研究者詳細 - 藤原　俊義

MISC - 藤原　俊義

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In vivo imaging of lymph node metastasis with telomerase-specific replication-selective adenovirus

Hiroyuki Kishimoto, Toru Kojima, Yuichi Watanabe, Shunsuke Kagawa, Toshiya Fujiwara, Futoshi Uno, Fuminori Teraishi, Satoru Kyo, Hiroyuki Mizuguchi, Yuuri Hashimoto, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

NATURE MEDICINE 12 ( 10 ) 1213 - 1219 2006年10月

記述言語：英語出版者・発行元：NATURE PUBLISHING GROUP

Currently available methods for detection of tumors in vivo such as computed tomography and magnetic resonance imaging are not specific for tumors. Here we describe a new approach for visualizing tumors whose fluorescence can be detected using telomerase-specific replication-competent adenovirus expressing green fluorescent protein (GFP) (OBP-401). OBP-401 contains the replication cassette, in which the human telomerase reverse transcriptase (hTERT) promoter drives expression of E1 genes, and the GFP gene for monitoring viral replication. When OBP-401 was intratumorally injected into HT29 tumors orthotopically implanted into the rectum in BALB/c nu/nu mice, para-aortic lymph node metastasis could be visualized at laparotomy under a three-chip color cooled charged-coupled device camera. Our results indicate that OBP-401 causes viral spread into the regional lymphatic area and selectively replicates in neoplastic lesions, resulting in GFP expression in metastatic lymph nodes. This technology is adaptable to detect lymph node metastasis in vivo as a preclinical model of surgical navigation.

DOI： 10.1038/nm1404

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Esophageal intramural pseudodiverticulosis with esophageal strictures successfully treated with dilation therapy

Fuminori Teraishi, Toshiyoshi Fujiwara, Atsushi Jikuhara, Shingo Kamitani, Yasuo Morino, Katsuaki Sato, Noriaki Tanaka

ANNALS OF THORACIC SURGERY 82 ( 3 ) 1119 - 1121 2006年9月

記述言語：英語出版者・発行元：ELSEVIER SCIENCE INC

We report a rare case of esophageal intramural pseudodiverticulosis with esophageal strictures. Barium esophagogram demonstrated multiple flask-shaped diverticula out of the esophageal wall with comprehensive luminal stenosis involving the proximal 8 cm and distal 4 cm of the esophagus. Chest computed tomographic scan demonstrated round wall thickening and several intramural gas collections of the proximal esophagus. Endoscopy revealed a fibrotic stricture and multiple small orifices of pseudodiverticula with mild inflammatory changes. Biopsy specimens showed active chronic inflammatory changes of the mucosa with candidiasis. Dysphagia improved dramatically with esophageal dilation. However, the tiny diverticula did not resolve after treatment.

DOI： 10.1016/j.athoracsur.2006.01.062

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1249 慎重な周術期管理を要した重症SLE合併進行食道癌の一例(食道癌治療2,一般演題,第61回日本消化器外科学会定期学術総会)

藤原康宏, 猶本良夫, 岩本高行, 金澤卓, 白川靖博, 山辻知樹, 藤原俊義, 岩垣博巳, 磯崎博司, 田中紀章

日本消化器外科学会雑誌 39 ( 7 ) 1196 - 1196 2006年7月

PD-8-3 消化器癌に対するテロメラーゼ活性を標的とした新規ウイルス療法の開発と臨床応用の可能性(消化器癌と分子生物学-臨床応用に向けて-,パネルディスカッション,第61回日本消化器外科学会定期学術総会)

藤原俊義, 香川俊輔, 宇野太, 寺石文則, 浦田泰生, 田中紀章

日本消化器外科学会雑誌 39 ( 7 ) 975 - 975 2006年7月

1225 胃原発性GISTの臨床病理学的および免疫組織学的検討 : hTERTの発現の検討を中心に(分子生物学2,一般演題,第61回日本消化器外科学会定期学術総会)

寺石文則, 宇野太, 香川俊輔, 藤原俊義, 合地明, 田中紀章

日本消化器外科学会雑誌 39 ( 7 ) 1190 - 1190 2006年7月

0005 放射線治療後に甲状腺低下を認めた食道癌患者の検討(食道良性1,一般演題,第61回日本消化器外科学会定期学術総会)

金澤卓, 猶本良夫, 湯浅壮司, 白川靖博, 山辻知樹, 藤原俊義, 松原長秀, 岩垣博巳, 松岡順治, 田中紀章

日本消化器外科学会雑誌 39 ( 7 ) 1037 - 1037 2006年7月

Enhanced antitumor efficacy of telomerase-selective oncolytic adenoviral agent OBP-401 with docetaxel: Preclinical evaluation of chemovirotherapy

