Intracellular activation and cytotoxic action of RS-1541 against cultured human tumor cells
Identifieur interne : 000652 ( Istex/Corpus ); précédent : 000651; suivant : 000653Intracellular activation and cytotoxic action of RS-1541 against cultured human tumor cells
Auteurs : Toshiro Takatori ; Takeshi Koizumi ; Taro Tokui ; Yoshihiro Mitsuhashi ; Akio Shiraishi ; Takashi TsuruoSource :
- Cancer Chemotherapy and Pharmacology [ 0344-5704 ] ; 1995-07-01.
English descriptors
- KwdEn :
- Teeft :
- Antitumor, Antitumor effects, Candida cylindracea, Cell line, Cell lines, Cellular homogenate, Chloroquine, Cholesterol esterase, Cholesterol esterase activity, Crude membrane, Crude membrane fraction, Cytosol, Cytosol fraction, Cytotoxic, Cytotoxic action, Cytotoxic effect, Cytotoxicity, Esterase, Homogenate, Icso, Icso value, Icso values, Initial cell density, Inoculum size, Lysosomal function, Lysosome, Macrocyclic lactone antibiotics, Membrane fraction, Rhizoxin, Same mode, Tsuruo, Tubulin, Tumor cells, Various concentrations.
Abstract
Abstract: RS-1541, an acyl-derivative of rhizoxin (Fig. 1), is a potent antitumor compound. This agent showed cytotoxicity in vitro on some cultured human tumor cells, although it was less potent than rhizoxin. Rhizoxin exhibited antitumor effects by inhibiting the polymerization of tubulin, whereas RS-1541 did not inhibit tubulin polymerization in vitro. However, cell cycle analysis in vivo showed that the two agents had the same mode of action. The cytotoxicity of RS-1541 was enhanced when the initial cell density of the cells was increased. The cytotoxicity was also enhanced when the membrane fraction of St-4 cells, which were the most sensitive to RS-1541 among the cell lines tested, was added to the target cells. When St-4 cells were incubated with [14C]-RS-1541, significant amounts of [14C]-rhizoxin were produced within the cells. Further fractionation of the crude membrane showed that the activity that enhanced the cytotoxicity of RS-1541 (RS-1541-enhancing activity) belonged to the mitochondrial-lysosomal fraction, not to the microsomal fraction. Both the enhancing activity and the activity that converting [14C]-RS-1541 to [14C]-rhizoxin (RS-1541-converting activity) were inhibited by treatment with chloroquine, an inhibitor of lysosomal function. Cholesterol esterase derived fromCandida cylindracea had RS-1541-enhancingand-converting activities. These data suggest that RS-1541 exerts its cytotoxic action after being converted to rhizoxin within the cells by a lysosomal enzyme such as cholesterol esterase.
Url:
DOI: 10.1007/BF00689446
Links to Exploration step
ISTEX:D7229730A8721E8275174A863A93D4B64D838A92Le document en format XML
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Pharmacol.</title><idno type="ISSN">0344-5704</idno><idno type="eISSN">1432-0843</idno><imprint><publisher>Springer-Verlag</publisher><pubPlace>Berlin/Heidelberg</pubPlace><date type="published" when="1995-07-01">1995-07-01</date><biblScope unit="volume">35</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="283">283</biblScope><biblScope unit="page" to="290">290</biblScope></imprint><idno type="ISSN">0344-5704</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0344-5704</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Cytotoxicity</term><term>RS-1541</term><term>Rhizoxin</term></keywords><keywords scheme="Teeft" xml:lang="en"><term>Antitumor</term><term>Antitumor effects</term><term>Candida cylindracea</term><term>Cell line</term><term>Cell lines</term><term>Cellular homogenate</term><term>Chloroquine</term><term>Cholesterol esterase</term><term>Cholesterol esterase activity</term><term>Crude membrane</term><term>Crude membrane fraction</term><term>Cytosol</term><term>Cytosol fraction</term><term>Cytotoxic</term><term>Cytotoxic action</term><term>Cytotoxic effect</term><term>Cytotoxicity</term><term>Esterase</term><term>Homogenate</term><term>Icso</term><term>Icso value</term><term>Icso values</term><term>Initial cell density</term><term>Inoculum size</term><term>Lysosomal function</term><term>Lysosome</term><term>Macrocyclic lactone antibiotics</term><term>Membrane fraction</term><term>Rhizoxin</term><term>Same