Faculty Profiles - FUJIWARA Toshiyoshi

MISC - FUJIWARA Toshiyoshi

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進行膵頭部癌に対する手術治療戦略

横道直佑, 楳田祐三, 松田浩明, 貞森裕, 篠浦先, 吉田龍一, 佐藤太祐, 内海方嗣, 杭瀬崇, 八木孝仁, 藤原俊義

日本臨床外科学会雑誌 71 ( 増刊 ) 705 - 705 2010.10

WS-1-7 テロメラーゼ活性を標的とするウイルス製剤の癌診断・治療への応用(癌治療向上のためのtranslational research,ワークショップ(1),第110回日本外科学会定期学術集会)

藤原俊義

日本外科学会雑誌 111 ( 2 ) 157 - 157 2010.3

A Phase I Study of Telomerase-specific Replication Competent Oncolytic Adenovirus (Telomelysin) for Various Solid Tumors

John Nemunaitis, Alex W. Tong, Michael Nemunaitis, Neil Senzer, Anagha P. Phadke, Cynthia Bedell, Ned Adams, Yu-An Zhang, Phillip B. Maples, Salina Chen, Beena Pappen, James Burke, Daiju Ichimaru, Yasuo Urata, Toshiyoshi Fujiwara

MOLECULAR THERAPY 18 ( 2 ) 429 - 434 2010.2

Language：English Publisher：NATURE PUBLISHING GROUP

A phase I clinical trial was conducted to determine the clinical safety of Telomelysin, a human telomerase reverse transcriptase (hTERT) promoter driven modified oncolytic adenovirus, in patients with advanced solid tumors. A single intratumoral injection (IT) of Telomelysin was administered to three cohorts of patients (1 x 10(10), 1 x 10(11), 1 x 10(12) viral particles). Safety, response and pharmacodynamics were evaluated. Sixteen patients with a variety of solid tumors were enrolled. IT of Telomelysin was well tolerated at all dose levels. Common grade 1 and 2 toxicities included injection site reactions (pain, induration) and systemic reactions (fever, chills). hTERT expression was demonstrated at biopsy in 9 of 12 patients. Viral DNA was transiently detected in plasma in 13 of 16 patients. Viral DNA was detectable in four patients in plasma or sputum at day 7 and 14 post-treatment despite below detectable levels at 24 h, suggesting viral replication. One patient had a partial response of the injected malignant lesion. Seven patients fulfilled Response Evaluation Criteria in Solid Tumors (RECIST) definition for stable disease at day 56 after treatment. Telomelysin was well tolerated. Evidence of antitumor activity was suggested.

DOI： 10.1038/mt.2009.262

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Intraperitoneal administration of telomerase-specific oncolytic adenovirus sensitizes ovarian cancer cells to cisplatin and affects survival in a xenograft model with peritoneal dissemination

M. Takakura, M. Nakamura, S. Kyo, M. Hashimoto, N. Mori, T. Ikoma, Y. Mizumoto, T. Fujiwara, Y. Urata, M. Inoue

CANCER GENE THERAPY 17 ( 1 ) 11 - 19 2010.1

Language：English Publisher：NATURE PUBLISHING GROUP

Despite tremendous development in chemotherapy for ovarian cancer over the past few decades, the prognosis of advanced cases with massive peritoneal dissemination is still unsatisfactory, and novel treatment modalities that can combine with chemotherapy are urgently needed. We recently developed virotherapy for solid tumors using telomerase-specific replication-selective adenoviruses (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) gene promoter has been inserted to direct tumor-specific E1 gene expression. In this study, we investigated the anti-tumor effects of OBP-301, combined with cisplatin (CDDP), on ovarian cancer cells. In vitro treatment of SKOV3 cells with OBP-301 at a multiplicity of infection (MOI) of 0.01-100 induced significant cell death in a dose-dependent manner, with moderate cytotoxicity at an MOI of 1-10 and maximal cytotoxicity at an MOI of 100. In contrast, OBP-301 treatment of normal human cells showed no significant cell death at an MOI of 1- 10 and exhibited modest cytotoxicity at an MOI of 100. The effects of low-dose CDDP at 0.5-1 mu M, which induced only 20% cell death, were significantly augmented by combination with OBP-301 at an MOI of 1- 10, finally achieving 40% cell death. Such enhancement of CDDP sensitivity was also observed in CDDP-resistant ovarian cancer cells. The combinatorial effects were further tested using a xenograft mouse model of SKOV3 with peritoneal dissemination. After intraperitoneal administration of OBP-301, we confirmed that injected OBP-301 fused with the green fluorescent protein (GFP) gene (OBP-401) was preferentially localized to peritoneal disseminations, as determined by fluorescence imaging. Treatment of mice with CDDP at low dose (0.5 mg kg(-1)) had modest effects, showing a 10% decrease in disseminations, whereas combination with intraperitoneal administration of OBP-301 at an MOI of 10 led to enhanced effects, achieving an approximately 80% decrease in disseminations. Kaplan-Meier analysis showed improved overall survival of mice treated with CDDP plus OBP-301 compared with CDDP alone. These findings support the therapeutic potential of intraperitoneal administration of OBP-301 to sensitize ovarian cancer cells to CDDP. Cancer Gene Therapy (2010) 17, 11-19; doi: 10.1038/cgt.2009.44; published online 7 August 2009

