InhibitionofDNARepairMachinery.PDFVIP

Published OnlineFirst November 2, 2010; DOI: 10.1158/0008-5472.CAN-10-2333 Therapeutics, Targets, and Chemical Biology Cancer Research Telomerase-Dependent Oncolytic Adenovirus Sensitizes Human Cancer Cells to Ionizing Radiation via Inhibition of DNA Repair Machinery Shinji Kuroda1, Toshiya Fujiwara1, Yasuhiro Shirakawa1, Yasumoto Yamasaki1, Shuya Yano1, Futoshi Uno1, Hiroshi Tazawa2, Yuuri Hashimoto1, Yuichi Watanabe1,3, Kazuhiro Noma1, Yasuo Urata3, Shunsuke Kagawa1, and Toshiyoshi Fujiwara1,2 Abstract The inability to repair DNA double-strand breaks (DSB) leads to radiosensitization, such that ionizing ra- diation combined with molecular inhibition of cellular DSB processing may greatly affect treatment of human cancer. As a variety of viral products interact with the DNA repair machinery, oncolytic virotherapy may im- prove the therapeutic window of conventional radiotherapy. Here, we describe the mechanistic basis for syn- ergy of irradiation and OBP-301 (Telomelysin), an attenuated type-5 adenovirus with oncolytic potency that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 infection led to E1B55kDa viral protein expression that degraded the complex formed by Mre11, Rad50, and NBS1, which senses DSBs. Subsequently, the phosphorylation of cellular ataxia-telangiectasia mutated protein was inhibited, disrupting the signaling pathway controlling DNA repair. Thus, tumor cells infected with OBP-301 could be rendered sensitive to ionizing radiation. Moreover, by using noninvasive whole-body imaging, we showed that intratumoral injection of OBP-301 followed by regional irradiation induces a substantial anti- tumor effect, resulting from tum