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A Novel Antiangiogenic Effect for Telomerase-Specific Virotherapy through Host Immune System¹

Yoshihiro Ikeda^*, Toru Kojima^*, Shinji Kuroda^*, Yoshikatsu Endo^*, Ryo Sakai^*, Masayoshi Hioki^*, Hiroyuki Kishimoto^*, Futoshi Uno^*, Shunsuke Kagawa^*,, Yuichi Watanabe, Yuuri Hashimoto, Yasuo Urata, Noriaki Tanaka^* and Toshiyoshi Fujiwara^2,*,

^* Division of Surgical Oncology, Department of Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Center for Gene and Cell Therapy, Okayama University Hospital, Okayama, and Oncolys BioPharma, Tokyo, Japan

Soluble factors in the tumor microenvironment may influence the process of angiogenesis; a process essential for the growth and progression of malignant tumors. In this study, we describe a novel antiangiogenic effect of conditional replication-selective adenovirus through the stimulation of host immune reaction. An attenuated adenovirus (OBP-301, Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of E1 genes, could replicate in and cause selective lysis of cancer cells. Mixed lymphocyte-tumor cell culture demonstrated that OBP-301-infected cancer cells stimulated PBMC to produce IFN- into the supernatants. When the supernatants were subjected to the assay of in vitro angiogenesis, the tube formation of HUVECs was inhibited more efficiently than recombinant IFN-. Moreover, in vivo angiogenic assay using a membrane-diffusion chamber system s.c. transplanted in nu/nu mice showed that tumor cell-induced neovascularization was markedly reduced when the chambers contained the mixed lymphocyte-tumor cell culture supernatants. The growth of s.c. murine colon tumors in syngenic mice was significantly inhibited due to the reduced vascularity by intratumoral injection of OBP-301. The antitumor as well as antiangiogenic effects, however, were less apparent in SCID mice due to the lack of host immune responses. Our data suggest that OBP-301 seems to have antiangiogenic properties through the stimulation of host immune cells to produce endogenous antiangiogenic factors such as IFN-.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants-in-Aid from the Ministry of Education, Science, and Culture, Japan (to T.F.) and grants from the Ministry of Health and Welfare, Japan (to T.F.).

² Address correspondence and reprint requests to Dr. Toshiyoshi Fujiwara, Center for Gene and Cell Therapy, Okayama University Hospital, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. E-mail address: toshi_f{at}md.okayama-u.ac.jp

³ Abbreviations used in this paper: VEGF, vascular endothelial growth factor; MLTC, mixed lymphocyte-tumor cell culture; MOI, multiplicity of infection.