研究者詳細 - 藤原　俊義

MISC - 藤原　俊義

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Virus-mediated oncolysis induces danger signal and stimulates cytotoxic T-lymphocyte activity via proteasome activator upregulation

Y. Endo, R. Sakai, M. Ouchi, H. Onimatsu, M. Hioki, S. Kagawa, F. Uno, Y. Watanabe, Y. Urata, N. Tanaka, T. Fujiwara

ONCOGENE 27 ( 17 ) 2375 - 2381 2008年4月

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

Dendritic cells ( DCs) are the most potent antigen-presenting cells and acquire cellular antigens and danger signals from dying cells to initiate antitumor immune responses via direct cell- to- cell interaction and cytokine production. The optimal forms of tumor cell death for priming DCs for the release of danger signals are not fully understood. OBP- 301 ( Telomelysin) is a telomerase-specific replication- competent adenovirus that induces selective E1 expression and exclusively kills human cancer cells. Here, we show that OBP- 301 replication produced the endogenous danger signaling molecule, uric acid, in infected human tumor cells, which in turn stimulated DCs to produce interferon-gamma ( IFN-gamma) and interleukin 12 ( IL- 12). Subsequently, IFN-gamma release upregulated the endogenous expression of the proteasome activator PA28 in tumor cells and resulted in the induction of cytotoxic T- lymphocytes. Our data suggest that virus- mediated oncolysis might be the effective stimulus for immature DCs to induce specific activity against human cancer cells.

DOI： 10.1038/sj.onc.1210884

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Establishment of biological and pharmacokinetic assays of telomerase-specific replication-selective adenovirus

Yuuri Hashimoto, Yuichi Watanabe, Yoshiko Shirakiya, Futoshi Uno, Shunsuke Kagawa, Hitoshi Kawamura, Katsuyuki Nagai, Noriaki Tanaka, Horomi Kumon, Yasuo Urata, Toshiyoshi Fujiwara

CANCER SCIENCE 99 ( 2 ) 385 - 390 2008年2月

記述言語：英語出版者・発行元：BLACKWELL PUBLISHING

The use of replication-selective tumor-specific viruses represents a novel approach for the treatment of neoplastic disease. We constructed an attenuated adenovirus, telomerase-specific replication-selective adenovirus (TRAD), in which the human telomerase reverse transcriptase promoter element drives the expression of the E1A and E1B genes linked with an internal ribosome entry site (IRES). Forty-eight hours after TRAD infection at a multiplicity of infection of 1.0, the cell viability of H1299 human lung cancer cells was consistently less than 50% and therefore this procedure could be used as a potency assay to assess the biological activity of TRAD. We also established a quantitative real-time polymerase chain reaction (PCR) analysis with consensus primers for either the adenovirus E1A or IRES sequence. The linear ranges of quantitation with E1A and IRES primers were 10(3)-10(8) and 10(2)-10(8) plaque-forming units/mL in the plasma, respectively. The PCR analysis demonstrated that the levels of E1A in normal tissues were more than 10(3) lower than in the tumors of A549 human lung tumor xenografts in nu/n mu mice at 28 days after intratumoral injection. Our results suggest that the cell-killing assay against H1299 cells and real-time PCR can be used to assess the biological activity and biodistribution of TRAD in clinical trials.

DOI： 10.1111/j.1349-7006.2007.00665.x

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Diagnostic and therapeutic application of telomerase-specific oncolytic adenoviral agents

Toshiyoshi Fujiwara, Yasuo Urata, Noriaki Tanaka

FRONTIERS IN BIOSCIENCE-LANDMARK 13 1881 - 1886 2008年1月

記述言語：英語出版者・発行元：FRONTIERS IN BIOSCIENCE INC

Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication. We constructed an attenuated adenovirus 5 vector (Telomelysin, OBP-301), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site (IRES). Telomelysin replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human cells lacking telomerase activity. We further modified the E3 region of OBP-301 to contain green fluorescent protein (GFP) gene for monitoring viral replication (TelomeScan, OBP-401). When TelomeScan was intratumorally injected into human tumors orthotopically implanted into the rectum in 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 TelomeScan causes viral spread into the regional lymphatic area and selectively replicates in neoplastic lesions, resulting in GFP expression in metastatic lymph nodes. This article reviews recent highlights in this rapidly evolving field: cancer therapeutic and cancer diagnostic approaches using the telomerase-specific oncolytic adenoviruses.

DOI： 10.2741/2807

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微小癌転移のin vivoイメージング技術.

藤原俊義, 田中紀章

Medical Science Digest 34 ( 2 ) 48 - 49 2008年

腫瘍融解ウイルスによる細胞死であるオンコライシスは細胞内にdanger signalを発生させ、プロテアソームアクチベーター（PA28）発現を増強することで細胞障害性Tリンパ球による免疫応答を活性化する.

遠藤芳克, 酒井亮, 大内正明, 鬼松秀樹, 日置勝義, 香川俊輔, 宇野太, 渡邉雄一, 浦田泰生, 田中紀章, 藤原俊義

岡山医学会雑誌 120 ( 3 ) 259 - 264 2008年

テロメラーゼ活性を標的とした腫瘍融解ウイルスのがん診断・治療への応用.

