Int J Biochem Mol Biol 2011;2(4):340-346

Original Article
DNA lesion bypass polymerases and 4’-thio-β-Darabinofuranosylcytosine (T-araC)

Yih-wen Chen, Kai-ming Chou

Department of Pharmacology and Toxicology, Indiana, University, Indianapolis, 635 Barnhill Dr, MS 552, Indianapolis, IN 46202

Received October 22, 2011; accepted November 22, 2011; Epub November 25, 2011; Published December 15, 2011

Abstract: The 4’-thio-β-D-arabinofuranosylcytosine (T-araC) is a newly developed nucleoside analog that has shown promising activity against
a broad spectrum of human solid tumors in both cellular and xenograft mice models. TaraC shares similar structure with another anticancer
deoxycytidine analog, β-D-arabinofuranosylcytosine (araC, cytarabine), which has been used in clinics for the treatment of acute myelogenous
leukemia but has a very limited efficacy against solid tumors. T-araC exerts its anticancer activity mainly by inhibiting replicative DNA
polymerases from further extension after its incorporation into DNA. Studies have shown DNA lesion bypass polymerases can reduce the
activity of these agents by handling DNA lesions introduced by therapeutic agents, such as cisplatin and araC. In this study, the potential
relationships between the lesion bypass Y-family DNA polymerases η, ι and κ (pol η, pol ι, and pol κ) and T-araC were examined. Biochemical
studies indicated that the triphosphate metabolite of T-araC is a less preferred substrate for the Y-family polymerases. In addition, cell viability
study indicated that pol η deficient human fibroblast cells were more sensitive to T-araC when compared with the normal human fibroblast
cells. Together, these results suggest that bypass polymerases reduced cell sensitivity to T-araC through helping cells to overcome the DNA
damages introduced by T-araC. (IJBMB1110004)

Keywords: Bypass polymerases, nucleoside analogs, araC

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Address all correspondence to:
Dr. Kai-ming Chou
Department of Pharmacology
and Toxicology, Indiana, University, Indianapolis,
635 Barnhill Dr, MS 552, Indianapolis, IN 46202
Tel: 317-278-8509
E-mail: chouk@iupui.edu
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