PMID: 24516620</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Actinium ; Actinium - therapeutic use ; Alpha Particles - therapeutic use ; Alpha rays ; Analysis ; Animals ; Apoptosis ; Beta rays ; Biocompatibility ; Biological effects ; Biology ; Cancer therapies ; Cell cycle ; Cell Cycle - radiation effects ; Cell Death - radiation effects ; Cell Line, Tumor ; Cytometry ; Cytotoxicity ; Daughters ; Deoxyribonucleic acid ; DNA ; DNA Breaks, Double-Stranded ; DNA damage ; Dosimetry ; Double-strand break repair ; Drug dosages ; Emissions ; Emitters ; Emitters (electron) ; Endocrinology ; Energy ; Flow cytometry ; Genetic research ; Immunofluorescence ; In vivo methods and tests ; Incubation ; Ionization ; Irradiation ; Isotopes ; Leukemia ; Lutetium ; Lutetium - therapeutic use ; Lymphoma ; Medical prognosis ; Medicine ; Neuroendocrine Tumors - pathology ; Neuroendocrine Tumors - radiotherapy ; Nuclear medicine ; Peptides ; Radiation therapy ; Radioisotopes ; Radioisotopes - therapeutic use ; Radiotherapy ; Rare earth metal compounds ; Rats ; Receptors, Somatostatin - genetics ; Receptors, Somatostatin - metabolism ; Relative biological effectiveness (RBE) ; Somatostatin ; Toxicity ; Toxicology ; Tumor cells ; Tumors ; Viability ; α Radiation</subject><ispartof>PloS one, 2014-02, Vol.9 (2), p.e88239</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Graf 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>2014 Graf et al 2014 Graf et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-25b55bdf76078be22ddbb3f2e210642bdb16a98e4ceb3f1a72b9a20e11cce8c03</citedby><cites>FETCH-LOGICAL-c758t-25b55bdf76078be22ddbb3f2e210642bdb16a98e4ceb3f1a72b9a20e11cce8c03</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/PMC3917860/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3917860/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24516620$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Sobol, Robert W.</contributor><creatorcontrib>Graf, Franziska</creatorcontrib><creatorcontrib>Fahrer, Jörg</creatorcontrib><creatorcontrib>Maus, Stephan</creatorcontrib><creatorcontrib>Morgenstern, Alfred</creatorcontrib><creatorcontrib>Bruchertseifer, Frank</creatorcontrib><creatorcontrib>Venkatachalam, Senthil</creatorcontrib><creatorcontrib>Fottner, Christian</creatorcontrib><creatorcontrib>Weber, Matthias M</creatorcontrib><creatorcontrib>Huelsenbeck, Johannes</creatorcontrib><creatorcontrib>Schreckenberger, Mathias</creatorcontrib><creatorcontrib>Kaina, Bernd</creatorcontrib><creatorcontrib>Miederer, Matthias</creatorcontrib><title>DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Key biologic effects of the alpha-particle emitter Actinium-225 in comparison to the beta-particle emitter Lutetium-177 labeled somatostatin-analogue DOTATOC in vitro and in vivo were studied to evaluate the significance of γH2AX-foci formation.
To determine the relative biological effectiveness (RBE) between the two isotopes (as - biological consequence of different ionisation-densities along a particle-track), somatostatin expressing AR42J cells were incubated with Ac-225-DOTATOC and Lu-177-DOTATOC up to 48 h and viability was analyzed using the MTT assay. DNA double strand breaks (DSB) were quantified by immunofluorescence staining of γH2AX-foci. Cell cycle was analyzed by flow cytometry. In vivo uptake of both radiolabeled somatostatin-analogues into subcutaneously growing AR42J tumors and the number of cells displaying γH2AX-foci were measured. Therapeutic efficacy was assayed by monitoring tumor growth after treatment with activities estimated from in vitro cytotoxicity.
