Characterization and drug resistance patterns of Ewing's sarcoma family tumor cell lines
Despite intensive treatment with chemotherapy, radiotherapy and surgery, over 70% of patients with metastatic Ewing's Sarcoma Family of Tumors (EFT) will die of their disease. We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will fac...
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| creator | May, William A Grigoryan, Rita S Keshelava, Nino Cabral, Daniel J Christensen, Laura L Jenabi, Jasmine Ji, Lingyun Triche, Timothy J Lawlor, Elizabeth R Reynolds, C Patrick |
| description | Despite intensive treatment with chemotherapy, radiotherapy and surgery, over 70% of patients with metastatic Ewing's Sarcoma Family of Tumors (EFT) will die of their disease. We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will facilitate the application of new therapeutic agents to EFT. To determine resistance patterns, we studied newly established EFT cell lines derived from different points in therapy: two established at diagnosis (CHLA-9, CHLA-32), two after chemotherapy and progressive disease (CHLA-10, CHLA-25), and two at relapse after myeloablative therapy and autologous bone marrow transplantation (post-ABMT) (CHLA-258, COG-E-352). The new lines were compared to widely studied EFT lines TC-71, TC-32, SK-N-MC, and A-673. These lines were extensively characterized with regard to identity (short tandem repeat (STR) analysis), p53, p16/14 status, and EWS/ETS breakpoint and target gene expression profile. The DIMSCAN cytotoxicity assay was used to assess in vitro drug sensitivity to standard chemotherapy agents. No association was found between drug resistance and the expression of EWS/ETS regulated genes in the EFT cell lines. No consistent association was observed between drug sensitivity and p53 functionality or between drug sensitivity and p16/14 functionality across the cell lines. Exposure to chemotherapy prior to cell line initiation correlated with drug resistance of EFT cell lines in 5/8 tested agents at clinically achievable concentrations (CAC) or the lower tested concentration (LTC): (cyclophosphamide (as 4-HC) and doxorubicin at CAC, etoposide, irinotecan (as SN-38) and melphalan at LTC; P |
| doi_str_mv | 10.1371/journal.pone.0080060 |
| format | Article |
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We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will facilitate the application of new therapeutic agents to EFT. To determine resistance patterns, we studied newly established EFT cell lines derived from different points in therapy: two established at diagnosis (CHLA-9, CHLA-32), two after chemotherapy and progressive disease (CHLA-10, CHLA-25), and two at relapse after myeloablative therapy and autologous bone marrow transplantation (post-ABMT) (CHLA-258, COG-E-352). The new lines were compared to widely studied EFT lines TC-71, TC-32, SK-N-MC, and A-673. These lines were extensively characterized with regard to identity (short tandem repeat (STR) analysis), p53, p16/14 status, and EWS/ETS breakpoint and target gene expression profile. The DIMSCAN cytotoxicity assay was used to assess in vitro drug sensitivity to standard chemotherapy agents. No association was found between drug resistance and the expression of EWS/ETS regulated genes in the EFT cell lines. No consistent association was observed between drug sensitivity and p53 functionality or between drug sensitivity and p16/14 functionality across the cell lines. Exposure to chemotherapy prior to cell line initiation correlated with drug resistance of EFT cell lines in 5/8 tested agents at clinically achievable concentrations (CAC) or the lower tested concentration (LTC): (cyclophosphamide (as 4-HC) and doxorubicin at CAC, etoposide, irinotecan (as SN-38) and melphalan at LTC; P<0.1 for one agent, and P<0.05 for four agents. This panel of well-characterized drug-sensitive and drug-resistant cell lines will facilitate in vitro preclinical testing of new agents for EFT.