mode</term><term>Tsuruo</term><term>Tubulin</term><term>Tumor cells</term><term>Various concentrations</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: RS-1541, an acyl-derivative of rhizoxin (Fig. 1), is a potent antitumor compound. This agent showed cytotoxicity in vitro on some cultured human tumor cells, although it was less potent than rhizoxin. Rhizoxin exhibited antitumor effects by inhibiting the polymerization of tubulin, whereas RS-1541 did not inhibit tubulin polymerization in vitro. However, cell cycle analysis in vivo showed that the two agents had the same mode of action. The cytotoxicity of RS-1541 was enhanced when the initial cell density of the cells was increased. The cytotoxicity was also enhanced when the membrane fraction of St-4 cells, which were the most sensitive to RS-1541 among the cell lines tested, was added to the target cells. When St-4 cells were incubated with [14C]-RS-1541, significant amounts of [14C]-rhizoxin were produced within the cells. Further fractionation of the crude membrane showed that the activity that enhanced the cytotoxicity of RS-1541 (RS-1541-enhancing activity) belonged to the mitochondrial-lysosomal fraction, not to the microsomal fraction. Both the enhancing activity and the activity that converting [14C]-RS-1541 to [14C]-rhizoxin (RS-1541-converting activity) were inhibited by treatment with chloroquine, an inhibitor of lysosomal function. Cholesterol esterase derived fromCandida cylindracea had RS-1541-enhancingand-converting activities. 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This agent showed cytotoxicity in vitro on some cultured human tumor cells, although it was less potent than rhizoxin. Rhizoxin exhibited antitumor effects by inhibiting the polymerization of tubulin, whereas RS-1541 did not inhibit tubulin polymerization in vitro. However, cell cycle analysis in vivo showed that the two agents had the same mode of action. The cytotoxicity of RS-1541 was enhanced when the initial cell density of the cells was increased. The cytotoxicity was also enhanced when the membrane fraction of St-4 cells, which were the most sensitive to RS-1541 among the cell lines tested, was added to the target cells. When St-4 cells were incubated with [14C]-RS-1541, significant amounts of [14C]-rhizoxin were produced within the cells. Further fractionation of the crude membrane showed that the activity that enhanced the cytotoxicity of RS-1541 (RS-1541-enhancing activity) belonged to the mitochondrial-lysosomal fraction, not to the microsomal fraction. Both the enhancing activity and the activity that converting [14C]-RS-1541 to [14C]-rhizoxin (RS-1541-converting activity) were inhibited by treatment with chloroquine, an inhibitor of lysosomal function. Cholesterol esterase derived fromCandida cylindracea had RS-1541-enhancingand-converting activities. These data suggest that RS-1541 exerts its cytotoxic action after being converted to rhizoxin within the cells by a lysosomal enzyme such as cholesterol esterase.</abstract><qualityIndicators><score>8.527</score><pdfWordCount>3935</pdfWordCount><pdfCharCount>24433</pdfCharCount><pdfVersion>1.3</pdfVersion><pdfPageCount>8</pdfPageCount><pdfPageSize>597.28 x 785 pts</pdfPageSize><refBibsNative>false</refBibsNative><abstractWordCount>216</abstractWordCount><abstractCharCount>1539</abstractCharCount><keywordCount>11</keywordCount></qualityIndicators><title>Intracellular activation and cytotoxic action of RS-1541 against cultured human tumor cells</title><genre><json:string>research-article</json:string></genre><host><title>Cancer Chemotherapy and Pharmacology</title><language><json:string>unknown</json:string></language><publicationDate>1995</publicationDate><copyrightDate>1995</copyrightDate><issn><json:string>0344-5704</json:string></issn><eissn><json:string>1432-0843</json:string></eissn><journalId><json:string>280</json:string></journalId><volume>35</volume><issue>4</issue><pages><first>283</first><last>290</last></pages><genre><json:string>journal</json:string></genre><subject><json:item><value>Cancer Research</value></json:item><json:item><value>Pharmacology/Toxicology</value></json:item><json:item><value>Oncology</value></json:item></subject></host><namedEntities><unitex><date></date><geogName></geogName><orgName></orgName><orgName_funder></orgName_funder><orgName_provider></orgName_provider><persName></persName><placeName></placeName><ref_url></ref_url><ref_bibl></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/1BB-101W2FM3-F</json:string></ark><categories><wos><json:string>1 - 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Pharmacol.