Targeting the cytotoxicity of topoisomerase II-directed epipodophyllotoxins to tumor cells in acidic environments.
Identifieur interne : 000526 ( PubMed/Corpus ); précédent : 000525; suivant : 000527Targeting the cytotoxicity of topoisomerase II-directed epipodophyllotoxins to tumor cells in acidic environments.
Auteurs : P B Jensen ; B S S Rensen ; M. Sehested ; P. Grue ; E J Demant ; H H HansenSource :
- Cancer research [ 0008-5472 ] ; 1994.
English descriptors
- KwdEn :
- Amsacrine (pharmacology), Animals, Carcinoma, Small Cell (metabolism), Chloroquine (metabolism), Chloroquine (pharmacology), DNA Damage (drug effects), DNA Topoisomerases, Type II, DNA, Neoplasm (drug effects), Drug Screening Assays, Antitumor, Drug Synergism, Etoposide (antagonists & inhibitors), Etoposide (pharmacology), Humans, Hydrogen-Ion Concentration, Leukemia L1210 (metabolism), Lung Neoplasms (metabolism), Mice, Tumor Cells, Cultured.
- MESH :
- chemical , antagonists & inhibitors : Etoposide.
- chemical , drug effects : DNA, Neoplasm.
- chemical , metabolism : Chloroquine.
- chemical , pharmacology : Amsacrine, Chloroquine, Etoposide.
- drug effects : DNA Damage.
- metabolism : Carcinoma, Small Cell, Leukemia L1210, Lung Neoplasms.
- Animals, DNA Topoisomerases, Type II, Drug Screening Assays, Antitumor, Drug Synergism, Humans, Hydrogen-Ion Concentration, Mice, Tumor Cells, Cultured.
Abstract
The epipodophyllotoxins etoposide and teniposide are probably the most important drugs in the treatment of small cell lung cancer. The drugs are used in maximally tolerated doses, and the toxicity of the drugs precludes significant dose increments. The cellular target is the nuclear enzyme topoisomerase II which, in the presence of these drugs, causes an extensive fragmentation of DNA. The cell kill can be antagonized by distinct drug types. We have demonstrated previously that the intercalating drug aclarubicin and the cardioprotecting agent ICRF-187 antagonize the cytotoxicity of etoposide in vitro. We have studied possible ways of using this antagonism as a means of differentially protecting normal tissue. Here we demonstrate that the intercalating agent chloroquine prevents the introduction of topoisomerase II-mediated DNA breaks and thereby antagonizes the cytotoxicity of etoposide. This interaction depends on the extracellular pH. Chloroquine, in contrast to etoposide, is a weak base and therefore does not enter the cell if the extracellular fluid is acidic, as is the case in most solid tumors. We propose that such a pH-dependent drug interaction may be useful in directing topoisomerase II drug effects toward solid tumors. Thus, by lowering the extracellular pH (pHe) from neutral (pHe = 7.4) to acidic (pHe = 6.0), [3H]chloroquine accumulation was decreased 5-fold in a human small cell lung cancer cell line, OC-NYH, and in murine leukemia L1210 cells. In parallel, the antagonism exhibited by chloroquine on etoposide cytotoxicity was pHe dependent. Thus, no protection by chloroquine was observed at pHe = 6.5, whereas at pHe = 7.4, etoposide cytotoxicity was almost completely antagonized with a 460-fold protection or more than eight doublings of the cell population. This exploitation of antagonist extracellular trapping by acidic pH is a novel model for regulation of anticancer drug effects.
