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Correlation of Platinum Cytotoxicity to Drug-DNA Adduct Levels in a Breast Cancer Cell Line Panel
Platinum drugs, including carboplatin and oxaliplatin, are commonly used chemotherapy drugs that kill cancer cells by forming toxic drug-DNA adducts. These drugs have a proven, but modest, efficacy against several aggressive subtypes of breast cancer but also cause several side effects that can lead...
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Published in: | Chemical research in toxicology 2018-12, Vol.31 (12), p.1293-1304 |
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creator | Wang, Sisi Scharadin, Tiffany M Zimmermann, Maike Malfatti, Michael A Turteltaub, Kenneth W de Vere White, Ralph Pan, Chong-Xian Henderson, Paul T |
description | Platinum drugs, including carboplatin and oxaliplatin, are commonly used chemotherapy drugs that kill cancer cells by forming toxic drug-DNA adducts. These drugs have a proven, but modest, efficacy against several aggressive subtypes of breast cancer but also cause several side effects that can lead to the cessation of treatment. There is a clinical need to identify patients who will respond to platinum drugs in order to better inform clinical decision making. Diagnostic microdosing involves dosing patients or patient samples with subtherapeutic doses of radiolabeled platinum followed by measurement of platinum-DNA adducts in blood or tumor tissue and may be used to predict patient response. We exposed a panel of six breast cancer cell lines to 14C-labeled carboplatin or oxaliplatin at therapeutic and microdose (1% therapeutic dose) concentrations for a range of exposure lengths and isolated DNA from the cells. The DNA was converted to graphite, and measurement of radiocarbon due to platinum-DNA adduction was quantified via accelerator mass spectrometry (AMS). We observed a linear correlation in adduct levels between the microdose and therapeutic dose, and the level of platinum-DNA adducts corresponded to cell line drug sensitivity for both carboplatin and oxaliplatin. These results showed a clear separation in adduct levels between the sensitive and resistant groups of cell lines that could not be fully explained or predicted by changes in DNA repair rates or mutations in DNA repair genes. Further, we were able to quantitate oxaliplatin-DNA adducts in the blood and tumor tissue of a metastatic breast cancer patient. Together, these data support the use of diagnostic microdosing for predicting patient sensitivity to platinum. Future studies will be aimed at replicating this data in a clinical feasibility trial. |
doi_str_mv | 10.1021/acs.chemrestox.8b00170 |
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These drugs have a proven, but modest, efficacy against several aggressive subtypes of breast cancer but also cause several side effects that can lead to the cessation of treatment. There is a clinical need to identify patients who will respond to platinum drugs in order to better inform clinical decision making. Diagnostic microdosing involves dosing patients or patient samples with subtherapeutic doses of radiolabeled platinum followed by measurement of platinum-DNA adducts in blood or tumor tissue and may be used to predict patient response. We exposed a panel of six breast cancer cell lines to 14C-labeled carboplatin or oxaliplatin at therapeutic and microdose (1% therapeutic dose) concentrations for a range of exposure lengths and isolated DNA from the cells. The DNA was converted to graphite, and measurement of radiocarbon due to platinum-DNA adduction was quantified via accelerator mass spectrometry (AMS). We observed a linear correlation in adduct levels between the microdose and therapeutic dose, and the level of platinum-DNA adducts corresponded to cell line drug sensitivity for both carboplatin and oxaliplatin. These results showed a clear separation in adduct levels between the sensitive and resistant groups of cell lines that could not be fully explained or predicted by changes in DNA repair rates or mutations in DNA repair genes. Further, we were able to quantitate oxaliplatin-DNA adducts in the blood and tumor tissue of a metastatic breast cancer patient. Together, these data support the use of diagnostic microdosing for predicting patient sensitivity to platinum. Future studies will be aimed at replicating this data in a clinical feasibility trial.