</title><idno type="pISSN">0344-5704</idno><idno type="eISSN">1432-0843</idno><idno type="journal-ID">true</idno><idno type="issue-article-count">17</idno><idno type="volume-issue-count">6</idno><imprint><publisher>Springer-Verlag</publisher><pubPlace>Berlin/Heidelberg</pubPlace><date type="published" when="1995-07-01"></date><biblScope unit="volume">35</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="283">283</biblScope><biblScope unit="page" to="290">290</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1994-01-25</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Abstract: RS-1541, an acyl-derivative of rhizoxin (Fig. 1), is a potent antitumor compound. This agent showed cytotoxicity in vitro on some cultured human tumor cells, although it was less potent than rhizoxin. Rhizoxin exhibited antitumor effects by inhibiting the polymerization of tubulin, whereas RS-1541 did not inhibit tubulin polymerization in vitro. However, cell cycle analysis in vivo showed that the two agents had the same mode of action. The cytotoxicity of RS-1541 was enhanced when the initial cell density of the cells was increased. The cytotoxicity was also enhanced when the membrane fraction of St-4 cells, which were the most sensitive to RS-1541 among the cell lines tested, was added to the target cells. When St-4 cells were incubated with [14C]-RS-1541, significant amounts of [14C]-rhizoxin were produced within the cells. Further fractionation of the crude membrane showed that the activity that enhanced the cytotoxicity of RS-1541 (RS-1541-enhancing activity) belonged to the mitochondrial-lysosomal fraction, not to the microsomal fraction. Both the enhancing activity and the activity that converting [14C]-RS-1541 to [14C]-rhizoxin (RS-1541-converting activity) were inhibited by treatment with chloroquine, an inhibitor of lysosomal function. Cholesterol esterase derived fromCandida cylindracea had RS-1541-enhancingand-converting activities. These data suggest that RS-1541 exerts its cytotoxic action after being converted to rhizoxin within the cells by a lysosomal enzyme such as cholesterol esterase.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Key words</head><item><term>RS-1541</term></item><item><term>Rhizoxin</term></item><item><term>Cytotoxicity</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>Abbreviations</head><item><term>DMSO</term><term>Dimethylsulfoxide</term></item><item><term>PBS (-) Ca2+</term><term>Mg2+-free phosphate-buffered saline</term></item><item><term>HCO60</term><term>hydrogenated castor oil polyethylene glycor ether</term></item><item><term>DMA</term><term>dimethylacetamide</term></item><item><term>RSB</term><term>reticulocyte standard buffer, consisting of 10mM NaCl, 1.5 mM MgCl2, and 10 mM TRIS-HCl, (pH 7.4)</term></item><item><term>TLC</term><term>thin-layer chromatography</term></item><item><term>ara-C</term><term>1-β-D-arabinofuranosylcytosine</term></item><item><term>LDL</term><term>low-density lipoprotein</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>Biomedicine</head><item><term>Cancer Research</term></item><item><term>Pharmacology/Toxicology</term></item><item><term>Oncology</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1994-01-25">Created</change><change when="1995-07-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/1BB-101W2FM3-F/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus springer-journals not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//Springer-Verlag//DTD A++ V2.4//EN" URI="http://devel.springer.de/A++/V2.4/DTD/A++V2.4.dtd" name="istex:docType"></istex:docType><istex:document><Publisher><PublisherInfo><PublisherName>Springer-Verlag</PublisherName><PublisherLocation>Berlin/Heidelberg</PublisherLocation></PublisherInfo><Journal><JournalInfo JournalProductType="ArchiveJournal" NumberingStyle="Unnumbered"><JournalID>280</JournalID><JournalPrintISSN>0344-5704</JournalPrintISSN><JournalElectronicISSN>1432-0843</JournalElectronicISSN><JournalTitle>Cancer Chemotherapy and Pharmacology</JournalTitle><JournalAbbreviatedTitle>Cancer Chemother. Pharmacol.