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0080060</identifier><identifier>PMID: 24312454</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Antineoplastic Agents - pharmacology ; Autografts ; Biochemistry ; Biotechnology ; Blood diseases ; Bone marrow ; Bone marrow transplantation ; Cancer therapies ; Care and treatment ; Cell Line, Tumor ; Chemical compounds ; Chemotherapy ; Children & youth ; Cloning ; Cyclin-Dependent Kinase Inhibitor p16 - genetics ; Cyclin-Dependent Kinase Inhibitor p16 - metabolism ; Cyclophosphamide ; Cytotoxicity ; Departments ; Disease ; Doxorubicin ; Drug dosages ; Drug resistance ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - genetics ; Drug Screening Assays, Antitumor ; Etoposide ; Ewing's sarcoma ; Ewings sarcoma ; EWS protein ; Gene expression ; Health sciences ; Hospitals ; Humans ; Internal medicine ; Irinotecan ; Laboratory models ; Leukemia ; Medicine ; Melphalan ; Metastases ; Metastasis ; p53 Protein ; Pediatrics ; Pharmacology ; Radiation therapy ; Risk factors ; Sarcoma ; Sarcoma, Ewing - genetics ; Sarcoma, Ewing - metabolism ; Sarcoma, Ewing - pathology ; Sensitivity ; Sensitivity analysis ; Surgery ; Syngeneic grafts ; Toxicity ; Transcription factors ; Transplantation ; Transplants & implants ; Tumor cell lines ; Tumor Suppressor Protein p14ARF - genetics ; Tumor Suppressor Protein p14ARF - metabolism ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Tumors ; Young adults</subject><ispartof>PloS one, 2013-12, Vol.8 (12), p.e80060-e80060</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 May et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/3.0/ (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>2013 May et al 2013 May et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-6d7c15508cab81920c682cf1f9edeb66e2167db86b948ff004c08e37eb445ab23</citedby><cites>FETCH-LOGICAL-c692t-6d7c15508cab81920c682cf1f9edeb66e2167db86b948ff004c08e37eb445ab23</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/PMC3846563/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3846563/$$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/24312454$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>May, William A</creatorcontrib><creatorcontrib>Grigoryan, Rita S</creatorcontrib><creatorcontrib>Keshelava, Nino</creatorcontrib><creatorcontrib>Cabral, Daniel J</creatorcontrib><creatorcontrib>Christensen, Laura L</creatorcontrib><creatorcontrib>Jenabi, Jasmine</creatorcontrib><creatorcontrib>Ji, Lingyun</creatorcontrib><creatorcontrib>Triche, Timothy J</creatorcontrib><creatorcontrib>Lawlor, Elizabeth R</creatorcontrib><creatorcontrib>Reynolds, C Patrick</creatorcontrib><title>Characterization and drug resistance patterns of Ewing's sarcoma family tumor cell lines</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Despite intensive treatment with chemotherapy, radiotherapy and surgery, over 70% of patients with metastatic Ewing's Sarcoma Family of Tumors (EFT) will die of their disease. We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will facilitate the application of new therapeutic agents to EFT. To determine resistance patterns, we studied newly established EFT cell lines derived from different points in therapy: two established at diagnosis (CHLA-9, CHLA-32), two after chemotherapy and progressive disease (CHLA-10, CHLA-25), and two at relapse after myeloablative therapy and autologous bone marrow transplantation (post-ABMT) (CHLA-258, COG-E-352). The new lines were compared to widely studied EFT lines TC-71, TC-32, SK-N-MC, and A-673. These lines were extensively characterized with regard to identity (short tandem repeat (STR) analysis), p53, p16/14 status, and EWS/ETS breakpoint and target gene expression profile. The DIMSCAN cytotoxicity assay was used to assess in vitro drug sensitivity to standard chemotherapy agents. No association was found between drug resistance and the expression of EWS/ETS regulated genes in the EFT cell lines. No consistent association was observed between drug sensitivity and p53 functionality or between drug sensitivity and p16/14 functionality across the cell lines. Exposure to chemotherapy prior to cell line initiation correlated with drug resistance of EFT cell lines in 5/8 tested agents at clinically achievable concentrations (CAC) or the lower tested concentration (LTC): (cyclophosphamide (as 4-HC) and doxorubicin at CAC, etoposide, irinotecan (as SN-38) and melphalan at LTC; P<0.1 for one agent, and P<0.05 for four agents. This panel of well-characterized drug-sensitive and drug-resistant cell lines will facilitate in vitro preclinical testing of new agents for EFT.