</description><identifier>ISSN: 0893-228X</identifier><identifier>EISSN: 1520-5010</identifier><identifier>DOI: 10.1021/acs.chemrestox.8b00170</identifier><identifier>PMID: 30381944</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>60 APPLIED LIFE SCIENCES ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Carboplatin - chemistry ; Carboplatin - toxicity ; Cell Line, Tumor ; Coordination Complexes - chemistry ; Coordination Complexes - toxicity ; DNA Adducts - analysis ; DNA Damage - drug effects ; DNA Repair - drug effects ; Female ; Humans ; Mass Spectrometry ; Oxaliplatin - chemistry ; Oxaliplatin - toxicity ; Platinum - chemistry</subject><ispartof>Chemical research in toxicology, 2018-12, Vol.31 (12), p.1293-1304</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a484t-d2b45958a7060b73a43ef2ae9b65e649764f2fc193862e8e7111b21dc717ed243</citedby><cites>FETCH-LOGICAL-a484t-d2b45958a7060b73a43ef2ae9b65e649764f2fc193862e8e7111b21dc717ed243</cites><orcidid>0000-0003-4238-0446 ; 0000000342380446</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30381944$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/servlets/purl/1513142$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Sisi</creatorcontrib><creatorcontrib>Scharadin, Tiffany M</creatorcontrib><creatorcontrib>Zimmermann, Maike</creatorcontrib><creatorcontrib>Malfatti, Michael A</creatorcontrib><creatorcontrib>Turteltaub, Kenneth W</creatorcontrib><creatorcontrib>de Vere White, Ralph</creatorcontrib><creatorcontrib>Pan, Chong-Xian</creatorcontrib><creatorcontrib>Henderson, Paul T</creatorcontrib><creatorcontrib>Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)</creatorcontrib><creatorcontrib>Univ. of California Davis, Sacramento, CA (United States)</creatorcontrib><title>Correlation of Platinum Cytotoxicity to Drug-DNA Adduct Levels in a Breast Cancer Cell Line Panel</title><title>Chemical research in toxicology</title><addtitle>Chem. Res. Toxicol</addtitle><description>Platinum drugs, including carboplatin and oxaliplatin, are commonly used chemotherapy drugs that kill cancer cells by forming toxic drug-DNA adducts. These drugs have a proven, but modest, efficacy against several aggressive subtypes of breast cancer but also cause several side effects that can lead to the cessation of treatment. There is a clinical need to identify patients who will respond to platinum drugs in order to better inform clinical decision making. Diagnostic microdosing involves dosing patients or patient samples with subtherapeutic doses of radiolabeled platinum followed by measurement of platinum-DNA adducts in blood or tumor tissue and may be used to predict patient response. We exposed a panel of six breast cancer cell lines to 14C-labeled carboplatin or oxaliplatin at therapeutic and microdose (1% therapeutic dose) concentrations for a range of exposure lengths and isolated DNA from the cells. The DNA was converted to graphite, and measurement of radiocarbon due to platinum-DNA adduction was quantified via accelerator mass spectrometry (AMS). We observed a linear correlation in adduct levels between the microdose and therapeutic dose, and the level of platinum-DNA adducts corresponded to cell line drug sensitivity for both carboplatin and oxaliplatin. These results showed a clear separation in adduct levels between the sensitive and resistant groups of cell lines that could not be fully explained or predicted by changes in DNA repair rates or mutations in DNA repair genes. Further, we were able to quantitate oxaliplatin-DNA adducts in the blood and tumor tissue of a metastatic breast cancer patient. Together, these data support the use of diagnostic microdosing for predicting patient sensitivity to platinum. Future studies will be aimed at replicating this data in a clinical feasibility trial.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Carboplatin - chemistry</subject><subject>Carboplatin - toxicity</subject><subject>Cell Line, Tumor</subject><subject>Coordination Complexes - chemistry</subject><subject>Coordination Complexes - toxicity</subject><subject>DNA Adducts - analysis</subject><subject>DNA Damage - drug effects</subject><subject>DNA Repair - drug effects</subject><subject>Female</subject><subject>Humans</subject><subject>Mass Spectrometry</subject><subject>Oxaliplatin - chemistry</subject><subject>Oxaliplatin - toxicity</subject><subject>Platinum - chemistry</subject><issn>0893-228X</issn><issn>1520-5010</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNqFkUFvFCEYhonR2LX6FxrifbZ8wMwwF5N1qtVkoz1o4o0wzDddmllogGncfy-brVVPniDhfR8-eAi5ALYGxuHS2LS2O9xHTDn8XKuBMWjZM7KCmrOqZsCekxVTnag4Vz_OyKuU7kqkdNuX5EwwoaCTckVMH2LE2WQXPA0TvTlu_bKn_SGHQnbW5QPNgV7F5ba6-rKhm3FcbKZbfMA5Ueepoe8jmpRpb7zFSHucZ7p1HumN8Ti_Ji8mMyd887iek-8fP3zrP1Xbr9ef-822MlLJXI18kHVXK9Oyhg2tMFLgxA12Q1NjI7u2kROfLHRCNRwVtgAwcBhtCy2OXIpz8u7EvV-GPY4WfY5m1vfR7U086GCc_vfEu52-DQ-6qYUSHS-AtydASNnpVB6OdmeD92izhhoEyGOoOYVsDClFnJ4uAKaPZnQxo_-Y0Y9mSvHi7_Gear9VlAA_BY6Au7BEX37rf9Rf_xKgIA</recordid><startdate>20181217</startdate><enddate>20181217</enddate><creator>Wang, Sisi</creator><creator>Scharadin, Tiffany M</creator><creator>Zimmermann, Maike</creator><creator>Malfatti, Michael A</creator><creator>Turteltaub, Kenneth W</creator><creator>de Vere White, Ralph</creator><creator>Pan, Chong-Xian</creator><creator>Henderson, Paul T</creator><general>American Chemical Society</general><general>American Chemical Society (ACS)</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>OIOZB</scope><scope>OTOTI</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4238-0446</orcidid><orcidid>https://orcid.org/0000000342380446</orcidid></search><sort><creationdate>20181217</creationdate><title>Correlation of Platinum Cytotoxicity to Drug-DNA Adduct Levels in a