</JournalAbbreviatedTitle><JournalSubjectGroup><JournalSubject Type="Primary">Biomedicine</JournalSubject><JournalSubject Type="Secondary">Cancer Research</JournalSubject><JournalSubject Type="Secondary">Pharmacology/Toxicology</JournalSubject><JournalSubject Type="Secondary">Oncology</JournalSubject></JournalSubjectGroup></JournalInfo><Volume><VolumeInfo VolumeType="Regular" TocLevels="0"><VolumeIDStart>35</VolumeIDStart><VolumeIDEnd>35</VolumeIDEnd><VolumeIssueCount>6</VolumeIssueCount></VolumeInfo><Issue IssueType="Regular"><IssueInfo TocLevels="0"><IssueIDStart>4</IssueIDStart><IssueIDEnd>4</IssueIDEnd><IssueArticleCount>17</IssueArticleCount><IssueHistory><CoverDate><DateString>1995</DateString><Year>1995</Year><Month>7</Month></CoverDate></IssueHistory><IssueCopyright><CopyrightHolderName>Springer-Verlag</CopyrightHolderName><CopyrightYear>1995</CopyrightYear></IssueCopyright></IssueInfo><Article ID="Art3"><ArticleInfo Language="En" ArticleType="OriginalPaper" NumberingStyle="Unnumbered" TocLevels="0" ContainsESM="No"><ArticleID>BF00689446</ArticleID><ArticleDOI>10.1007/BF00689446</ArticleDOI><ArticleSequenceNumber>3</ArticleSequenceNumber><ArticleTitle Language="En">Intracellular activation and cytotoxic action of RS-1541 against cultured human tumor cells</ArticleTitle><ArticleCategory>Original Article</ArticleCategory><ArticleSubCategory>RS-1541, Rhizoxin, Cytotoxicity</ArticleSubCategory><ArticleFirstPage>283</ArticleFirstPage><ArticleLastPage>290</ArticleLastPage><ArticleHistory><RegistrationDate><Year>2004</Year><Month>11</Month><Day>9</Day></RegistrationDate><Received><Year>1994</Year><Month>1</Month><Day>25</Day></Received><Accepted><Year>1994</Year><Month>7</Month><Day>15</Day></Accepted></ArticleHistory><ArticleCopyright><CopyrightHolderName>Springer-Verlag</CopyrightHolderName><CopyrightYear>1995</CopyrightYear></ArticleCopyright><ArticleGrants Type="Regular"><MetadataGrant Grant="OpenAccess"></MetadataGrant><AbstractGrant Grant="OpenAccess"></AbstractGrant><BodyPDFGrant Grant="Restricted"></BodyPDFGrant><BodyHTMLGrant Grant="Restricted"></BodyHTMLGrant><BibliographyGrant Grant="Restricted"></BibliographyGrant><ESMGrant Grant="Restricted"></ESMGrant></ArticleGrants><ArticleContext><JournalID>280</JournalID><VolumeIDStart>35</VolumeIDStart><VolumeIDEnd>35</VolumeIDEnd><IssueIDStart>4</IssueIDStart><IssueIDEnd>4</IssueIDEnd></ArticleContext></ArticleInfo><ArticleHeader><AuthorGroup><Author AffiliationIDS="Aff1 Aff2"><AuthorName DisplayOrder="Western"><GivenName>Toshiro</GivenName><FamilyName>Takatori</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff2"><AuthorName DisplayOrder="Western"><GivenName>Takeshi</GivenName><FamilyName>Koizumi</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff3"><AuthorName DisplayOrder="Western"><GivenName>Taro</GivenName><FamilyName>Tokui</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Yoshihiro</GivenName><FamilyName>Mitsuhashi</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff1"><AuthorName DisplayOrder="Western"><GivenName>Akio</GivenName><FamilyName>Shiraishi</FamilyName></AuthorName></Author><Author AffiliationIDS="Aff2" CorrespondingAffiliationID="Aff2"><AuthorName DisplayOrder="Western"><GivenName>Takashi</GivenName><FamilyName>Tsuruo</FamilyName></AuthorName></Author><Affiliation ID="Aff1"><OrgDivision>Biological Research Laboratories</OrgDivision><OrgName>Sankyo Co., Ltd.</OrgName><OrgAddress><Street>Shinagawa-ku</Street><Postcode>140</Postcode><City>Tokyo</City><Country>Japan</Country></OrgAddress></Affiliation><Affiliation ID="Aff3"><OrgDivision>Analytical and Metabolic Research Laboratories</OrgDivision><OrgName>Sankyo Co., Ltd.