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Received for publication December 6, 2005.
Revised February 7, 2006.
Accepted for publication February 13, 2006.
Beta-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. Here, we study whether APE-1 protein may play a role in the cytotoxicity of L-OddC. We established RKO (human colorectal carcinoma) cell lines that can be induced by doxycycline to over-express 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 shRNA to 10% of the original level. Clonogenic results indicated that the induction of wt or C65A, but not E96A or E96Q, made cells about 2-fold resistant to L-OddC and L-Fd4C while the down regulation of APE-1 sensitized cells about 2-fold to L-OddC and L-Fd4C. The alteration of APE-1 in cells did not change the sensitivity of these cells to dFdC and 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 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.
Key words:
Regulation of gene expression, DNA damage and repair, Overexpression, RNA/siRNA, Nucleoside/Nucleotide derivatives
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