QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: mol.105.021527v1 69/5/1607    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lam, W. Articles by Cheng, Y.-C. Search for Related Content PubMed PubMed Citation Articles by Lam, W. Articles by Cheng, Y.-C.

Apurinic/Apyrimidinic Endonuclease-1 Protein Level Is Associated with the Cytotoxicity of L-Configuration Deoxycytidine Analogs (Troxacitabine and -L-2',3'-Dideoxy-2',3'-didehydro-5-fluorocytidine) but Not D-Configuration Deoxycytidine Analogs (Gemcitabine and -D-Arabinofuranosylcytosine)

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut

-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 -L-2',3'-dideoxy-2',3'-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 -D-2',2'-difluorodeoxycytidine (dFdC; gemcitabine) and -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.

Address correspondence to: Dr. Yung-chi Cheng, Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520. E-mail: cheng.lab{at}yale.edu

This article has been cited by other articles:

				S. Yang, B. J. Misner, R. J. Chiu, and F. L. Meyskens Jr Redox effector factor-1, combined with reactive oxygen species, plays an important role in the transformation of JB6 cells Carcinogenesis, November 1, 2007; 28(11): 2382 - 2390. [Abstract] [Full Text] [PDF]

				W. Lam, C.-H. Leung, S. Bussom, and Y.-C. Cheng The Impact of Hypoxic Treatment on the Expression of Phosphoglycerate Kinase and the Cytotoxicity of Troxacitabine and Gemcitabine Mol. Pharmacol., September 1, 2007; 72(3): 536 - 544. [Abstract] [Full Text] [PDF]

				M. A. Rodrigues, D. A. Gomes, M. F. Leite, W. Grant, L. Zhang, W. Lam, Y.-C. Cheng, A. M. Bennett, and M. H. Nathanson Nucleoplasmic Calcium Is Required for Cell Proliferation J. Biol. Chem., June 8, 2007; 282(23): 17061 - 17068. [Abstract] [Full Text] [PDF]

				D. R. McNeill and D. M. Wilson III A Dominant-Negative Form of the Major Human Abasic Endonuclease Enhances Cellular Sensitivity to Laboratory and Clinical DNA-Damaging Agents Mol. Cancer Res., January 1, 2007; 5(1): 61 - 70. [Abstract] [Full Text] [PDF]

				C.-H. Leung, S. P. Grill, W. Lam, W. Gao, H.-D. Sun, and Y.-C. Cheng Eriocalyxin B Inhibits Nuclear Factor-{kappa}B Activation by Interfering with the Binding of Both p65 and p50 to the Response Element in a Noncompetitive Manner Mol. Pharmacol., December 1, 2006; 70(6): 1946 - 1955. [Abstract] [Full Text] [PDF]