</OrgName><OrgAddress><Street>Shinagawa-ku</Street><Postcode>140</Postcode><City>Tokyo</City><Country>Japan</Country></OrgAddress></Affiliation><Affiliation ID="Aff2"><OrgDivision>Institute of Molecular and Cellular Bioscience</OrgDivision><OrgName>University of Tokyo</OrgName><OrgAddress><Street>Yayoi, Bunkyo-ku</Street><Postcode>113</Postcode><City>Tokyo</City><Country>Japan</Country></OrgAddress></Affiliation></AuthorGroup><Abstract ID="Abs1" Language="En"><Heading>Abstract</Heading><Para>RS-1541, an acyl-derivative of rhizoxin (Fig. 1), is a potent antitumor compound. This agent showed cytotoxicity in vitro on some cultured human tumor cells, although it was less potent than rhizoxin. Rhizoxin exhibited antitumor effects by inhibiting the polymerization of tubulin, whereas RS-1541 did not inhibit tubulin polymerization in vitro. However, cell cycle analysis in vivo showed that the two agents had the same mode of action. The cytotoxicity of RS-1541 was enhanced when the initial cell density of the cells was increased. The cytotoxicity was also enhanced when the membrane fraction of St-4 cells, which were the most sensitive to RS-1541 among the cell lines tested, was added to the target cells. When St-4 cells were incubated with [<Superscript>14</Superscript>C]-RS-1541, significant amounts of [<Superscript>14</Superscript>C]-rhizoxin were produced within the cells. Further fractionation of the crude membrane showed that the activity that enhanced the cytotoxicity of RS-1541 (RS-1541-enhancing activity) belonged to the mitochondrial-lysosomal fraction, not to the microsomal fraction. Both the enhancing activity and the activity that converting [<Superscript>14</Superscript>C]-RS-1541 to [<Superscript>14</Superscript>C]-rhizoxin (RS-1541-converting activity) were inhibited by treatment with chloroquine, an inhibitor of lysosomal function. Cholesterol esterase derived from<Emphasis Type="Italic">Candida cylindracea</Emphasis> had RS-1541-enhancing<Emphasis Type="Italic">and</Emphasis>-converting activities. These data suggest that RS-1541 exerts its cytotoxic action after being converted to rhizoxin within the cells by a lysosomal enzyme such as cholesterol esterase.</Para></Abstract><KeywordGroup Language="En"><Heading>Key words</Heading><Keyword>RS-1541</Keyword><Keyword>Rhizoxin</Keyword><Keyword>Cytotoxicity</Keyword></KeywordGroup><AbbreviationGroup><Heading>Abbreviations</Heading><DefinitionList><DefinitionListEntry><Term><Emphasis Type="Italic">DMSO</Emphasis></Term><Description><Para>Dimethylsulfoxide</Para></Description></DefinitionListEntry><DefinitionListEntry><Term><Emphasis Type="Italic">PBS</Emphasis>(-) Ca<Superscript>2+</Superscript></Term><Description><Para>Mg<Superscript>2+</Superscript>-free phosphate-buffered saline</Para></Description></DefinitionListEntry><DefinitionListEntry><Term><Emphasis Type="Italic">HCO60</Emphasis></Term><Description><Para>hydrogenated castor oil polyethylene glycor ether</Para></Description></DefinitionListEntry><DefinitionListEntry><Term><Emphasis Type="Italic">DMA</Emphasis></Term><Description><Para>dimethylacetamide</Para></Description></DefinitionListEntry><DefinitionListEntry><Term><Emphasis Type="Italic">RSB</Emphasis></Term><Description><Para>reticulocyte standard buffer, consisting of 10m<Emphasis Type="Italic">M</Emphasis> NaCl, 1.5 m<Emphasis Type="Italic">M</Emphasis> MgCl<Subscript>2</Subscript>, and 10 m<Emphasis Type="Italic">M</Emphasis> TRIS-HCl, (pH 7.4)</Para></Description></DefinitionListEntry><DefinitionListEntry><Term><Emphasis Type="Italic">TLC</Emphasis></Term><Description><Para>thin-layer chromatography</Para></Description></DefinitionListEntry><DefinitionListEntry><Term><Emphasis Type="Italic">ara-C</Emphasis></Term><Description><Para>1-β-D-arabinofuranosylcytosine</Para></Description></DefinitionListEntry><DefinitionListEntry><Term><Emphasis Type="Italic">LDL</Emphasis></Term><Description><Para>low-density lipoprotein</Para></Description></DefinitionListEntry></DefinitionList></AbbreviationGroup></ArticleHeader><NoBody></NoBody></Article></Issue></Volume></Journal></Publisher></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Intracellular activation and cytotoxic action of RS-1541 against cultured human tumor cells</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Intracellular activation and cytotoxic action of RS-1541 against cultured human tumor cells</title></titleInfo><name type="personal"><namePart type="given">Toshiro</namePart><namePart