Protection from doxorubicin-induced cardiac toxicity in mice with a null allele of carbonyl reductase 1
Doxorubicin is a highly effective antineoplastic agent, but it can produce the serious side effects of acute cardiac injury and chronic congestive heart failure. Carbonyl reductase (CBR) has been implicated in the development of doxorubicin-induced cardiotoxicity. To test whether a decrease in CBR l...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2003-10, Vol.63 (20), p.6602-6606 |
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| container_title | Cancer research (Chicago, Ill.) |
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| creator | OLSON, Lisa E BEDJA, Djahida ALVEY, Sara J CARDOUNEL, A. J GABRIELSON, Kathleen L REEVES, Roger H |
| description | Doxorubicin is a highly effective antineoplastic agent, but it can produce the serious side effects of acute cardiac injury and chronic congestive heart failure. Carbonyl reductase (CBR) has been implicated in the development of doxorubicin-induced cardiotoxicity. To test whether a decrease in CBR levels was protective against doxorubicin toxicity, we created a null allele of the Cbr1 gene. Mice with one functional copy of the gene (Cbr1 +/-) were healthy and grossly normal despite having decreased levels of Cbr1 transcript and protein. Control and Cbr1 +/- mice were administered doxorubicin at 20 mg/kg i.p. Cbr1 +/- mice showed decreased circulating levels of the cardiotoxic metabolite, doxorubicinol, after administration. Within 2 weeks, 91% of wild-type mice were severely affected (n = 11) compared with 18% of Cbr1 +/- mice (n = 11). Echocardiography and histological analysis showed that Cbr1 +/- mice were protected from gross and cellular level pathologies associated with doxorubicin treatment. Demonstration that inhibition of carbonyl reductase blocks the toxic effects on the heart has important implications for improving the use of doxorubicin in chemotherapy. |
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J ; GABRIELSON, Kathleen L ; REEVES, Roger H</creator><creatorcontrib>OLSON, Lisa E ; BEDJA, Djahida ; ALVEY, Sara J ; CARDOUNEL, A. J ; GABRIELSON, Kathleen L ; REEVES, Roger H</creatorcontrib><description>Doxorubicin is a highly effective antineoplastic agent, but it can produce the serious side effects of acute cardiac injury and chronic congestive heart failure. Carbonyl reductase (CBR) has been implicated in the development of doxorubicin-induced cardiotoxicity. To test whether a decrease in CBR levels was protective against doxorubicin toxicity, we created a null allele of the Cbr1 gene. Mice with one functional copy of the gene (Cbr1 +/-) were healthy and grossly normal despite having decreased levels of Cbr1 transcript and protein. Control and Cbr1 +/- mice were administered doxorubicin at 20 mg/kg i.p. Cbr1 +/- mice showed decreased circulating levels of the cardiotoxic metabolite, doxorubicinol, after administration. Within 2 weeks, 91% of wild-type mice were severely affected (n = 11) compared with 18% of Cbr1 +/- mice (n = 11). Echocardiography and histological analysis showed that Cbr1 +/- mice were protected from gross and cellular level pathologies associated with doxorubicin treatment. Demonstration that inhibition of carbonyl reductase blocks the toxic effects on the heart has important implications for improving the use of doxorubicin in chemotherapy.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>PMID: 14583452</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Alcohol Oxidoreductases - deficiency ; Alcohol Oxidoreductases - genetics ; Alleles ; Animals ; Antibiotics, Antineoplastic - pharmacokinetics ; Antibiotics, Antineoplastic - toxicity ; Antineoplastic agents ; Biological and medical sciences ; Doxorubicin - analogs & derivatives ; Doxorubicin - pharmacokinetics ; Doxorubicin - toxicity ; Electrocardiography - drug effects ; Female ; Heart - drug effects ; Heart Diseases - chemically induced ; Heart Diseases - enzymology ; Heart Diseases - prevention & control ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Myocardium - enzymology ; Myocardium - pathology ; Pharmacology. Drug treatments ; Pregnancy ; Tumors ; Weight Loss - drug effects</subject><ispartof>Cancer research (Chicago, Ill.), 2003-10, Vol.63 (20), p.6602-6606</ispartof><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15249096$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14583452$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>OLSON, Lisa E</creatorcontrib><creatorcontrib>BEDJA, Djahida</creatorcontrib><creatorcontrib>ALVEY, Sara J</creatorcontrib><creatorcontrib>CARDOUNEL, A. J</creatorcontrib><creatorcontrib>GABRIELSON, Kathleen L</creatorcontrib><creatorcontrib>REEVES, Roger H</creatorcontrib><title>Protection from doxorubicin-induced cardiac toxicity in mice with a null allele of carbonyl reductase 1</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Doxorubicin is a highly effective antineoplastic agent, but it can produce the serious side effects of acute cardiac injury and chronic congestive heart failure. Carbonyl reductase (CBR) has been implicated in the development of doxorubicin-induced cardiotoxicity. To test whether a decrease in CBR levels was protective against doxorubicin toxicity, we created a null allele of the Cbr1 gene. Mice with one functional copy of the gene (Cbr1 +/-) were healthy and grossly normal despite having decreased levels of Cbr1 transcript and protein. Control and Cbr1 +/- mice were administered doxorubicin at 20 mg/kg i.p. Cbr1 +/- mice showed decreased circulating levels of the cardiotoxic metabolite, doxorubicinol, after administration. Within 2 weeks, 91% of wild-type mice were severely affected (n = 11) compared with 18% of Cbr1 +/- mice (n = 11). Echocardiography and histological analysis showed that Cbr1 +/- mice were protected from gross and cellular level pathologies associated with doxorubicin treatment. Demonstration that inhibition of carbonyl reductase blocks the toxic effects on the heart has important implications for improving the use of doxorubicin in chemotherapy.</description><subject>Alcohol Oxidoreductases - deficiency</subject><subject>Alcohol Oxidoreductases - genetics</subject><subject>Alleles</subject><subject>Animals</subject><subject>Antibiotics, Antineoplastic - pharmacokinetics</subject><subject>Antibiotics, Antineoplastic - toxicity</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Doxorubicin - analogs & derivatives</subject><subject>Doxorubicin - pharmacokinetics</subject><subject>Doxorubicin - toxicity</subject><subject>Electrocardiography - drug effects</subject><subject>Female</subject><subject>Heart - drug effects</subject><subject>Heart Diseases - chemically induced</subject><subject>Heart Diseases - enzymology</subject><subject>Heart Diseases - prevention & control</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Inbred ICR</subject><subject>Myocardium - enzymology</subject><subject>Myocardium - pathology</subject><subject>Pharmacology. Drug treatments</subject><subject>Pregnancy</subject><subject>Tumors</subject><subject>Weight Loss - drug effects</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFj09LAzEUxIMotla_guTicSHZJG32KMV_IOhBzyV5ebGRbFKyWWy_vStWvMzwht88mBMy50roZiWlOiVzxphulFy1M3IxDJ_TqThT52TGpdJCqnZOPl5Lrgg15ER9yT11eZ_LaAOE1ITkRkBHwRQXDNCa91NeDzQk2gdA-hXqlhqaxhipiREj0ux_cJvTIdKCU7-aASm_JGfexAGvjr4g7_d3b-vH5vnl4Wl9-9xsWyZq0wFwtMiXCr3DttPGoXUIoLgCx5RvsTPo1FJPIvhKIyBKbTuG3jrhxYJc__7djbZHt9mV0Jty2PwtnoCbI2AGMNEXkyAM_5xqZce6pfgGV9JjhQ</recordid><startdate>20031015</startdate><enddate>20031015</enddate><creator>OLSON, Lisa E</creator><creator>BEDJA, Djahida</creator><creator>ALVEY, Sara J</creator><creator>CARDOUNEL, A. J</creator><creator>GABRIELSON, Kathleen L</creator><creator>REEVES, Roger H</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20031015</creationdate><title>Protection from doxorubicin-induced cardiac toxicity in mice with a null allele of carbonyl reductase 1</title><author>OLSON, Lisa E ; BEDJA, Djahida ; ALVEY, Sara J ; CARDOUNEL, A. J ; GABRIELSON, Kathleen L ; REEVES, Roger