Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and catalytic inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle.
Identifieur interne : 000515 ( PubMed/Curation ); précédent : 000514; suivant : 000516Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and catalytic inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle.
Auteurs : M. Sehested [Danemark] ; P B JensenSource :
- Biochemical pharmacology [ 0006-2952 ] ; 1996.
Descripteurs français
- KwdFr :
- ADN topoisomérases de type II (), ADN topoisomérases de type II (physiologie), Aclarubicine (pharmacologie), Cellules cancéreuses en culture, Diterpènes (pharmacologie), Humains, Razoxane (pharmacologie), Relation dose-effet des médicaments, Technique de Western, Tumeurs du poumon (traitement médicamenteux), Étoposide (pharmacologie).
- MESH :
- pharmacologie : Aclarubicine, Diterpènes, Razoxane, Étoposide.
- physiologie : ADN topoisomérases de type II.
- traitement médicamenteux : Tumeurs du poumon.
- ADN topoisomérases de type II, Cellules cancéreuses en culture, Humains, Relation dose-effet des médicaments, Technique de Western.
English descriptors
- KwdEn :
- Aclarubicin (pharmacology), Blotting, Western, DNA Topoisomerases, Type II (drug effects), DNA Topoisomerases, Type II (physiology), Diterpenes (pharmacology), Dose-Response Relationship, Drug, Etoposide (pharmacology), Humans, Lung Neoplasms (drug therapy), Razoxane (pharmacology), Tumor Cells, Cultured.
- MESH :
- chemical , drug effects : DNA Topoisomerases, Type II.
- chemical , pharmacology : Aclarubicin, Diterpenes, Etoposide, Razoxane.
- chemical , physiology : DNA Topoisomerases, Type II.
- drug therapy : Lung Neoplasms.
- Blotting, Western, Dose-Response Relationship, Drug, Humans, Tumor Cells, Cultured.
Abstract
The complex catalytic cycle of topoisomerase II is the target of important antitumor agents. Topoisomerase II poisons, such as etoposide and daunorubicin, inhibit the resealing of DNA breaks created by the enzyme. This enzyme-coupled cell kill is susceptible to pharmacological regulation by drugs interfering with other steps in the enzyme's catalytic cycle (i.e. so-called catalytic inhibitors). From in vitro studies, is appears that there are 2 distinct sites in the cycle at which a complete antagonism of the toxicity of topoisomerase II poisons can be obtained. The first is the inhibition of the enzyme's binding to its DNA substrate as seen with intercalating drugs such as chloroquine and aclarubicin; a second, more specific, interaction is elicited by bisdioxopiperazines, which are thought to lock the homodimeric topoisomerase II in the form of a closed bracelet surrounding the DNA at the postreligation step. To investigate these in vitro findings in the more complex whole cell system, we studied enzyme-DNA binding in Western blots of 0.35 M NaCL nuclear extracts from human small cell lung cancer OC-NYH cells incubated with the bisdioxopiperazine ICRF-187 and aclarubicin. With ICRF-187, we found a reversible ATP dependent decrease in the extractable levels of both the alpha and the beta isoforms of topoisomerase II. In contrast to ICRF-187, aclarubicin increased the amount of extractable enzyme from cells. Further, when using the terpenoid clerocidin, which differs from conventional topoisomerase II poisons by forming a salt-and heat-stable inhibition of DNA resealing, no antagonism was found by ICRF-187 on formation of DNA strand breaks and cytotoxicity. However, aclarubicin, which interferes early in the topoisomerase II catalytic cycle, was able to antagonize DNA breaks and cytotoxicity caused by clerocidin. The results indicate 4 different steps in the topoisomerase II cycle that can be uncoupled in the cell by different drug types: etoposide and clerocidin cause reversible and irreversible inhibition of DNA resealing, respectively, and DNA intercalating agents, such as aclarubicin, inhibit binding of topoisomerase II enzyme to its DNA substrate. Finally, bisdioxopiperazines as ICRF-187 partake in an energy dependent inappropriate binding of topoisomerase II to DNA after the resealing step. This knowledge may enable the design of rational combinations of topoisomerase II poisons and catalytic inhibitors to enhance the efficacy of anticancer therapy.