type="family">Takatori</namePart><affiliation>Biological Research Laboratories, Sankyo Co., Ltd., Shinagawa-ku, 140, Tokyo, Japan</affiliation><affiliation>Institute of Molecular and Cellular Bioscience, University of Tokyo, Yayoi, Bunkyo-ku, 113, Tokyo, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Takeshi</namePart><namePart type="family">Koizumi</namePart><affiliation>Institute of Molecular and Cellular Bioscience, University of Tokyo, Yayoi, Bunkyo-ku, 113, Tokyo, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Taro</namePart><namePart type="family">Tokui</namePart><affiliation>Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., Shinagawa-ku, 140, Tokyo, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yoshihiro</namePart><namePart type="family">Mitsuhashi</namePart><affiliation>Biological Research Laboratories, Sankyo Co., Ltd., Shinagawa-ku, 140, Tokyo, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Akio</namePart><namePart type="family">Shiraishi</namePart><affiliation>Biological Research Laboratories, Sankyo Co., Ltd., Shinagawa-ku, 140, Tokyo, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Takashi</namePart><namePart type="family">Tsuruo</namePart><affiliation>Institute of Molecular and Cellular Bioscience, University of Tokyo, Yayoi, Bunkyo-ku, 113, Tokyo, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="OriginalPaper" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>Springer-Verlag</publisher><place><placeTerm type="text">Berlin/Heidelberg</placeTerm></place><dateCreated encoding="w3cdtf">1994-01-25</dateCreated><dateIssued encoding="w3cdtf">1995-07-01</dateIssued><copyrightDate encoding="w3cdtf">1995</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><abstract lang="en">Abstract: RS-1541, an acyl-derivative of rhizoxin (Fig. 1), is a potent antitumor compound. This agent showed cytotoxicity in vitro on some cultured human tumor cells, although it was less potent than rhizoxin. Rhizoxin exhibited antitumor effects by inhibiting the polymerization of tubulin, whereas RS-1541 did not inhibit tubulin polymerization in vitro. However, cell cycle analysis in vivo showed that the two agents had the same mode of action. The cytotoxicity of RS-1541 was enhanced when the initial cell density of the cells was increased. The cytotoxicity was also enhanced when the membrane fraction of St-4 cells, which were the most sensitive to RS-1541 among the cell lines tested, was added to the target cells. When St-4 cells were incubated with [14C]-RS-1541, significant amounts of [14C]-rhizoxin were produced within the cells. Further fractionation of the crude membrane showed that the activity that enhanced the cytotoxicity of RS-1541 (RS-1541-enhancing activity) belonged to the mitochondrial-lysosomal fraction, not to the microsomal fraction. Both the enhancing activity and the activity that converting [14C]-RS-1541 to [14C]-rhizoxin (RS-1541-converting activity) were inhibited by treatment with chloroquine, an inhibitor of lysosomal function. Cholesterol esterase derived fromCandida cylindracea had RS-1541-enhancingand-converting activities. These data suggest that RS-1541 exerts its cytotoxic action after being converted to rhizoxin within the cells by a lysosomal enzyme such as cholesterol esterase.</abstract><note>Original Article/RS-1541, Rhizoxin, Cytotoxicity</note><subject lang="en"><genre>Key words</genre><topic>RS-1541</topic><topic>Rhizoxin</topic><topic>Cytotoxicity</topic></subject><subject><genre>Abbreviations</genre><topic>DMSO : Dimethylsulfoxide</topic><topic>PBS (-) Ca2+ : Mg2+-free phosphate-buffered saline</topic><topic>HCO60 : hydrogenated castor oil polyethylene glycor ether</topic><topic>DMA : dimethylacetamide</topic><topic>RSB : reticulocyte standard buffer, consisting of 10mM NaCl, 1.5 mM MgCl2, and 10 mM TRIS-HCl, (pH 7.4)</topic><topic>TLC : thin-layer chromatography</topic><topic>ara-C : 1-β-D-arabinofuranosylcytosine</topic><topic>LDL : low-density lipoprotein</topic></subject><relatedItem type="host"><titleInfo><title>Cancer Chemotherapy and Pharmacology</title></titleInfo><titleInfo type="abbreviated"><title>Cancer Chemother. 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