</description><subject>Analysis</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Autografts</subject><subject>Biochemistry</subject><subject>Biotechnology</subject><subject>Blood diseases</subject><subject>Bone marrow</subject><subject>Bone marrow transplantation</subject><subject>Cancer therapies</subject><subject>Care and treatment</subject><subject>Cell Line, Tumor</subject><subject>Chemical compounds</subject><subject>Chemotherapy</subject><subject>Children & youth</subject><subject>Cloning</subject><subject>Cyclin-Dependent Kinase Inhibitor p16 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p16 - metabolism</subject><subject>Cyclophosphamide</subject><subject>Cytotoxicity</subject><subject>Departments</subject><subject>Disease</subject><subject>Doxorubicin</subject><subject>Drug dosages</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Etoposide</subject><subject>Ewing's sarcoma</subject><subject>Ewings sarcoma</subject><subject>EWS protein</subject><subject>Gene expression</subject><subject>Health sciences</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Internal medicine</subject><subject>Irinotecan</subject><subject>Laboratory models</subject><subject>Leukemia</subject><subject>Medicine</subject><subject>Melphalan</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>p53 Protein</subject><subject>Pediatrics</subject><subject>Pharmacology</subject><subject>Radiation therapy</subject><subject>Risk factors</subject><subject>Sarcoma</subject><subject>Sarcoma, Ewing - genetics</subject><subject>Sarcoma, Ewing - metabolism</subject><subject>Sarcoma, Ewing - pathology</subject><subject>Sensitivity</subject><subject>Sensitivity analysis</subject><subject>Surgery</subject><subject>Syngeneic grafts</subject><subject>Toxicity</subject><subject>Transcription factors</subject><subject>Transplantation</subject><subject>Transplants & implants</subject><subject>Tumor cell lines</subject><subject>Tumor Suppressor Protein p14ARF - genetics</subject><subject>Tumor Suppressor Protein p14ARF - metabolism</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumors</subject><subject>Young adults</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk12L1DAUhoso7rr6D0QLgh8XM6ZtmqY3wjLs6sDCgl94F07T006GNhmTVF1__aY73WUqeyG5aEif9z3N23Oi6HlClklWJO-3ZrAauuXOaFwSwglh5EF0nJRZumApyR4e7I-iJ85tCckzztjj6CilWZLSnB5HP1YbsCA9WvUXvDI6Bl3HtR3a2KJTzoOWGO_AB0K72DTx2W-l2zcudmCl6SFuoFfdVeyH3thYYtfFndLonkaPGugcPpueJ9G387Ovq0-Li8uP69XpxUKyMvULVhcyyXPCJVQ8KVMiGU9lkzQl1lgxhmnCirrirCopbxpCqCQcswIrSnOo0uwkern33XXGiSkUJxLKMhIkBQnEek_UBrZiZ1UP9koYUOLmwNhWgPVKdiiYJAUFWaaAwaCoAGle1YyRoqo5z2Xw-jBVG6oea4naW-hmpvM3Wm1Ea36JjFOWsywYvJ0MrPk5oPOiV25MDTSa4ea7cx5IXgb01T_o_bebqBbCBZRuTKgrR1NxSgtOQ0xspJb3UGHV2CsZOqhR4XwmeDcTBMbjH9_C4JxYf_n8_-zl9zn7-oDdIHR-40w3jK3n5iDdg9Ia5yw2dyEnRIwDcJuGGAdATAMQZC8Of9Cd6Lbjs2srgQCg</recordid><startdate>20131202</startdate><enddate>20131202</enddate><creator>May, William A</creator><creator>Grigoryan, Rita S</creator><creator>Keshelava, Nino</creator><creator>Cabral, Daniel J</creator><creator>Christensen, Laura L</creator><creator>Jenabi, Jasmine</creator><creator>Ji, Lingyun</creator><creator>Triche, Timothy J</creator><creator>Lawlor, Elizabeth R</creator><creator>Reynolds, C Patrick</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>AEUYN</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>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20131202</creationdate><title>Characterization and drug resistance patterns of Ewing's sarcoma family tumor cell lines</title><author>May, William A ; Grigoryan, Rita S ; Keshelava, Nino ; Cabral, Daniel J ; Christensen, Laura L ; Jenabi, Jasmine ; Ji, Lingyun ; Triche, Timothy J ; Lawlor, Elizabeth R ; Reynolds, C Patrick</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-6d7c15508cab81920c682cf1f9edeb66e2167db86b948ff004c08e37eb445ab23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Analysis</topic><topic>Antineoplastic Agents - 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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>May, William A</au><au>Grigoryan, Rita