Toshiya Fujiwara, Shunsuke Kagawa, Hiroyuki Kishimoto, Yoshikatsu Endo, Masayoshi Hioki, Yoshihiro Ikeda, Ryo Sakai, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

INTERNATIONAL JOURNAL OF CANCER 119 ( 2 ) 432 - 440 2006年7月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

Oncolytic adenoviruses are being developed as novel anticancer therapeutics and currently undergoing clinical trials. We previously demonstrated that telomerase-specific replication-competent adenovirus (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) promoter regulates viral replication, efficiently killed human tumor cells. We further constructed OBP-401 (Telomelysin-GFP) that expresses the green fluorescent protein (GFP) reporter gene under the control of the cytomegalovirus promoter in the E3 region to monitor viral distribution. Here, we examined the feasibility of a single-agent therapy with OBP-401 as well as of combining OBP-401 with chemotherapeutic agents. Infection of OBP-401 alone or followed by the treatment of a chemotherapeutic drug, docetaxel (Taxotere), resulted in a profound in vitro cytotoxicity and GFP expression in various human cancer cell lines originating from different organs (lung, colon, esophagus, stomach, liver and prostate), although the magnitude of antitumor effect varied among the cell types. Other chemotherapeutic drugs such as vinorelbine (Navelbine) and SN38 (the potent active metabolite of irinotecan) combined with OBP-401 also inhibited the growth of human cancer cells. Quantitative real-time PCR analysis demonstrated that docetaxel did not affect viral replication. For in vivo evaluation, nu/nu mice xenografted with H1299 human lung tumor received intratumoral injection of OBP-401 and intraperitoneal administration of docetaxel. Analysis of growth of implanted tumors showed a significant, therapeutic synergism, although OBP-401 alone and docetaxel alone showed modest inhibition of tumor growth. Thus, OBP-401 in combination with docetaxel efficiently enhances the antitumor efficacy both in vitro and in vivo, and the outcome has important implications for tumor-specific oncolytic chemovirotherapies for human cancers. (c) 2006 Wiley-Liss, Inc.

DOI： 10.1002/ijc.21846

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当科におけるN4食道癌の治療

白川靖博, 猶本良夫, 岩本高行, 小林正彦, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 岩垣博巳, 松岡順治, 羽井佐実, 田中紀章

岡山医学会雑誌 118 ( 1 ) 85 - 85 2006年5月

SLEを合併した進行食道癌の一切除例

岩本高行, 猶本良夫, 小林正彦, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 岩垣博巳, 松岡順治, 田中紀章

岡山医学会雑誌 118 ( 1 ) 85 - 85 2006年5月

Multicenter phase I study of repeated intratumoral delivery of adenoviral p53 in patients with advanced non-small-cell lung cancer

T Fujiwara, N Tanaka, S Kanazawa, S Ohtani, Y Saijo, T Nukiwa, K Yoshimura, T Sato, Y Eto, S Chada, H Nakamura, H Kato

JOURNAL OF CLINICAL ONCOLOGY 24 ( 11 ) 1689 - 1699 2006年4月

記述言語：英語出版者・発行元：AMER SOC CLINICAL ONCOLOGY

Purpose
To determine the feasibility, safety, humoral immune response, and biologic activity of multiple intratumoral injections of Ad5CMV-p53, and to characterize the pharmacokinetics of Ad5CMV-p53 in patients with advanced non-small-cell lung cancer (NSCLC).
Patients and Methods
Fifteen patients with histologically confirmed NSCLC and p53 mutations were enrolled onto this phase I trial. Nine patients received escalating dose levels of Ad5CMV-p53 (1 X 10(9) to 1 X 10(11) plaque-forming units) as monotherapy once every 4 weeks. Six patients were treated on a 28-day schedule with Ad5CMV-p53 in combination with intravenous administration of cisplatin (80 mg/m(2)). Patients were monitored for toxicity, vector distribution, antibody formation, and tumor response.
Results
Fifteen patients received a total of 63 intratumoral injections of Ad5CMV-p53 without dose-limiting toxicity. The most common treatment-related toxicity was a transient fever. Specific p53 transgene expression was detected using reverse-transcriptase polymerase chain reaction in biopsied tumor tissues throughout the period of treatment despite of the presence of neutralizing antiadenovirus antibody. Distribution studies revealed that the vector was detected in the gargle and plasma, but rarely in the urine. Thirteen of 15 patients were assessable for efficacy; one patient had a partial response (squamous cell carcinoma at the Carina), 10 patients had stable disease, with three lasting at least 9 months, and two patients had progressive disease.
Conclusion
Multiple courses of intratumoral Ad5CMV-p53 injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit.