Breast Cancer Cell Line Panel</title><author>Wang, Sisi ; Scharadin, Tiffany M ; Zimmermann, Maike ; Malfatti, Michael A ; Turteltaub, Kenneth W ; de Vere White, Ralph ; Pan, Chong-Xian ; Henderson, Paul T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a484t-d2b45958a7060b73a43ef2ae9b65e649764f2fc193862e8e7111b21dc717ed243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Carboplatin - chemistry</topic><topic>Carboplatin - toxicity</topic><topic>Cell Line, Tumor</topic><topic>Coordination Complexes - chemistry</topic><topic>Coordination Complexes - toxicity</topic><topic>DNA Adducts - analysis</topic><topic>DNA Damage - drug effects</topic><topic>DNA Repair - drug effects</topic><topic>Female</topic><topic>Humans</topic><topic>Mass Spectrometry</topic><topic>Oxaliplatin - chemistry</topic><topic>Oxaliplatin - toxicity</topic><topic>Platinum - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Sisi</creatorcontrib><creatorcontrib>Scharadin, Tiffany M</creatorcontrib><creatorcontrib>Zimmermann, Maike</creatorcontrib><creatorcontrib>Malfatti, Michael A</creatorcontrib><creatorcontrib>Turteltaub, Kenneth W</creatorcontrib><creatorcontrib>de Vere White, Ralph</creatorcontrib><creatorcontrib>Pan, Chong-Xian</creatorcontrib><creatorcontrib>Henderson, Paul T</creatorcontrib><creatorcontrib>Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)</creatorcontrib><creatorcontrib>Univ. of California Davis, Sacramento, CA (United States)</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>OSTI.GOV - Hybrid</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Chemical research in toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Sisi</au><au>Scharadin, Tiffany M</au><au>Zimmermann, Maike</au><au>Malfatti, Michael A</au><au>Turteltaub, Kenneth W</au><au>de Vere White, Ralph</au><au>Pan, Chong-Xian</au><au>Henderson, Paul T</au><aucorp>Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)</aucorp><aucorp>Univ. of California Davis, Sacramento, CA (United States)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Correlation of Platinum Cytotoxicity to Drug-DNA Adduct Levels in a Breast Cancer Cell Line Panel</atitle><jtitle>Chemical research in toxicology</jtitle><addtitle>Chem. Res. Toxicol</addtitle><date>2018-12-17</date><risdate>2018</risdate><volume>31</volume><issue>12</issue><spage>1293</spage><epage>1304</epage><pages>1293-1304</pages><issn>0893-228X</issn><eissn>1520-5010</eissn><abstract>Platinum drugs, including carboplatin and oxaliplatin, are commonly used chemotherapy drugs that kill cancer cells by forming toxic drug-DNA adducts. These drugs have a proven, but modest, efficacy against several aggressive subtypes of breast cancer but also cause several side effects that can lead to the cessation of treatment. There is a clinical need to identify patients who will respond to platinum drugs in order to better inform clinical decision making. Diagnostic microdosing involves dosing patients or patient samples with subtherapeutic doses of radiolabeled platinum followed by measurement of platinum-DNA adducts in blood or tumor tissue and may be used to predict patient response. We exposed a panel of six breast cancer cell lines to 14C-labeled carboplatin or oxaliplatin at therapeutic and microdose (1% therapeutic dose) concentrations for a range of exposure lengths and isolated DNA from the cells. The DNA was converted to graphite, and measurement of radiocarbon due to platinum-DNA adduction was quantified via accelerator mass spectrometry (AMS). We observed a linear correlation in adduct levels between the microdose and therapeutic dose, and the level of platinum-DNA adducts corresponded to cell line drug sensitivity for both carboplatin and oxaliplatin. These results showed a clear separation in adduct levels between the sensitive and resistant groups of cell lines that could not be fully explained or predicted by changes in DNA repair rates or mutations in DNA repair genes. Further, we were able to quantitate oxaliplatin-DNA adducts in the blood and tumor tissue of a metastatic breast cancer patient. Together, these data support the use of diagnostic microdosing for predicting patient sensitivity to platinum. Future studies will be aimed at replicating this data in a clinical feasibility trial.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>30381944</pmid><doi>10.1021/acs.chemrestox.8b00170</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-4238-0446</orcidid><orcidid>https://orcid.org/0000000342380446</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | 60 APPLIED LIFE SCIENCES Breast Neoplasms - metabolism Breast Neoplasms - pathology Carboplatin - chemistry Carboplatin - toxicity Cell Line, Tumor Coordination Complexes - chemistry Coordination Complexes - toxicity DNA Adducts - analysis DNA Damage - drug effects DNA Repair - drug effects Female Humans Mass Spectrometry Oxaliplatin - chemistry Oxaliplatin - toxicity Platinum - chemistry |
title | Correlation of Platinum Cytotoxicity to Drug-DNA Adduct Levels in a Breast Cancer Cell Line Panel |
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