| Co-Investigator(Kenkyū-buntansha) |
YOKOYAMA Kazunari 独立行政法人理化学研究所, BioResourse Center, RIKEN Institute, Head of Gene Engineering Division (80182707)
HAMADA Hirofumi Sapporo Medical University, Department of Molecular Medicine, Professor (00189614)
轟 健 筑波大学, 大学院人間総合科学研究科, 助教授 (70114105)
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| Budget Amount *help |
¥9,200,000 (Direct Cost: ¥9,200,000)
Fiscal Year 2006: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2005: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2004: ¥3,400,000 (Direct Cost: ¥3,400,000)
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| Research Abstract |
Cancers of biliary system represent highly malignant diseases of dismal prognosis. We have previously introduced an E1A, E1B-double restricted oncolytic adenovirus, AxdAdB3, which showed excellent infectivity and oncolytic efficacy in half of the biliary cancer lines with an enhanced safety to normal cells. The purpose of this study was to evaluate whether RGD-fiber modification of AxdAdB3 (AxdAdB3-F/RGD), which enables integrin-dependent infection, can to improve the infectivity and efficacy of AxdAdB3 for biliary cancers. Expressions of adenoviral receptors, coxsackievirus adenovirus receptor (CAR) and integrins (avb3, avb5), were compared with the level of infectivity of LacZ-expressing replication-defective adenoviruses with wild type fibers or RGD-modified fibers in a panel of biliary cancer cell lines in vitro. Viral replication and cytotoxicity of AxdAdB3-F/RGD, a novel E1A, E1B double restricted adenovirus with RGD-modified fibers, in various biliary cancer cells and in normal
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cells, were compared with those of its parent virus, AxdAdB-3, in vitro. Antitumor effects in vivo of these oncolytic viruses were compared in a xenograft tumor model. Expression of CAR significantly correlated with the Ad infectivity, while integrin αvβ5 was abundantly expressed in all biliary cancer cells. While AxdAdB3 effectively replicated and lysed only the biliary cancer cells with a preserved expression of CAR, AxdAdB3-F/RGD exhibited efficient replication and potent oncolysis in both CAR-positive and CAR-negative biliary cancer cells. AxdAdB3-F/RGD showed attenuated replication and little cytopathy in human normal cells (ie ; hepatocytes, WI-38 cells) as well as AxdAdB3. Furthermore, in nude mice with subcutaneous xenografts of CAR-deficient human biliary cancer, i.t. AxdAdB3-F/RGD therapy caused a marked inhibition of tumor growth. In conclusion, the RGD fiber modification strategy exhibited enhanced infectivity, replication, and oncolytic efficacy of the E1A, E1B-double mutated adenovirus for CAR-deficient biliary cancers. In addition, it preserved the merit of excellent safety of the double-restricted virus for normal cells. These results suggest a potential use of this agent for the treatment of biliary cancers. Less
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