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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)

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)
Authors
Issue Date2006
PublisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.org
Citation
Molecular Pharmacology, 2006, v. 69 n. 5, p. 1607-1614 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/168012
ISSN
2014 Impact Factor: 4.128
2014 SCImago Journal Rankings: 1.904
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLam, Wen_US
dc.contributor.authorPark, SYen_US
dc.contributor.authorLeung, CHen_US
dc.contributor.authorCheng, YCen_US
dc.date.accessioned2012-10-08T03:14:07Z-
dc.date.available2012-10-08T03:14:07Z-
dc.date.issued2006en_US
dc.identifier.citationMolecular Pharmacology, 2006, v. 69 n. 5, p. 1607-1614en_US
dc.identifier.issn0026-895Xen_US
dc.identifier.urihttp://hdl.handle.net/10722/168012-
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.en_US
dc.languageengen_US
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.orgen_US
dc.relation.ispartofMolecular Pharmacologyen_US
dc.subject.meshCell Line, Tumoren_US
dc.subject.meshCell Survival - Drug Effectsen_US
dc.subject.meshColorectal Neoplasmsen_US
dc.subject.meshCytosine - Analogs & Derivatives - Pharmacokinetics - Pharmacologyen_US
dc.subject.meshDna-(Apurinic Or Apyrimidinic Site) Lyase - Geneticsen_US
dc.subject.meshDeoxycytidine - Analogs & Derivatives - Pharmacokinetics - Pharmacologyen_US
dc.subject.meshDioxolanes - Pharmacokinetics - Pharmacologyen_US
dc.subject.meshGene Expression Regulation, Enzymologic - Drug Effectsen_US
dc.subject.meshGene Expression Regulation, Neoplastic - Drug Effectsen_US
dc.subject.meshHumansen_US
dc.subject.meshRna, Small Interfering - Geneticsen_US
dc.subject.meshTransfectionen_US
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)en_US
dc.typeArticleen_US
dc.identifier.emailLeung, CH:duncanl@hkucc.hku.hken_US
dc.identifier.authorityLeung, CH=rp00730en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1124/mol.105.021527en_US
dc.identifier.pmid16481390en_US
dc.identifier.scopuseid_2-s2.0-33645820026en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33645820026&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume69en_US
dc.identifier.issue5en_US
dc.identifier.spage1607en_US
dc.identifier.epage1614en_US
dc.identifier.isiWOS:000236874100014-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridLam, W=7203021943en_US
dc.identifier.scopusauthoridPark, SY=13404645500en_US
dc.identifier.scopusauthoridLeung, CH=7402612570en_US
dc.identifier.scopusauthoridCheng, YC=36041844200en_US

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