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DNA Damage and Cellular Stress Responses

A Novel Role of DNA Polymerase in Modulating Cellular Sensitivity to Chemotherapeutic Agents

¹ Cancer Research Institute and ² Department of Cell Biology and Neuroscience, University of South Alabama, Mobile, Alabama; ³ Auerback Melanoma Laboratory, University of California at San Francisco Cancer Center, University of California, San Francisco, California; and ⁴ Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan

Requests for reprints: Kai-ming Chou, Department of Cell Biology and Neuroscience, University of South Alabama, 307 North University Boulevard, MSB 2350, Mobile, AL 36688. Phone: 251-460-6604; Fax: 251-460-6771. E-mail: kchou{at}usouthal.edu

Genetic defects in polymerase (pol ; hRad30a gene) result in xeroderma pigmentosum variant syndrome (XP-V), and XP-V patients are sensitive to sunlight and highly prone to cancer development. Here, we show that pol plays a significant role in modulating cellular sensitivity to DNA-targeting anticancer agents. When compared with normal human fibroblast cells, pol –deficient cells derived from XP-V patients were 3-fold more sensitive to ß-D-arabinofuranosylcytosine, gemcitabine, or cis-diamminedichloroplatinum (cisplatin) single-agent treatments and at least 10-fold more sensitive to the gemcitabine/cisplatin combination treatment, a commonly used clinical regimen for treating a wide spectrum of cancers. Cellular and biochemical analyses strongly suggested that the higher sensitivity of XP-V cells to these agents was due to the inability of pol –deficient cells to help resume the DNA replication process paused by the gemcitabine/cisplatin-introduced DNA lesions. These results indicated that pol can play an important role in determining the cellular sensitivity to therapeutic agents. The findings not only illuminate pol as a potential pharmacologic target for developing new anticancer agents but also provide new directions for improving future chemotherapy regimen design considering the use of nucleoside analogues and cisplatin derivatives. (Mol Cancer Res 2006;4(4):257–65)

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