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E1A, E1B Double-Restricted Adenovirus with RGD-Fiber Modification Exhibits Enhanced Oncolysis for CAR–Deficient Biliary Cancers

Authors' Affiliations: ¹ Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan; ² Division of Gene Engineering, BioResource Center, RIKEN (Institute of Physical and Chemical Research), Tsukuba, Ibaraki, Japan; and ³ Department of Molecular Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan

Requests for reprints: Masato Abei, Division of Gastroenterology, University of Tsukuba Graduate School of Comprehensive Human Sciences, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan. Phone: 81-298-53-3125; Fax: 81-298-53-3218; E-mail: m-abeic{at}md.tsukuba.ac.jp.

Purpose: Cancers of biliary system represent highly malignant diseases of dismal prognosis. We have previously introduced AxdAdB3, an E1A, E1B double-restricted oncolytic adenovirus, which showed excellent oncolytic efficacy for approximately 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 (AxdAdB3-F/RGD), which enables integrin-dependent infection, can improve the infectivity and efficacy of AxdAdB3 for biliary cancers.

Experimental Design: Expressions of adenoviral receptors, coxsackievirus adenovirus receptor (CAR) and integrins (_vß₃ and _vß₅), 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 in vitro of AxdAdB3-F/RGD, a novel E1A, E1B double-restricted replication-selective adenovirus with RGD-modified fibers, were compared with those of its parent virus, AxdAdB3, in various biliary cancer cells and in normal cells. In vivo antitumor effects of these oncolytic viruses were compared in a xenograft tumor model.

Results: Expression of CAR significantly correlated with the adenovirus infectivity, whereas integrin _vß₅ was abundantly expressed in almost all biliary cancer cells. Whereas 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 (i.e., hepatocytes, WI-38 cells) as well as AxdAdB3. Furthermore, in nude mice with s.c. xenografts of CAR-deficient human biliary cancer, i.t. AxdAdB3-F/RGD therapy caused a marked inhibition of tumor growth.

Conclusions: The RGD-fiber modification strategy enhanced the infectivity, replication, and oncolytic effects of the E1A, E1B double-restricted oncolytic 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.