File Download
  • No File Attached
 
Links for fulltext
(May Require Subscription)
 
Supplementary

Article: Apurinic/apyrimidinic endonuclease-1 protein level is associated with the cytotoxicity of L-configuration deoxycytidine analogs (troxacitabine and β-L-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine) but not D-configuration deoxycytidine analogs (gemcitabine and β-D-arabinofuranosylcytosine)
  • Basic View
  • Metadata View
  • XML View
TitleApurinic/apyrimidinic endonuclease-1 protein level is associated with the cytotoxicity of L-configuration deoxycytidine analogs (troxacitabine and β-L-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine) but not D-configuration deoxycytidine analogs (gemcitabine and β-D-arabinofuranosylcytosine)
 
AuthorsLam, W
Park, SY
Leung, CH
Cheng, YC1
 
Issue Date2006
 
PublisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.org
 
CitationMolecular Pharmacology, 2006, v. 69 n. 5, p. 1607-1614 [How to Cite?]
DOI: http://dx.doi.org/10.1124/mol.105.021527
 
Abstractβ-L-Dioxolane-cytidine (L-OddC, BCH-4556, Troxacitabine), a novel L-configuration deoxycytidine analog, is under phase III clinical trial for cancer treatment. We showed that human apurinic/apyrimidinic endonuclease (APE-1) has exonuclease activity for preferentially removing L-OddC and other L-configuration nucleosides over D-configuration nucleosides from the 3′ terminus of DNA in vitro. In this study, we examined whether APE-1 protein plays a role in the cytotoxicity of L-OddC. We established RKO (human colorectal carcinoma) cell lines that can be induced by doxycycline to overexpress 4- to 5-fold either APE-1 wild type (wt), C65A (redox deficient), E96A (exonuclease deficient), or E96Q (exonuclease deficient) mutants and to down-regulate endogenous APE-1 by short hairpin RNA to 10% of the original level. Clonogenic results indicated that the induction of wt or C65A, but not E96A or E96Q, made cells approximately 2-fold resistant to L-OddC and β-L-2′,3′- dideoxy-2′,3β-didehydro-5-fluorocytidine (L-Fd4C), whereas the down-regulation of APE-1 sensitized cells by approximately 2-fold to L-OddC and L-Fd4C. The alteration of APE-1 in cells did not change the sensitivity of these cells to β-D-2′,2′-difluorodeoxycytidine (dFdC; gemcitabine) and β-D-arabinofuranosylcytosine (AraC), both of which are D-configuration deoxycytidine analogs. The DNA incorporation of L-OddC, but not that of dFdC, was decreased by the induction of wt APE-1 but not E96A mutant and was increased by the down-regulation of APE-1. The rate of retention of L-OddC was inversely correlated to the level of APE-1 in isolated nuclei; however, this was not the case for dFdC. In conclusion, this study supports the hypothesis that APE-1 plays a critical role in the actions of L-configuration but not D-configuration nucleoside analogs. Copyright © 2006 The American Society for Pharmacology and Experimental Therapeutics.
 
ISSN0026-895X
2013 Impact Factor: 4.120
 
DOIhttp://dx.doi.org/10.1124/mol.105.021527
 
ISI Accession Number IDWOS:000236874100014
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorLam, W
 