DOI: 10.1016/0006-2952(95)02241-4
PubMed: 8651936
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<author><name sortKey="Jensen, P B" sort="Jensen, P B" uniqKey="Jensen P" first="P B" last="Jensen">P B Jensen</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and catalytic inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle.</title>
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<term>DNA Topoisomerases, Type II (physiology)</term>
<term>Diterpenes (pharmacology)</term>
<term>Dose-Response Relationship, Drug</term>
<term>Etoposide (pharmacology)</term>
<term>Humans</term>
<term>Lung Neoplasms (drug therapy)</term>
<term>Razoxane (pharmacology)</term>
<term>Tumor Cells, Cultured</term>
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<keywords scheme="KwdFr" xml:lang="fr"><term>ADN topoisomérases de type II ()</term>
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<term>Aclarubicine (pharmacologie)</term>
<term>Cellules cancéreuses en culture</term>
<term>Diterpènes (pharmacologie)</term>
<term>Humains</term>
<term>Razoxane (pharmacologie)</term>
<term>Relation dose-effet des médicaments</term>
<term>Technique de Western</term>
<term>Tumeurs du poumon (traitement médicamenteux)</term>
<term>Étoposide (pharmacologie)</term>
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<keywords scheme="MESH" type="chemical" qualifier="drug effects" xml:lang="en"><term>DNA Topoisomerases, Type II</term>
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<term>Diterpenes</term>
<term>Etoposide</term>
<term>Razoxane</term>
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<term>Diterpènes</term>
<term>Razoxane</term>
<term>Étoposide</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>ADN topoisomérases de type II</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Tumeurs du poumon</term>
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<keywords scheme="MESH" xml:lang="en"><term>Blotting, Western</term>
<term>Dose-Response Relationship, Drug</term>
<term>Humans</term>
<term>Tumor Cells, Cultured</term>
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<keywords scheme="MESH" xml:lang="fr"><term>ADN topoisomérases de type II</term>
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<front><div type="abstract" xml:lang="en">The complex catalytic cycle of topoisomerase II is the target of important antitumor agents. Topoisomerase II poisons, such as etoposide and daunorubicin, inhibit the resealing of DNA breaks created by the enzyme. This enzyme-coupled cell kill is susceptible to pharmacological regulation by drugs interfering with other steps in the enzyme's catalytic cycle (i.e. so-called catalytic inhibitors). From in vitro studies, is appears that there are 2 distinct sites in the cycle at which a complete antagonism of the toxicity of topoisomerase II poisons can be obtained. The first is the inhibition of the enzyme's binding to its DNA substrate as seen with intercalating drugs such as chloroquine and aclarubicin; a second, more specific, interaction is elicited by bisdioxopiperazines, which are thought to lock the homodimeric topoisomerase II in the form of a closed bracelet surrounding the DNA at the postreligation step. To investigate these in vitro findings in the more complex whole cell system, we studied enzyme-DNA binding in Western blots of 0.35 M NaCL nuclear extracts from human small cell lung cancer OC-NYH cells incubated with the bisdioxopiperazine ICRF-187 and aclarubicin. With ICRF-187, we found a reversible ATP dependent decrease in the extractable levels of both the alpha and the beta isoforms of topoisomerase II. In contrast to ICRF-187, aclarubicin increased the amount of extractable enzyme from cells. Further, when using the terpenoid clerocidin, which differs from conventional topoisomerase II poisons by forming a salt-and heat-stable inhibition of DNA resealing, no antagonism was found by ICRF-187 on formation of DNA strand breaks and cytotoxicity. However, aclarubicin, which interferes early in the topoisomerase II catalytic cycle, was able to antagonize DNA breaks and cytotoxicity caused by clerocidin. The results indicate 4 different steps in the topoisomerase II cycle that can be uncoupled in the cell by different drug types: etoposide and clerocidin cause reversible and irreversible inhibition of DNA resealing, respectively, and DNA intercalating agents, such as aclarubicin, inhibit binding of topoisomerase II enzyme to its DNA substrate. Finally, bisdioxopiperazines as ICRF-187 partake in an energy dependent inappropriate binding of topoisomerase II to DNA after the resealing step. This knowledge may enable the design of rational combinations of topoisomerase II poisons and catalytic inhibitors to enhance the efficacy of anticancer therapy.</div>
</front>
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<ArticleTitle>Mapping of DNA topoisomerase II poisons (etoposide, clerocidin) and catalytic inhibitors (aclarubicin, ICRF-187) to four distinct steps in the topoisomerase II catalytic cycle.</ArticleTitle>
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<Abstract><AbstractText>The complex catalytic cycle of topoisomerase II is the target of important antitumor agents. Topoisomerase II poisons, such as etoposide and daunorubicin, inhibit the resealing of DNA breaks created by the enzyme. This enzyme-coupled cell kill is susceptible to pharmacological regulation by drugs interfering with other steps in the enzyme's catalytic cycle (i.e. so-called catalytic inhibitors). From in vitro studies, is appears that there are 2 distinct sites in the cycle at which a complete antagonism of the toxicity of topoisomerase II poisons can be obtained. The first is the inhibition of the enzyme's binding to its DNA substrate as seen with intercalating drugs such as chloroquine and aclarubicin; a second, more specific, interaction is elicited by bisdioxopiperazines, which are thought to lock the homodimeric topoisomerase II in the form of a closed bracelet surrounding the DNA at the postreligation step. To investigate these in vitro findings in the more complex whole cell system, we studied enzyme-DNA binding in Western blots of 0.35 M NaCL nuclear extracts from human small cell lung cancer OC-NYH cells incubated with the bisdioxopiperazine ICRF-187 and aclarubicin. With ICRF-187, we found a reversible ATP dependent decrease in the extractable levels of both the alpha and the beta isoforms of topoisomerase II. In contrast to ICRF-187, aclarubicin increased the amount of extractable enzyme from cells. Further, when using the terpenoid clerocidin, which differs from conventional topoisomerase II poisons by forming a salt-and heat-stable inhibition of DNA resealing, no antagonism was found by ICRF-187 on formation of DNA strand breaks and cytotoxicity. However, aclarubicin, which interferes early in the topoisomerase II catalytic cycle, was able to antagonize DNA breaks and cytotoxicity caused by clerocidin. The results indicate 4 different steps in the topoisomerase II cycle that can be uncoupled in the cell by different drug types: etoposide and clerocidin cause reversible and irreversible inhibition of DNA resealing, respectively, and DNA intercalating agents, such as aclarubicin, inhibit binding of topoisomerase II enzyme to its DNA substrate. Finally, bisdioxopiperazines as ICRF-187 partake in an energy dependent inappropriate binding of topoisomerase II to DNA after the resealing step. This knowledge may enable the design of rational combinations of topoisomerase II poisons and catalytic inhibitors to enhance the efficacy of anticancer therapy.</AbstractText>
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