DOI： 10.1038/cgt.2009.44

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保存的加療にて軽快した腸管気腫症の一例

藤原裕子, 田邊俊介, 白川靖博, 近藤喜太, 野間和広, 宇野太, 永坂岳司, 香川俊輔, 山辻知樹, 貞森裕, 小林直哉, 藤原俊義, 八木孝仁, 猶本良夫

岡山医学会雑誌 122 ( 2 ) 2010

当院のおける中・下咽頭表在癌に対するESDの工夫

白川靖博, 田邊俊介, 野間和広, 櫻間教文, 山辻知樹, 松岡順治, 高岡宗徳, 河原祥朗, 岡田裕之, 猶本良夫, 藤原俊義

Gastroenterological Endoscopy 52 ( Supplement 2 ) 2010

パラチノースを糖質源とした流動食MHN-01を用いた食道癌周術期栄養管理

山辻知樹, 田邉俊介, 藤原康宏, 藤原康宏, 野間和広, 櫻間教文, 櫻間教文, 高岡宗徳, 白川靖博, 藤原俊義, 木下真一郎, 深澤拓也, 林次郎, 繁光薫, 吉田和弘, 森田一郎, 猶本良夫

日本臨床外科学会雑誌 71 2010

消化管再建法-合併症ゼロへの工夫-I.食道切除後再建法 5.結腸再建

山辻知樹, 白川靖博, 繁光薫, 野間和広, 藤原俊義, 猶本良夫

手術 64 ( 10 ) 2010

当科にて経験した食道GISTの2例

渡邉伸一郎, 白川靖博, 田邊俊介, 野間和広, 櫻間教文, 繁光薫, 山辻知樹, 羽井佐実, 猶本良夫, 藤原俊義

日本食道学会学術集会プログラム・抄録集 64th 2010

食道癌周術期の新しい栄養管理

山辻知樹, 田邊俊介, 野間和広, 櫻間教文, 白川靖博, 藤原俊義, 木下真一郎, 林次郎, 繁光薫, 吉田和弘, 森田一郎, 猶本良夫

岡山医学会雑誌 122 ( 3 ) 2010

小腸間置による胃機能温存食道切除再建術とその臨床的評価

猶本良夫, 山田英司, 田辺俊介, 藤原康宏, 野間和広, 高岡宗徳, 白川靖博, 木下真一郎, 深澤拓也, 繁光薫, 林次郎, 山辻知樹, 吉田和弘, 森田一郎, 藤原俊義

General Thoracic and Cardiovascular Surgery 58 ( Supplement ) 2010

食道原発悪性黒色腫の3例

渡邉伸一郎, 白川靖博, 田辺俊介, 野間和広, 櫻間教文, 繁光薫, 山辻知樹, 羽井佐実, 松岡順治, 猶本良夫, 藤原俊義

General Thoracic and Cardiovascular Surgery 58 ( Supplement ) 2010

当科における回結腸を用いた食道再建術の工夫

白川靖博, 渡邉伸一郎, 田邊俊介, 野間和広, 櫻間教文, 重光薫, 山辻知樹, 羽井佐実, 猶本良夫, 藤原俊義

日本食道学会学術集会プログラム・抄録集 64th 2010

右鎖骨下動脈起始異常と非反回下喉頭神経を伴う食道癌に対する手術経験

田辺俊介, 白川靖博, 二萬英斗, 渡邉伸一郎, 野間和広, 櫻間教文, 繁光薫, 山辻知樹, 羽井佐実, 松岡順治, 猶本良夫, 藤原俊義

General Thoracic and Cardiovascular Surgery 58 ( Supplement ) 2010

当科におけるハイリスク食道癌症例に対する治療方針

白川靖博, 田邊俊介, 藤原康宏, 野間和広, 櫻間教文, 山辻知樹, 貞森裕, 藤原俊義, 八木孝仁, 猶本良夫

日本消化器外科学会雑誌 43 ( Supplement1 (Web) ) 2010

Imatinib耐性GISTに対するSunitinib使用経験

藤原康宏, 田邊俊介, 野間和広, 永坂岳司, 白川靖博, 山辻知樹, 貞森裕, 八木孝仁, 藤原俊義, 猶本良夫

日本消化器外科学会雑誌 43 ( Supplement1 (Web) ) 2010

食道癌再発巣に対する治療方針-PET導入後の治療手段の変遷-

田邊俊介, 藤原康宏, 野間和広, 櫻間教文, 白川靖博, 山辻知樹, 貞森裕, 藤原俊義, 八木孝仁, 猶本良夫

日本消化器外科学会雑誌 43 ( Supplement1 (Web) ) 2010

Use of telomelysin (OBP-301) in mouse xenografts of human head and neck cancer

Oumi Nakajima, Daiju Ichimaru, Yasuo Urata, Toshiyoshi Fujiwara, Tomohisa Horibe, Masayuki Kohno, Koji Kawakami

