RT Journal Article
SR Electronic
T1 Apurinic/Apyrimidinic Endonuclease-1 Protein Level Is Associated with the Cytotoxicity of <span class="sc">l</span>-Configuration Deoxycytidine Analogs (Troxacitabine and β-<span class="sc">l</span>-2′,3′-Dideoxy-2′,3′-didehydro-5-fluorocytidine) but Not <span class="sc">d</span>-Configuration Deoxycytidine Analogs (Gemcitabine and β-<span class="sc">d</span>-Arabinofuranosylcytosine)
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1607
OP 1614
DO 10.1124/mol.105.021527
VO 69
IS 5
A1 Lam, Wing
A1 Park, Shin-Young
A1 Leung, Chung-Hang
A1 Cheng, Yung-Chi
YR 2006
UL http://molpharm.aspetjournals.org/content/69/5/1607.abstract
AB 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′,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 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.