S</au><au>Keshelava, Nino</au><au>Cabral, Daniel J</au><au>Christensen, Laura L</au><au>Jenabi, Jasmine</au><au>Ji, Lingyun</au><au>Triche, Timothy J</au><au>Lawlor, Elizabeth R</au><au>Reynolds, C Patrick</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Characterization and drug resistance patterns of Ewing's sarcoma family tumor cell lines</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-12-02</date><risdate>2013</risdate><volume>8</volume><issue>12</issue><spage>e80060</spage><epage>e80060</epage><pages>e80060-e80060</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Despite intensive treatment with chemotherapy, radiotherapy and surgery, over 70% of patients with metastatic Ewing's Sarcoma Family of Tumors (EFT) will die of their disease. We hypothesize that properly characterized laboratory models reflecting the drug resistance of clinical tumors will facilitate the application of new therapeutic agents to EFT. To determine resistance patterns, we studied newly established EFT cell lines derived from different points in therapy: two established at diagnosis (CHLA-9, CHLA-32), two after chemotherapy and progressive disease (CHLA-10, CHLA-25), and two at relapse after myeloablative therapy and autologous bone marrow transplantation (post-ABMT) (CHLA-258, COG-E-352). The new lines were compared to widely studied EFT lines TC-71, TC-32, SK-N-MC, and A-673. These lines were extensively characterized with regard to identity (short tandem repeat (STR) analysis), p53, p16/14 status, and EWS/ETS breakpoint and target gene expression profile. The DIMSCAN cytotoxicity assay was used to assess in vitro drug sensitivity to standard chemotherapy agents. No association was found between drug resistance and the expression of EWS/ETS regulated genes in the EFT cell lines. No consistent association was observed between drug sensitivity and p53 functionality or between drug sensitivity and p16/14 functionality across the cell lines. Exposure to chemotherapy prior to cell line initiation correlated with drug resistance of EFT cell lines in 5/8 tested agents at clinically achievable concentrations (CAC) or the lower tested concentration (LTC): (cyclophosphamide (as 4-HC) and doxorubicin at CAC, etoposide, irinotecan (as SN-38) and melphalan at LTC; P<0.1 for one agent, and P<0.05 for four agents. This panel of well-characterized drug-sensitive and drug-resistant cell lines will facilitate in vitro preclinical testing of new agents for EFT.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24312454</pmid><doi>10.1371/journal.pone.0080060</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-12, Vol.8 (12), p.e80060-e80060 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1463094870 |
| source | PubMed (Medline); PLoS; MEDLINE; DOAJ Directory of Open Access Journals; Free Full-Text Journals in Chemistry; EZB Electronic Journals Library |
| subjects | Analysis Antineoplastic Agents - pharmacology Autografts Biochemistry Biotechnology Blood diseases Bone marrow Bone marrow transplantation Cancer therapies Care and treatment Cell Line, Tumor Chemical compounds Chemotherapy Children & youth Cloning Cyclin-Dependent Kinase Inhibitor p16 - genetics Cyclin-Dependent Kinase Inhibitor p16 - metabolism Cyclophosphamide Cytotoxicity Departments Disease Doxorubicin Drug dosages Drug resistance Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Drug Screening Assays, Antitumor Etoposide Ewing's sarcoma Ewings sarcoma EWS protein Gene expression Health sciences Hospitals Humans Internal medicine Irinotecan Laboratory models Leukemia Medicine Melphalan Metastases Metastasis p53 Protein Pediatrics Pharmacology Radiation therapy Risk factors Sarcoma Sarcoma, Ewing - genetics Sarcoma, Ewing - metabolism Sarcoma, Ewing - pathology Sensitivity Sensitivity analysis Surgery Syngeneic grafts Toxicity Transcription factors Transplantation Transplants & implants Tumor cell lines Tumor Suppressor Protein p14ARF - genetics Tumor Suppressor Protein p14ARF - metabolism Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumors Young adults |
| title | Characterization and drug resistance patterns of Ewing's sarcoma family tumor cell lines |
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