dc.contributor.authorPark, SY
 
dc.contributor.authorLeung, CH
 
dc.contributor.authorCheng, YC
 
dc.date.accessioned2012-10-08T03:14:07Z
 
dc.date.available2012-10-08T03:14:07Z
 
dc.date.issued2006
 
dc.description.abstractβ-L-Dioxolane-cytidine (L-OddC, BCH-4556, Troxacitabine), a novel L-configuration deoxycytidine analog, is under phase III clinical trial for cancer treatment. We showed that human apurinic/apyrimidinic endonuclease (APE-1) has exonuclease activity for preferentially removing L-OddC and other L-configuration nucleosides over D-configuration nucleosides from the 3′ terminus of DNA in vitro. In this study, we examined whether APE-1 protein plays a role in the cytotoxicity of L-OddC. We established RKO (human colorectal carcinoma) cell lines that can be induced by doxycycline to overexpress 4- to 5-fold either APE-1 wild type (wt), C65A (redox deficient), E96A (exonuclease deficient), or E96Q (exonuclease deficient) mutants and to down-regulate endogenous APE-1 by short hairpin RNA to 10% of the original level. Clonogenic results indicated that the induction of wt or C65A, but not E96A or E96Q, made cells approximately 2-fold resistant to L-OddC and β-L-2′,3′- dideoxy-2′,3β-didehydro-5-fluorocytidine (L-Fd4C), whereas the down-regulation of APE-1 sensitized cells by approximately 2-fold to L-OddC and L-Fd4C. The alteration of APE-1 in cells did not change the sensitivity of these cells to β-D-2′,2′-difluorodeoxycytidine (dFdC; gemcitabine) and β-D-arabinofuranosylcytosine (AraC), both of which are D-configuration deoxycytidine analogs. The DNA incorporation of L-OddC, but not that of dFdC, was decreased by the induction of wt APE-1 but not E96A mutant and was increased by the down-regulation of APE-1. The rate of retention of L-OddC was inversely correlated to the level of APE-1 in isolated nuclei; however, this was not the case for dFdC. In conclusion, this study supports the hypothesis that APE-1 plays a critical role in the actions of L-configuration but not D-configuration nucleoside analogs. Copyright © 2006 The American Society for Pharmacology and Experimental Therapeutics.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationMolecular Pharmacology, 2006, v. 69 n. 5, p. 1607-1614 [How to Cite?]
DOI: http://dx.doi.org/10.1124/mol.105.021527
 
dc.identifier.doihttp://dx.doi.org/10.1124/mol.105.021527
 
dc.identifier.epage1614
 
dc.identifier.isiWOS:000236874100014
 
dc.identifier.issn0026-895X
2013 Impact Factor: 4.120
 
dc.identifier.issue5
 
dc.identifier.pmid16481390
 
dc.identifier.scopuseid_2-s2.0-33645820026
 
dc.identifier.spage1607
 
dc.identifier.urihttp://hdl.handle.net/10722/168012
 
dc.identifier.volume69
 
dc.languageeng
 
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.org
 
dc.publisher.placeUnited States
 
dc.relation.ispartofMolecular Pharmacology
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshCell Line, Tumor
 
dc.subject.meshCell Survival - Drug Effects
 
dc.subject.meshColorectal Neoplasms
 
dc.subject.meshCytosine - Analogs & Derivatives - Pharmacokinetics - Pharmacology
 
dc.subject.meshDna-(Apurinic Or Apyrimidinic Site) Lyase - Genetics
 
dc.subject.meshDeoxycytidine - Analogs & Derivatives - Pharmacokinetics - Pharmacology
 
dc.subject.meshDioxolanes - Pharmacokinetics - Pharmacology
 
dc.subject.meshGene Expression Regulation, Enzymologic - Drug Effects
 
dc.subject.meshGene Expression Regulation, Neoplastic - Drug Effects
 
dc.subject.meshHumans
 
dc.subject.meshRna, Small Interfering - Genetics
 
dc.subject.meshTransfection
 
dc.titleApurinic/apyrimidinic endonuclease-1 protein level is associated with the cytotoxicity of L-configuration deoxycytidine analogs (troxacitabine and β-L-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine) but not D-configuration deoxycytidine analogs (gemcitabine and β-D-arabinofuranosylcytosine)
 