PubMed: 8187081
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Targeting the cytotoxicity of topoisomerase II-directed epipodophyllotoxins to tumor cells in acidic environments.</title><author><name sortKey="Jensen, P B" sort="Jensen, P B" uniqKey="Jensen P" first="P B" last="Jensen">P B Jensen</name><affiliation><nlm:affiliation>Department of Oncology, Finsen Institute, Rigshospitalet, Copenhagen, Denmark.</nlm:affiliation></affiliation></author><author><name sortKey="S Rensen, B S" sort="S Rensen, B S" uniqKey="S Rensen B" first="B S" last="S Rensen">B S S Rensen</name></author><author><name sortKey="Sehested, M" sort="Sehested, M" uniqKey="Sehested M" first="M" last="Sehested">M. Sehested</name></author><author><name sortKey="Grue, P" sort="Grue, P" uniqKey="Grue P" first="P" last="Grue">P. Grue</name></author><author><name sortKey="Demant, E J" sort="Demant, E J" uniqKey="Demant E" first="E J" last="Demant">E J Demant</name></author><author><name sortKey="Hansen, H H" sort="Hansen, H H" uniqKey="Hansen H" first="H H" last="Hansen">H H Hansen</name></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="1994">1994</date><idno type="RBID">pubmed:8187081</idno><idno type="pmid">8187081</idno><idno type="wicri:Area/PubMed/Corpus">000526</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000526</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Targeting the cytotoxicity of topoisomerase II-directed epipodophyllotoxins to tumor cells in acidic environments.</title><author><name sortKey="Jensen, P B" sort="Jensen, P B" uniqKey="Jensen P" first="P B" last="Jensen">P B Jensen</name><affiliation><nlm:affiliation>Department of Oncology, Finsen Institute, Rigshospitalet, Copenhagen, Denmark.</nlm:affiliation></affiliation></author><author><name sortKey="S Rensen, B S" sort="S Rensen, B S" uniqKey="S Rensen B" first="B S" last="S Rensen">B S S Rensen</name></author><author><name sortKey="Sehested, M" sort="Sehested, M" uniqKey="Sehested M" first="M" last="Sehested">M. Sehested</name></author><author><name sortKey="Grue, P" sort="Grue, P" uniqKey="Grue P" first="P" last="Grue">P. Grue</name></author><author><name sortKey="Demant, E J" sort="Demant, E J" uniqKey="Demant E" first="E J" last="Demant">E J Demant</name></author><author><name sortKey="Hansen, H H" sort="Hansen, H H" uniqKey="Hansen H" first="H H" last="Hansen">H H Hansen</name></author></analytic><series><title level="j">Cancer research</title><idno type="ISSN">0008-5472</idno><imprint><date when="1994" type="published">1994</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amsacrine (pharmacology)</term><term>Animals</term><term>Carcinoma, Small Cell (metabolism)</term><term>Chloroquine (metabolism)</term><term>Chloroquine (pharmacology)</term><term>DNA Damage (drug effects)</term><term>DNA Topoisomerases, Type II</term><term>DNA, Neoplasm (drug effects)</term><term>Drug Screening Assays, Antitumor</term><term>Drug Synergism</term><term>Etoposide (antagonists & inhibitors)</term><term>Etoposide (pharmacology)</term><term>Humans</term><term>Hydrogen-Ion Concentration</term><term>Leukemia L1210 (metabolism)</term><term>Lung Neoplasms (metabolism)</term><term>Mice</term><term>Tumor Cells, Cultured</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Etoposide</term></keywords><keywords scheme="MESH" type="chemical" qualifier="drug effects" xml:lang="en"><term>DNA, Neoplasm</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Chloroquine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Amsacrine</term><term>Chloroquine</term><term>Etoposide</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>DNA Damage</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Carcinoma, Small Cell</term><term>Leukemia L1210</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>DNA Topoisomerases, Type II</term><term>Drug Screening Assays, Antitumor</term><term>Drug Synergism</term><term>Humans</term><term>Hydrogen-Ion Concentration</term><term>Mice</term><term>Tumor Cells, Cultured</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The epipodophyllotoxins etoposide and teniposide are probably the most important drugs in the treatment of small cell lung cancer. The drugs are used in maximally tolerated doses, and the toxicity of the drugs precludes significant dose increments. The cellular target is the nuclear enzyme topoisomerase II which, in the presence of these drugs, causes an extensive fragmentation of DNA. The cell kill can be antagonized by distinct drug types. We have demonstrated previously that the intercalating drug aclarubicin and the cardioprotecting agent ICRF-187 antagonize the cytotoxicity of etoposide in vitro. We have studied possible ways of using this antagonism as a means of differentially protecting normal tissue. Here we demonstrate that the intercalating agent chloroquine prevents the introduction of topoisomerase II-mediated DNA breaks and thereby antagonizes the cytotoxicity of etoposide. This interaction depends on the extracellular pH. Chloroquine, in contrast to etoposide, is a weak base and therefore does not enter the cell if the extracellular fluid is acidic, as is the case in most solid tumors. We propose that such a pH-dependent drug interaction may be useful in directing topoisomerase II drug effects toward solid tumors. Thus, by lowering the extracellular pH (pHe) from neutral (pHe = 7.4) to acidic (pHe = 6.0), [3H]chloroquine accumulation was decreased 5-fold in a human small cell lung cancer cell line, OC-NYH, and in murine leukemia L1210 cells. In parallel, the antagonism exhibited by chloroquine on etoposide cytotoxicity was pHe dependent. Thus, no protection by chloroquine was observed at pHe = 6.5, whereas at pHe = 7.4, etoposide cytotoxicity was almost completely antagonized with a 460-fold protection or more than eight doublings of the cell population. This exploitation of antagonist extracellular trapping by acidic pH is a novel model for regulation of anticancer drug effects.