ONCOLOGY REPORTS 22 ( 5 ) 1039 - 1043 2009.11

Language：English Publisher：SPANDIDOS PUBL LTD

We previously reported that telomerase-specific replication-component adenovirous, Telomelysin (OBP-301) has cytotoxic activity to the YCUT892, KCCT873, KCCT891, KCCL871, YCUM862, HN12, and KCCOR891 cell lines in vitro, and investigated the association between cytotoxic activity and adenoviral receptor expression. In this study, we evaluated the most appropriate way to administer telomelysin (OBP-301) in the treatment of squamous cell carcinoma of the head and neck (SCCHN), and assessed the effect of OBP-301 in large subcutaneous KCCT873 human SCCHN tumors in immunodeficient mice. We also compared antitumor responses following three intratumoral (i.t.) injections of OBP-301 given daily, every 2 days or weekly. To investigate the mechanism of the antitumor effect, we evaluated cellular infiltration in treated tumors. OBP-301 showed remarkable antitumor activity against large KCCT873 tumors, and three treatment schedules produced similar antitumor effects. The weekly regimen also significantly reduced the growth of large tumors. Immunochemistry revealed that macrophages, but not natural killer cells, were responsible for tumor regression. A regimen of three weekly injections of OBP-301 has remarkable antitumor effects against large KCCT873 tumors. These results may provide a new platform for treating patients with localized SCCHN.

DOI： 10.3892/or_00000533

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Selective metastatic tumor labeling with green fluorescent protein and killing by systemic administration of telomerase-dependent adenoviruses

Hiroyuki Kishimoto, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara, Robert M. Hoffman

MOLECULAR CANCER THERAPEUTICS 8 ( 11 ) 3001 - 3008 2009.11

Language：English Publisher：AMER ASSOC CANCER RESEARCH

We previously constructed telomerase-dependent, replication-selective adenoviruses OBP-301 (Telomelysin) and OBP-401 [Telomelysin-green fluorescent protein (GFP); TelomeScan], the replication of which is regulated by the human telomerase reverse transcriptase promoter. By intratumoral injection, these viruses could replicate within the primary tumor and subsequent lymph node metastasis. The aim of the present study was to evaluate the possibility of systemic administration of these telomerase-dependent adenoviruses. We assessed the antitumor efficacy of OBP-301 and the ability of OBP-401 to deliver GFP in hepatocellular carcinoma (HCC) and metastatic colon cancer nude mouse models. We showed that i.v. administration of OBP-301 significantly inhibited colon cancer liver metastases and orthotopically implanted HCC. Further, we showed that OBP-401 could visualize liver metastases by tumor-specific expression of the GFP gene after portal venous or i.v. administration. Thus, systemic administration of these adenoviral vectors should have clinical potential to treat and detect liver metastasis and HCC. [Mol Cancer Ther 2009;8(11):3001-8]

DOI： 10.1158/1535-7163.MCT-09-0556

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A simple biological imaging system for detecting viable human circulating tumor cells

Toru Kojima, Yuuri Hashimoto, Yuichi Watanabe, Shunsuke Kagawa, Futoshi Uno, Shinji Kuroda, Hiroshi Tazawa, Satoru Kyo, Hiroyuki Mizuguchi, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

JOURNAL OF CLINICAL INVESTIGATION 119 ( 10 ) 3172 - 3181 2009.10

Language：English Publisher：AMER SOC CLINICAL INVESTIGATION INC

The presence of circulating tumor cells (CTCs) in the peripheral blood is associated with short survival, making the detection of CTCs clinically useful as a prognostic factor of disease outcome and/or a surrogate marker of treatment response. Recent technical advances in immunocytometric analysis and quantitative real-time PCR have made it possible to detect a few CTCs in the blood; however, there is no sensitive assay to specifically detect viable CTCs. Here, we report what we believe to be a new approach to visually detect live human CTCs among millions of peripheral blood leukocytes, using a telomerase-specific replication-selective adenovirus expressing GFP. First, we constructed a GFP-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication (OBP-401; TelomeScan). We then used OBP-401 to establish a simple ex vivo method that was able to detect viable human CTCs in the peripheral blood. The detection method involved a 3-step procedure, including the lysis of rbc, the subsequent addition of OBP-401 to the cell pellets, and an automated scan using fluorescence microscopy. OBP-401 infection increased the signal-to-background ratio as a tumor-specific probe, because the fluorescent signal was amplified only in viable, infected human tumor cells, by viral replication. This GFP-expressing virus-based method is remarkably simple and allows precise enumeration of CTCs.

DOI： 10.1172/JCI38609

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