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)
| Title | 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) |
|---|---|
| Authors | Lam, W Park, SY Leung, CH Cheng, YC1 |
| Issue Date | 2006 |
| Publisher | American 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?] DOI: http://dx.doi.org/10.1124/mol.105.021527 |
| Abstract | β-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. |
| ISSN | 0026-895X 2011 Impact Factor: 4.883 2011 SCImago Journal Rankings: 0.514 |
| DOI | http://dx.doi.org/10.1124/mol.105.021527 |
| References | References in Scopus |
| dc.contributor.author | Lam, W |
|---|---|
| dc.contributor.author | Park, SY |
| dc.contributor.author | Leung, CH |
| dc.contributor.author | Cheng, YC |
| dc.date.accessioned | 2012-10-08T03:14:07Z |
| dc.date.available | 2012-10-08T03:14:07Z |
| dc.date.issued | 2006 |
| dc.description.abstract | β-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.nature | Link_to_subscribed_fulltext |
| dc.identifier.citation | Molecular Pharmacology, 2006, v. 69 n. 5, p. 1607-1614 [How to Cite?] DOI: http://dx.doi.org/10.1124/mol.105.021527 |
| dc.identifier.doi | http://dx.doi.org/10.1124/mol.105.021527 |
| dc.identifier.epage | 1614 |
| dc.identifier.issn | 0026-895X 2011 Impact Factor: 4.883 2011 SCImago Journal Rankings: 0.514 |
| dc.identifier.issue | 5 |
| dc.identifier.pmid | 16481390 |
| dc.identifier.scopus | eid_2-s2.0-33645820026 |
| dc.identifier.spage | 1607 |
| dc.identifier.uri | http://hdl.handle.net/10722/168012 |
| dc.identifier.volume | 69 |
| dc.language | eng |
| dc.publisher | American Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.org |
| dc.publisher.place | United States |
| dc.relation.ispartof | Molecular Pharmacology |
| dc.relation.references | References in Scopus |
| dc.subject.mesh | Cell Line, Tumor |
| dc.subject.mesh | Cell Survival - Drug Effects |
| dc.subject.mesh | Colorectal Neoplasms |
| dc.subject.mesh | Cytosine - Analogs & Derivatives - Pharmacokinetics - Pharmacology |
| dc.subject.mesh | Dna-(Apurinic Or Apyrimidinic Site) Lyase - Genetics |
| dc.subject.mesh | Deoxycytidine - Analogs & Derivatives - Pharmacokinetics - Pharmacology |
| dc.subject.mesh | Dioxolanes - Pharmacokinetics - Pharmacology |
| dc.subject.mesh | Gene Expression Regulation, Enzymologic - Drug Effects |
| dc.subject.mesh | Gene Expression Regulation, Neoplastic - Drug Effects |
| dc.subject.mesh | Humans |
| dc.subject.mesh | Rna, Small Interfering - Genetics |
| dc.subject.mesh | Transfection |
| dc.title | 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) |
| dc.type | Article |
Author Affiliations
- Yale University School of Medicine