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">8187081</PMID><DateCompleted><Year>1994</Year><Month>06</Month><Day>21</Day></DateCompleted><DateRevised><Year>2015</Year><Month>11</Month><Day>19</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0008-5472</ISSN><JournalIssue CitedMedium="Print"><Volume>54</Volume><Issue>11</Issue><PubDate><Year>1994</Year><Month>Jun</Month><Day>01</Day></PubDate></JournalIssue><Title>Cancer research</Title><ISOAbbreviation>Cancer Res.</ISOAbbreviation></Journal><ArticleTitle>Targeting the cytotoxicity of topoisomerase II-directed epipodophyllotoxins to tumor cells in acidic environments.</ArticleTitle><Pagination><MedlinePgn>2959-63</MedlinePgn></Pagination><Abstract><AbstractText>The epipodophyllotoxins etoposide and teniposide are probably the most important drugs in the treatment of small cell lung cancer. The drugs are used in maximally tolerated doses, and the toxicity of the drugs precludes significant dose increments. The cellular target is the nuclear enzyme topoisomerase II which, in the presence of these drugs, causes an extensive fragmentation of DNA. The cell kill can be antagonized by distinct drug types. We have demonstrated previously that the intercalating drug aclarubicin and the cardioprotecting agent ICRF-187 antagonize the cytotoxicity of etoposide in vitro. We have studied possible ways of using this antagonism as a means of differentially protecting normal tissue. Here we demonstrate that the intercalating agent chloroquine prevents the introduction of topoisomerase II-mediated DNA breaks and thereby antagonizes the cytotoxicity of etoposide. This interaction depends on the extracellular pH. Chloroquine, in contrast to etoposide, is a weak base and therefore does not enter the cell if the extracellular fluid is acidic, as is the case in most solid tumors. We propose that such a pH-dependent drug interaction may be useful in directing topoisomerase II drug effects toward solid tumors. Thus, by lowering the extracellular pH (pHe) from neutral (pHe = 7.4) to acidic (pHe = 6.0), [3H]chloroquine accumulation was decreased 5-fold in a human small cell lung cancer cell line, OC-NYH, and in murine leukemia L1210 cells. In parallel, the antagonism exhibited by chloroquine on etoposide cytotoxicity was pHe dependent. Thus, no protection by chloroquine was observed at pHe = 6.5, whereas at pHe = 7.4, etoposide cytotoxicity was almost completely antagonized with a 460-fold protection or more than eight doublings of the cell population. This exploitation of antagonist extracellular trapping by acidic pH is a novel model for regulation of anticancer drug effects.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Jensen</LastName><ForeName>P B</ForeName><Initials>PB</Initials><AffiliationInfo><Affiliation>Department of Oncology, Finsen Institute, Rigshospitalet, Copenhagen, Denmark.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sørensen</LastName><ForeName>B S</ForeName><Initials>BS</Initials></Author><Author ValidYN="Y"><LastName>Sehested</LastName><ForeName>M</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Grue</LastName><ForeName>P</ForeName><Initials>P</Initials></Author><Author ValidYN="Y"><LastName>Demant</LastName><ForeName>E J</ForeName><Initials>EJ</Initials></Author><Author ValidYN="Y"><LastName>Hansen</LastName><ForeName>H H</ForeName><Initials>HH</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Cancer Res</MedlineTA><NlmUniqueID>2984705R</NlmUniqueID><ISSNLinking>0008-5472</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004273">DNA, Neoplasm</NameOfSubstance></Chemical><Chemical><RegistryNumber>00DPD30SOY</RegistryNumber><NameOfSubstance UI="D000677">Amsacrine</NameOfSubstance></Chemical><Chemical><RegistryNumber>6PLQ3CP4P3</RegistryNumber><NameOfSubstance UI="D005047">Etoposide</NameOfSubstance></Chemical><Chemical><RegistryNumber>886U3H6UFF</RegistryNumber><NameOfSubstance UI="D002738">Chloroquine</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 5.99.1.3</RegistryNumber><NameOfSubstance UI="D004250">DNA Topoisomerases, Type II</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000677" MajorTopicYN="N">Amsacrine</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018288" MajorTopicYN="N">Carcinoma, Small Cell</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002738" MajorTopicYN="N">Chloroquine</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004249" MajorTopicYN="N">DNA Damage</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004250" MajorTopicYN="N">DNA Topoisomerases, Type II</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004273" MajorTopicYN="N">DNA, Neoplasm</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004354" MajorTopicYN="N">Drug Screening Assays, Antitumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004357" MajorTopicYN="N">Drug Synergism</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005047" MajorTopicYN="N">Etoposide</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006863" 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