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Title Alternative
Preclinical evaluation of telomerase-specific oncolytic virotherapy for human bone and soft tissue sarcomas
Author
Sasaki, Tsuyoshi
Hasei, Jo
Kunisada, Toshiyuki
Yoshida, Aki
Hashimoto, Yuuri
Yano, Shuya
Yoshida, Ryosuke
Morimoto, Yuki
Urata, Yasuo
Abstract
骨・軟部肉腫は, 一部に治療抵抗性で予後の悪い症例が存在するため, 新たな治療法の確立が重要な課題である. 我々は, 5型アデノウイルスを基本骨格として, テロメラーゼ活性に依存して増殖する腫瘍融解ウイルス(OBP-301)や, coxsackie and adenovirus receptor(CAR)陰性の腫瘍細胞に感染するファイバー改変型ウイルス(OBP-405)を用い, 骨・軟部肉腫細胞に対する抗腫瘍効果を検討した.   14種類の骨・軟部肉腫細胞株に対してOBP-301の細胞障害活性を検討し, 12種類の細胞株でOBP-301に感受性を認めた. また, OBP-301の細胞障害活性はCARの発現と相関していた. さらに, テロメラーゼ活性の低い細胞に対しても, 5型アデノウイルスの複製に必須のE1Aによりテロメラーゼ活性の増強効果がおこり, 強い抗腫瘍活性を示すことを明らかにした. 次に, 骨肉腫脛骨同所性移植動物モデルを作成しOBP-301を投与したところ, OBP-301投与群では対象群と比べて有意に腫瘍増殖を抑制した. 最後に, OBP-301に感受性を認めなかったCAR陰性細胞株に対してOBP-405を用いて検討し, OBP-405が有効に作用することを確認した.   OBP-301やOBP-405を用いたウイルス療法は, 骨・軟部肉腫に対する新たな治療法となる可能性がある. 
Keywords
アデノウイルス
肉腫
ALT
ヒトテロメラーゼ逆転写酵素
Note
平成23年度岡山医学会賞(山田賞)受賞論文 (The 2011 Okayama Medical Association Award)
Published Date
2012-08-01
Publication Title
岡山医学会雑誌
Publication Title Alternative
Journal of Okayama Medical Association
Volume
volume124
Issue
issue2
Publisher
岡山医学会
Publisher Alternative
Okayama Medical Association
Start Page
105
End Page
110
ISSN
0030-1558
NCID
AN00032489
Content Type
Journal Article
Related Url
http://www.okayama-u.ac.jp/user/oma/
References
1) Hameed M, Dorfman H : Primary malignant bone tumors--recent developments. Semin Diagn Pathol (2011) 28, 86-101.
2) Mendenhall WM, Indelicato DJ, Scarborough MT, Zlotecki RA, Gibbs CP, Mendenhall NP, Mendenhall CM, Enneking WF : The management of adult soft tissue sarcomas. Am J Clin Oncol (2009) 32, 436-442.
3) Kawashima T, Kagawa S, Kobayashi N, Shirakiya Y, Umeoka T, Teraishi F, Taki M, Kyo S, Tanaka N, Fujiwara T : Telomerase-specific replication-selective virotherapy for human cancer. Clin Cancer Res (2004) 10, 285-292.
4) Taki M, Kagawa S, Nishizaki M, Mizuguchi H, Hayakawa T, Kyo S, Nagai K, Urata Y, Tanaka N, Fujiwara T : Enhanced oncolysis by a tropism-modified telomerase-specific replication-selective adenoviral agent OBP-405 ('Telomelysin-RGD'). Oncogene (2005) 24, 3130-3140.
5) Nemunaitis J, Tong AW, Nemunaitis M, Senzer N, Phadke AP, Bedell C, Adams N, Zhang YA, Maples PB, Chen S, Pappen B, Burke J, et al. : A phase I study of telomerase-specific replication competent oncolytic adenovirus (telomelysin) for various solid tumors. Mol Ther (2009) 18, 429-434.
6) Reddel RR : Alternative lengthening of telomeres, telomerase, and cancer. Cancer Lett (2003) 194, 155-162.
7) Sasaki T, Tazawa H, Hasei J, Kunisada T, Yoshida A, Hashimoto Y, Yano S, Yoshida R, Uno F, Kagawa S, Morimoto Y, Urata Y, et al. : Preclinical evaluation of telomerase-specific oncolytic virotherapy for human bone and soft tissue sarcomas. Clin Cancer Res (2011) 17, 1828-1838.
8) Bryan TM, Englezou A, Dalla-Pozza L, Dunham MA, Reddel RR : Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat Med (1997) 3, 1271-1274.
9) Kuroda S, Fujiwara T, Shirakawa Y, Yamasaki Y, Yano S, Uno F, Tazawa H, Hashimoto Y, Watanabe Y, Noma K, Urata Y, Kagawa S : Telomerase-dependent oncolytic adenovirus sensitizes human cancer cells to ionizing radiation via inhibition of DNA repair machinery. Cancer Res (2010) 70, 9339-9348.
10) Takakura M, Nakamura M, Kyo S, Hashimoto M, Mori N, Ikoma T, Mizumoto Y, Fujiwara T, Urata Y, Inoue M : Intraperitoneal administration of telomerase-specific oncolytic adenovirus sensitizes ovarian cancer cells to cisplatin and affects survival in a xenograft model with peritoneal dissemination. Cancer Gene Ther (2010) 17, 11-19.
11) Liu D, Kojima T, Ouchi M, Kuroda S, Watanabe Y, Hashimoto Y, Onimatsu H, Urata Y, Fujiwara T : Preclinical evaluation of synergistic effect of telomerase-specific oncolytic virotherapy and gemcitabine for human lung cancer. Mol Cancer Ther (2009) 8, 980-987.
12) Anders M, Vieth M, Rocken C, Ebert M, Pross M, Gretschel S, Schlag PM, Wiedenmann B, Kemmner W, Hocker M : Loss of the coxsackie and adenovirus receptor contributes to gastric cancer progression. Br J Cancer (2009) 100, 352-359.
13) Kuster K, Koschel A, Rohwer N, Fischer A, Wiedenmann B, Anders M : Downregulation of the coxsackie and adenovirus receptor in cancer cells by hypoxia depends on HIF-1alpha. Cancer Gene Ther (2010) 17, 141-146.
14) Watanabe T, Hioki M, Fujiwara T, Nishizaki M, Kagawa S, Taki M, Kishimoto H, Endo Y, Urata Y, Tanaka N : Histone deacetylase inhibitor FR901228 enhances the antitumor effect of telomerase-specific replication-selective adenoviral agent OBP-301 in human lung cancer cells. Exp Cell Res (2006) 312, 256-265.
15) Sasaki T, Tazawa H, Hasei J, Osaki S, Kunisada T, Yoshida A, Hashimoto Y, Yano S, Yoshida R, Kagawa S, Uno F, Urata Y, et al. : A simple detection system for adenovirus receptor expression using a telomerase-specific replication-competent adenovirus. Gene Ther (in press). 
language
日本語
Copyright Holders
Copyright (c) 2012 岡山医学会
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joma