DOI： 10.1200/JCO.2005.03.4116

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追加発言 : テロメラーゼ特異的GFP蛍光発現ウイルス製剤OBP-401を用いた消化器癌微小転移のin vivoイメージング・システムの開発

児島亨, 藤原俊義, 岸本浩行, 橋本悠里, 香川俊輔, 宇野太, 浦田泰生, 田中紀章

日本外科学会雑誌 107 ( 2 ) 176 - 176 2006年3月

K-ras変異型腫瘍に対するプロテアソームインヒビターbortezomibの有用性およびその作用機序に関する検討

寺石文則, Fang Bingliang, Liu Jinsong, 白澤専二, 笹月健彦, 香川俊輔, 藤原俊義, 田中紀章

日本外科学会雑誌 107 ( 2 ) 607 - 607 2006年3月

Three cases of adenocarcinoma arising in extremely long-segment Barrett's esophagus

T Fujiwara, Y Naomoto, T Yamatsuji, Y Shirakawa, H Noguchi, T Fujiwara, N Oohara, M Gunduz, H Nagatsuka, M Nishie, H Uetsuka, S Hamazaki, N Tanaka

DIGESTIVE DISEASES AND SCIENCES 51 ( 3 ) 533 - 538 2006年3月

Histone deacetylase inhibitor FR901228 enhances the antitumor effect of telomerase-specific replication-selective adenoviral agent OBP-301 in human lung cancer cells

T Watanabe, M Hioki, T Fujiwara, M Nishizaki, S Kagawa, M Taki, H Kishimoto, Y Endo, Y Urata, N Tanaka, T Fujiwara

EXPERIMENTAL CELL RESEARCH 312 ( 3 ) 256 - 265 2006年2月

記述言語：英語出版者・発行元：ELSEVIER INC

Replication-competent oncolytic viruses are being developed for human cancer therapy. We previously reported that an attenuated adenovirus OBP-301 (Telomelysin), in which the human telomerase reverse transcriptase promoter element drives expression of EIA and El B genes linked with an internal ribosome entry site, could replicate in and causes selective lysis, of human cancer cells. Infection efficiency in target cancer cells is the most important factor that predicts the antitumor effects of OBP-301. The ob objectives of this study are to examine the effects of the histone deacetylase inhibitor FR901228 on the level of coxsackie and adenovirus receptor (CAR) expression and OBP-301-mediated oncolysis in human non-small cell lung cancer cell lines. Flow cytometric analysis revealed up-regulated CAR expression in A549 and H460 cells following treatment with 1 ng/ml of FR901228. which was associated with increased infection efficiency as confirmed by replication-deficient beta-galactosidase-expressing adenovirus vector. In contrast. neither CAR expression nor infection efficiency was affected by FR901228 in H1299 cells. To visualize and quantify viral replication in the presence of FR901228, we used 01311-401 (Telomelysin-GFP) that expresses the green fluorescent protein (GFP) reporter gene under the control of the cytomegalovirus promoter in the E3 region. Fluorescence microscopy and flow cytometry showed that FR901228 increased GFP expression in A549 and 11460 cells following OBP-401 infection in a dose-dependent manner, but this effect did not occur in H1299 cells. In addition. OBP-301 and FR901228 demonstrated a synergistic antitumor effect in A549 cells in vitro, as confirmed by isobologram analysis. Our data indicate that FR901228 preferentially increases adenovirus infectivity via up-regulation of CAR expression, leading to a profound oncolytic effect, which may have a significant impact on the outcome of adenovirus-based oncolytic virotherapy. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.yexcr.2005.10.026

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胃癌術後縦隔リンパ節再発による気管狭窄にステント+放射線治療が奏効した1例

香川俊輔, 藤原俊義, 西崎正彦, 徳永尚之, 合地明, 田中紀章

癌と化学療法 2006年

Homozygous deletion and reduced expression of the DOCK8 gene in human lung cancer.

Takahashi K, Kohno T, Ajima R, Sasaki H, Minna JD, Fujiwara T, Tanaka N, Yokota J

Int J Oncol 2006年

テロメラーゼ特異的に増幅するGFP蛋白を用いたマウスの固形腫瘍の胸膜播種の可視化

梅岡達生, 川嶋健, 香川俊輔, 寺石文則, 滝正樹, 京哲, 永井勝幸, 浦田泰生, 田中紀章, 藤原俊義

岡山医学会雑誌 2006年