H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-h203t-9cc1ebe165efde298adebdecc515cd05f2e9aed568ed53178ecee48b90efbd3f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Alcohol Oxidoreductases - deficiency</topic><topic>Alcohol Oxidoreductases - genetics</topic><topic>Alleles</topic><topic>Animals</topic><topic>Antibiotics, Antineoplastic - pharmacokinetics</topic><topic>Antibiotics, Antineoplastic - toxicity</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Doxorubicin - analogs & derivatives</topic><topic>Doxorubicin - pharmacokinetics</topic><topic>Doxorubicin - toxicity</topic><topic>Electrocardiography - drug effects</topic><topic>Female</topic><topic>Heart - drug effects</topic><topic>Heart Diseases - chemically induced</topic><topic>Heart Diseases - enzymology</topic><topic>Heart Diseases - prevention & control</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Inbred ICR</topic><topic>Myocardium - enzymology</topic><topic>Myocardium - pathology</topic><topic>Pharmacology. Drug treatments</topic><topic>Pregnancy</topic><topic>Tumors</topic><topic>Weight Loss - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>OLSON, Lisa E</creatorcontrib><creatorcontrib>BEDJA, Djahida</creatorcontrib><creatorcontrib>ALVEY, Sara J</creatorcontrib><creatorcontrib>CARDOUNEL, A. J</creatorcontrib><creatorcontrib>GABRIELSON, Kathleen L</creatorcontrib><creatorcontrib>REEVES, Roger H</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>OLSON, Lisa E</au><au>BEDJA, Djahida</au><au>ALVEY, Sara J</au><au>CARDOUNEL, A. J</au><au>GABRIELSON, Kathleen L</au><au>REEVES, Roger H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Protection from doxorubicin-induced cardiac toxicity in mice with a null allele of carbonyl reductase 1</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2003-10-15</date><risdate>2003</risdate><volume>63</volume><issue>20</issue><spage>6602</spage><epage>6606</epage><pages>6602-6606</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Doxorubicin is a highly effective antineoplastic agent, but it can produce the serious side effects of acute cardiac injury and chronic congestive heart failure. Carbonyl reductase (CBR) has been implicated in the development of doxorubicin-induced cardiotoxicity. To test whether a decrease in CBR levels was protective against doxorubicin toxicity, we created a null allele of the Cbr1 gene. Mice with one functional copy of the gene (Cbr1 +/-) were healthy and grossly normal despite having decreased levels of Cbr1 transcript and protein. Control and Cbr1 +/- mice were administered doxorubicin at 20 mg/kg i.p. Cbr1 +/- mice showed decreased circulating levels of the cardiotoxic metabolite, doxorubicinol, after administration. Within 2 weeks, 91% of wild-type mice were severely affected (n = 11) compared with 18% of Cbr1 +/- mice (n = 11). Echocardiography and histological analysis showed that Cbr1 +/- mice were protected from gross and cellular level pathologies associated with doxorubicin treatment. Demonstration that inhibition of carbonyl reductase blocks the toxic effects on the heart has important implications for improving the use of doxorubicin in chemotherapy.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>14583452</pmid><tpages>5</tpages></addata></record> |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Alcohol Oxidoreductases - deficiency Alcohol Oxidoreductases - genetics Alleles Animals Antibiotics, Antineoplastic - pharmacokinetics Antibiotics, Antineoplastic - toxicity Antineoplastic agents Biological and medical sciences Doxorubicin - analogs & derivatives Doxorubicin - pharmacokinetics Doxorubicin - toxicity Electrocardiography - drug effects Female Heart - drug effects Heart Diseases - chemically induced Heart Diseases - enzymology Heart Diseases - prevention & control Medical sciences Mice Mice, Inbred C57BL Mice, Inbred ICR Myocardium - enzymology Myocardium - pathology Pharmacology. Drug treatments Pregnancy Tumors Weight Loss - drug effects |
| title | Protection from doxorubicin-induced cardiac toxicity in mice with a null allele of carbonyl reductase 1 |
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