dc.typeArticle
 
<?xml encoding="utf-8" version="1.0"?>
<item><contributor.author>Lam, W</contributor.author>
<contributor.author>Park, SY</contributor.author>
<contributor.author>Leung, CH</contributor.author>
<contributor.author>Cheng, YC</contributor.author>
<date.accessioned>2012-10-08T03:14:07Z</date.accessioned>
<date.available>2012-10-08T03:14:07Z</date.available>
<date.issued>2006</date.issued>
<identifier.citation>Molecular Pharmacology, 2006, v. 69 n. 5, p. 1607-1614</identifier.citation>
<identifier.issn>0026-895X</identifier.issn>
<identifier.uri>http://hdl.handle.net/10722/168012</identifier.uri>
<description.abstract>&#946;-L-Dioxolane-cytidine (L-OddC, BCH-4556, Troxacitabine), a novel L-configuration deoxycytidine analog, is under phase III clinical trial for cancer treatment. We showed that human apurinic/apyrimidinic endonuclease (APE-1) has exonuclease activity for preferentially removing L-OddC and other L-configuration nucleosides over D-configuration nucleosides from the 3&#8242; terminus of DNA in vitro. In this study, we examined whether APE-1 protein plays a role in the cytotoxicity of L-OddC. We established RKO (human colorectal carcinoma) cell lines that can be induced by doxycycline to overexpress 4- to 5-fold either APE-1 wild type (wt), C65A (redox deficient), E96A (exonuclease deficient), or E96Q (exonuclease deficient) mutants and to down-regulate endogenous APE-1 by short hairpin RNA to 10% of the original level. Clonogenic results indicated that the induction of wt or C65A, but not E96A or E96Q, made cells approximately 2-fold resistant to L-OddC and &#946;-L-2&#8242;,3&#8242;- dideoxy-2&#8242;,3&#946;-didehydro-5-fluorocytidine (L-Fd4C), whereas the down-regulation of APE-1 sensitized cells by approximately 2-fold to L-OddC and L-Fd4C. The alteration of APE-1 in cells did not change the sensitivity of these cells to &#946;-D-2&#8242;,2&#8242;-difluorodeoxycytidine (dFdC; gemcitabine) and &#946;-D-arabinofuranosylcytosine (AraC), both of which are D-configuration deoxycytidine analogs. The DNA incorporation of L-OddC, but not that of dFdC, was decreased by the induction of wt APE-1 but not E96A mutant and was increased by the down-regulation of APE-1. The rate of retention of L-OddC was inversely correlated to the level of APE-1 in isolated nuclei; however, this was not the case for dFdC. In conclusion, this study supports the hypothesis that APE-1 plays a critical role in the actions of L-configuration but not D-configuration nucleoside analogs. Copyright &#169; 2006 The American Society for Pharmacology and Experimental Therapeutics.</description.abstract>
<language>eng</language>
<publisher>American Society for Pharmacology and Experimental Therapeutics. The Journal&apos;s web site is located at http://www.molpharm.org</publisher>
<relation.ispartof>Molecular Pharmacology</relation.ispartof>
<subject.mesh>Cell Line, Tumor</subject.mesh>
<subject.mesh>Cell Survival - Drug Effects</subject.mesh>
<subject.mesh>Colorectal Neoplasms</subject.mesh>
<subject.mesh>Cytosine - Analogs &amp; Derivatives - Pharmacokinetics - Pharmacology</subject.mesh>
<subject.mesh>Dna-(Apurinic Or Apyrimidinic Site) Lyase - Genetics</subject.mesh>
<subject.mesh>Deoxycytidine - Analogs &amp; Derivatives - Pharmacokinetics - Pharmacology</subject.mesh>
<subject.mesh>Dioxolanes - Pharmacokinetics - Pharmacology</subject.mesh>
<subject.mesh>Gene Expression Regulation, Enzymologic - Drug Effects</subject.mesh>
<subject.mesh>Gene Expression Regulation, Neoplastic - Drug Effects</subject.mesh>
<subject.mesh>Humans</subject.mesh>
<subject.mesh>Rna, Small Interfering - Genetics</subject.mesh>
<subject.mesh>Transfection</subject.mesh>
<title>Apurinic/apyrimidinic endonuclease-1 protein level is associated with the cytotoxicity of L-configuration deoxycytidine analogs (troxacitabine and &#946;-L-2&#8242;,3&#8242;-dideoxy-2&#8242;,3&#8242;-didehydro-5-fluorocytidine) but not D-configuration deoxycytidine analogs (gemcitabine and &#946;-D-arabinofuranosylcytosine)</title>
<type>Article</type>
<description.nature>link_to_subscribed_fulltext</description.nature>
<identifier.doi>10.1124/mol.105.021527</identifier.doi>
<identifier.pmid>16481390</identifier.pmid>
<identifier.scopus>eid_2-s2.0-33645820026</identifier.scopus>
<relation.references>http://www.scopus.com/mlt/select.url?eid=2-s2.0-33645820026&amp;selection=ref&amp;src=s&amp;origin=recordpage</relation.references>
<identifier.volume>69</identifier.volume>
<identifier.issue>5</identifier.issue>
<identifier.spage>1607</identifier.spage>
<identifier.epage>1614</identifier.epage>
<identifier.isi>WOS:000236874100014</identifier.isi>
<publisher.place>United States</publisher.place>
</item>
Author Affiliations
  1. Yale University School of Medicine