Ac-225-DOTATOC resulted in ED50 values of 14 kBq/ml after 48 h, whereas Lu-177-DOTATOC displayed ED50 values of 10 MBq/ml. The number of DSB grew with increasing concentration of Ac-225-DOTATOC and similarly with Lu-177-DOTATOC when applying a factor of 700-fold higher activity compared to Ac-225. Already 24 h after incubation with 2.5-10 kBq/ml, Ac-225-DOTATOC cell-cycle studies showed up to a 60% increase in the percentage of tumor cells in G2/M phase. After 72 h an apoptotic subG1 peak was also detectable. Tumor uptake for both radio peptides at 48 h was identical (7.5%ID/g), though the overall number of cells with γH2AX-foci was higher in tumors treated with 48 kBq Ac-225-DOTATOC compared to tumors treated with 30 MBq Lu-177-DOTATOC (35% vs. 21%). Tumors with a volume of 0.34 ml reached delayed exponential tumor growth after 25 days (44 kBq Ac-225-DOTATOC) and after 21 days (34 MBq Lu-177-DOTATOC).
γH2AX-foci formation, triggered by beta- and alpha-irradiation, is an early key parameter in predicting response to internal radiotherapy.</description><subject>Actinium</subject><subject>Actinium - therapeutic use</subject><subject>Alpha Particles - therapeutic use</subject><subject>Alpha rays</subject><subject>Analysis</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Beta rays</subject><subject>Biocompatibility</subject><subject>Biological effects</subject><subject>Biology</subject><subject>Cancer therapies</subject><subject>Cell cycle</subject><subject>Cell Cycle - radiation effects</subject><subject>Cell Death - radiation effects</subject><subject>Cell Line, Tumor</subject><subject>Cytometry</subject><subject>Cytotoxicity</subject><subject>Daughters</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Breaks, Double-Stranded</subject><subject>DNA damage</subject><subject>Dosimetry</subject><subject>Double-strand break repair</subject><subject>Drug dosages</subject><subject>Emissions</subject><subject>Emitters</subject><subject>Emitters (electron)</subject><subject>Endocrinology</subject><subject>Energy</subject><subject>Flow cytometry</subject><subject>Genetic research</subject><subject>Immunofluorescence</subject><subject>In vivo methods and tests</subject><subject>Incubation</subject><subject>Ionization</subject><subject>Irradiation</subject><subject>Isotopes</subject><subject>Leukemia</subject><subject>Lutetium</subject><subject>Lutetium - therapeutic use</subject><subject>Lymphoma</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Neuroendocrine Tumors - pathology</subject><subject>Neuroendocrine Tumors - radiotherapy</subject><subject>Nuclear medicine</subject><subject>Peptides</subject><subject>Radiation therapy</subject><subject>Radioisotopes</subject><subject>Radioisotopes - therapeutic use</subject><subject>Radiotherapy</subject><subject>Rare earth metal compounds</subject><subject>Rats</subject><subject>Receptors, Somatostatin - genetics</subject><subject>Receptors, Somatostatin - metabolism</subject><subject>Relative biological effectiveness (RBE)</subject><subject>Somatostatin</subject><subject>Toxicity</subject><subject>Toxicology</subject><subject>Tumor cells</subject><subject>Tumors</subject><subject>Viability</subject><subject>α Radiation</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk9uKFDEQhhtR3HX1DUQDguBFj0n6fCMM62lhccHTbaikKzMZezptkhbnhXxO007vMAMKkouEqq_-Cn9SSfKY0QXLKvZyY0fXQ7cYbI8LSuuaZ82d5Jw1GU9LTrO7R-ez5IH3G0qLrC7L-8kZzwtWxsR58uv1hyVp7Sg7JD446FsiHcI3T8CTwWFrVLCOWE1Qa6NA7aZzWCOBblhDOoALRsVi3JoQ0JGlSjkvyCQ0UdihCs72h_z1mLKqIjqKeruFYH2AYHriUOEwtQrgVhiwJQ5aY6OGg2H3MLmnofP4aN4vki9v33y-fJ9e37y7ulxep6oq6pDyQhaFbHVV0qqWyHnbSplpjpzRMueylayEpsZcYQwzqLhsgFNkTCmsFc0ukqd73aGzXswWe8HyJirSjJeRuNoTrYWNGJzZgtsJC0b8CVi3ErMlAlWuoWxkWYPOJVVQsZKxSkGdgy6qqdurudsot9gq7OMLdCeip5nerMXK_hBZw6q6nASezQLOfh_Rh39ceaZWEG9lem2jmNoar8Qyr-LHobzIIrX4CxVXG59OxU-mTYyfFLw4KYhMwJ9hBaP34urTx_9nb76ess-P2DVCF9bedmMwtvenYL4HlbPeO9QH5xgV04zcuiGmGRHzjMSyJ8euH4puhyL7DZy6DwI</recordid><startdate>20140207</startdate><enddate>20140207</enddate><creator>Graf, Franziska</creator><creator>Fahrer, Jörg</creator><creator>Maus, Stephan</creator><creator>Morgenstern, Alfred</creator><creator>Bruchertseifer, Frank</creator><creator>Venkatachalam, Senthil</creator><creator>Fottner, Christian</creator><creator>Weber, Matthias M</creator><creator>Huelsenbeck, Johannes</creator><creator>Schreckenberger, Mathias</creator><creator>Kaina, Bernd</creator><creator>Miederer, Matthias</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140207</creationdate><title>DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy</title><author>Graf, Franziska ; Fahrer, Jörg ; Maus, Stephan ; Morgenstern, Alfred ; Bruchertseifer, Frank ; Venkatachalam, Senthil ; Fottner, Christian ; Weber, Matthias M ; Huelsenbeck, Johannes ; Schreckenberger, Mathias ; Kaina, Bernd ; Miederer, Matthias</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-25b55bdf76078be22ddbb3f2e210642bdb16a98e4ceb3f1a72b9a20e11cce8c03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Actinium</topic><topic>Actinium - therapeutic use</topic><topic>Alpha Particles - therapeutic use</topic><topic>Alpha rays</topic><topic>Analysis</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Beta rays</topic><topic>Biocompatibility</topic><topic>Biological effects</topic><topic>Biology</topic><topic>Cancer therapies</topic><topic>Cell cycle</topic><topic>Cell Cycle - radiation effects</topic><topic>Cell Death - radiation effects</topic><topic>Cell Line, Tumor</topic><topic>Cytometry</topic><topic>Cytotoxicity</topic><topic>Daughters</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA Breaks, Double-Stranded</topic><topic>DNA damage</topic><topic>Dosimetry</topic><topic>Double-strand break repair</topic><topic>Drug dosages</topic><topic>Emissions</topic><topic>Emitters</topic><topic>Emitters (electron)</topic><topic>Endocrinology</topic><topic>Energy</topic><topic>Flow cytometry</topic><topic>Genetic research</topic><topic>Immunofluorescence</topic><topic>In vivo methods and tests</topic><topic>Incubation</topic><topic>Ionization</topic><topic>Irradiation</topic><topic>Isotopes</topic><topic>Leukemia</topic><topic>Lutetium</topic><topic>Lutetium - therapeutic use</topic><topic>Lymphoma</topic><topic>Medical prognosis</topic><topic>Medicine</topic><topic>Neuroendocrine Tumors - pathology</topic><topic>Neuroendocrine Tumors - radiotherapy</topic><topic>Nuclear medicine</topic><topic>Peptides</topic><topic>Radiation therapy</topic><topic>Radioisotopes</topic><topic>Radioisotopes - therapeutic use</topic><topic>Radiotherapy</topic><topic>Rare earth metal compounds</topic><topic>Rats</topic><topic>Receptors, Somatostatin - genetics</topic><topic>Receptors, Somatostatin - metabolism</topic><topic>Relative biological effectiveness (RBE)</topic><topic>Somatostatin</topic><topic>Toxicity</topic><topic>Toxicology</topic><topic>Tumor cells</topic><topic>Tumors</topic><topic>Viability</topic><topic>α Radiation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Graf, Franziska</creatorcontrib><creatorcontrib>Fahrer, Jörg</creatorcontrib><creatorcontrib>Maus, Stephan</creatorcontrib><creatorcontrib>Morgenstern, Alfred</creatorcontrib><creatorcontrib>Bruchertseifer, Frank</creatorcontrib><creatorcontrib>Venkatachalam, Senthil</creatorcontrib><creatorcontrib>Fottner, Christian</creatorcontrib><creatorcontrib>Weber, Matthias M</creatorcontrib><creatorcontrib>Huelsenbeck, Johannes</creatorcontrib><creatorcontrib>Schreckenberger, Mathias</creatorcontrib><creatorcontrib>Kaina, Bernd</creatorcontrib><creatorcontrib>Miederer, Matthias</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</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>Graf, Franziska</au><au>Fahrer, Jörg</au><au>Maus, Stephan</au><au>Morgenstern, Alfred</au><au>Bruchertseifer, Frank</au><au>Venkatachalam, Senthil</au><au>Fottner, Christian</au><au>Weber, Matthias M</au><au>Huelsenbeck, Johannes</au><au>Schreckenberger, Mathias</au><au>Kaina, Bernd</au><au>Miederer, Matthias</au><au>Sobol, Robert W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-02-07</date><risdate>2014</risdate><volume>9</volume><issue>2</issue><spage>e88239</spage><pages>e88239-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Key biologic effects of the alpha-particle emitter Actinium-225 in comparison to the beta-particle emitter Lutetium-177 labeled somatostatin-analogue DOTATOC in vitro and in vivo were studied to evaluate the significance of γH2AX-foci formation.
To determine the relative biological effectiveness (RBE) between the two isotopes (as - biological consequence of different ionisation-densities along a particle-track), somatostatin expressing AR42J cells were incubated with Ac-225-DOTATOC and Lu-177-DOTATOC up to 48 h and viability was analyzed using the MTT assay. DNA double strand breaks (DSB) were quantified by immunofluorescence staining of γH2AX-foci. Cell cycle was analyzed by flow cytometry. In vivo uptake of both radiolabeled somatostatin-analogues into subcutaneously growing AR42J tumors and the number of cells displaying γH2AX-foci were measured. Therapeutic efficacy was assayed by monitoring tumor growth after treatment with activities estimated from in vitro cytotoxicity.
Ac-225-DOTATOC resulted in ED50 values of 14 kBq/ml after 48 h, whereas Lu-177-DOTATOC displayed ED50 values of 10 MBq/ml. The number of DSB grew with increasing concentration of Ac-225-DOTATOC and similarly with Lu-177-DOTATOC when applying a factor of 700-fold higher activity compared to Ac-225. Already 24 h after incubation with 2.5-10 kBq/ml, Ac-225-DOTATOC cell-cycle studies showed up to a 60% increase in the percentage of tumor cells in G2/M phase. After 72 h an apoptotic subG1 peak was also detectable. Tumor uptake for both radio peptides at 48 h was identical (7.5%ID/g), though the overall number of cells with γH2AX-foci was higher in tumors treated with 48 kBq Ac-225-DOTATOC compared to tumors treated with 30 MBq Lu-177-DOTATOC (35% vs. 21%). Tumors with a volume of 0.34 ml reached delayed exponential tumor growth after 25 days (44 kBq Ac-225-DOTATOC) and after 21 days (34 MBq Lu-177-DOTATOC).
γH2AX-foci formation, triggered by beta- and alpha-irradiation, is an early key parameter in predicting response to internal radiotherapy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24516620</pmid><doi>10.1371/journal.pone.0088239</doi><tpages>e88239</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-02, Vol.9 (2), p.e88239 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1496070326 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Actinium Actinium - therapeutic use Alpha Particles - therapeutic use Alpha rays Analysis Animals Apoptosis Beta rays Biocompatibility Biological effects Biology Cancer therapies Cell cycle Cell Cycle - radiation effects Cell Death - radiation effects Cell Line, Tumor Cytometry Cytotoxicity Daughters Deoxyribonucleic acid DNA DNA Breaks, Double-Stranded DNA damage Dosimetry Double-strand break repair Drug dosages Emissions Emitters Emitters (electron) Endocrinology Energy Flow cytometry Genetic research Immunofluorescence In vivo methods and tests Incubation Ionization Irradiation Isotopes Leukemia Lutetium Lutetium - therapeutic use Lymphoma Medical prognosis Medicine Neuroendocrine Tumors - pathology Neuroendocrine Tumors - radiotherapy Nuclear medicine Peptides Radiation therapy Radioisotopes Radioisotopes - therapeutic use Radiotherapy Rare earth metal compounds Rats Receptors, Somatostatin - genetics Receptors, Somatostatin - metabolism Relative biological effectiveness (RBE) Somatostatin Toxicity Toxicology Tumor cells Tumors Viability α Radiation |
| title | DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy |
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