藤原俊義, 田中紀章

Cancer Frontier 10 ( 1 ) 49 - 56 2008年

遺伝子治療.

藤原俊義, 田中紀章

日本臨床 66 ( Suppl 6 ) 173 - 179 2008年

ウイルスによる細胞死とがん治療への応用.

藤原俊義, 田中紀章

がん分子標的治療 6 ( 3 ) 152 - 159 2008年

がんに対する遺伝子治療の現況と展望.

藤原俊義, 田中紀章

岡山医学会雑誌 120 ( 3 ) 321 - 327 2008年

テロメラーゼ活性を標的とした悪性腫瘍に対するウイルス療法の開発.

藤原俊義, 田中紀章

ウイルス 58 ( 1 ) 11 - 18 2008年

記述言語：日本語出版者・発行元：日本ウイルス学会

ウイルスは本来ヒトの細胞に感染，増殖し，その細胞を様々な機序により破壊する．遺伝子工学技術によりこの増殖機能に選択性を付加することにより，ウイルスを癌細胞のみを傷害する治療用医薬品として用いることが可能となる．Telomelysin（OBP-301）は，かぜ症状の原因となるアデノウイルスを基本骨格とし，ウイルス増殖に必須のE1遺伝子をテロメラーゼ・プロモーターで制御するよう改変された国産のウイルス製剤である．In vitroでは肺癌，大腸癌，胃癌，食道癌，頭頸部癌，乳癌，肝癌，膵癌，前立腺癌，子宮頸癌，卵巣癌などに対して広範な抗腫瘍活性がみられ，in vivoでは腫瘍内投与による有意な増殖抑制が認められるとともに，ウイルスは血中を循環し，遠隔部位の腫瘍内でも増殖することが確認された．固形癌に対するTelomelysinの第I相臨床試験は，米国食品医薬品局（Food and Drug Administration; FDA）の治験承認のもと米国にて進行中である．TelomelysinにGFP蛍光遺伝子を搭載したTelomeScan（OBP-401）は，高感度蛍光検出装置により微小癌組織を可視化することができ，診断用医薬品として応用可能である．原発巣内に投与されたTelomeScanは所属リンパ域へ拡散し，微小リンパ節転移でGFP発現を発する．高感度プローブあるいはビデオスコープにより転移リンパ節を同定することができ，本技術は微小癌，微小転移の早期発見に有用であるとともに，優れた外科ナビゲーション・システムとなりうると期待される．本稿では，従来のがん治療とは異なる新たな戦略として開発されているこれらの新規ウイルス製剤のがん診断・治療への応用の可能性を概説する．

DOI： 10.2222/jsv.58.11

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その他リンク： https://jlc.jst.go.jp/DN/JALC/00323509631?from=CiNii

テロメラーゼ特異的制限増殖型アデノウイルスを用いた転移リンパ節の生体内イメージング.

岸本浩行, 児島亨, 渡邉雄一, 香川俊輔, 藤原俊哉, 宇野太, 寺石文則, 京哲, 水口裕之, 橋本悠里, 浦田泰生, 田中紀章, 藤原俊義

岡山医学会雑誌 120 ( 1 ) 13 - 21 2008年

制限増殖型アデノウイルス製剤を用いた、消化器癌微小リンパ節転移の診断、および治療への応用.

児島亨, 田中紀章, 浦田泰生, 藤原俊義

癌の臨床 54 ( 3 ) 163 - 168 2008年

微小リンパ節転移を標的とするテロメラーゼ特異的腫瘍融解ナノバイオウイルス製剤によるイメージングシステムおよび治療法の開発.

児島亨, 田中紀章, 浦田泰生, 藤原俊義

Biotherapy 22 ( 2 ) 87 - 95 2008年

PET/CTによる肺癌RFA後の再発診断の至適時期の検討

奥村能啓, 郷原英夫, 井上大作, 平木隆夫, 三村秀文, 佐藤修平, 加藤勝也, 加地充昌, 佐野由文, 藤原俊義, 金澤右

肺癌 48 ( 5 ) 2008年

当科における食道切除後,遺残食道癌症例の検討

野間和広, 猶本良夫, 藤智和, 田邊俊介, 近藤喜太, 藤原康宏, 吉田亮介, 櫻間一史, 宇野太, 香川俊輔, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 松岡順治, 田中紀章

岡山医学会雑誌 120 ( 2 ) 2008年

当科における食道切除後,再建胃管癌症例の検討

田邊俊介, 猶本良夫, 藤智和, 近藤喜太, 藤原康宏, 吉田亮介, 野間和広, 櫻間一史, 宇野太, 香川俊輔, 白川靖博, 山辻知樹, 小林直哉, 藤原俊義, 松原長秀, 松岡順治, 田中紀章

岡山医学会雑誌 120 ( 2 ) 2008年

Adenomyoma of the stomach presenting as localized peritonitis

Shunsuke Kagawa, Toshiyoshi Fujiwara, Masahiko Nishizaki, Yoshio Naomoto, Isozaki Hiroshi, Noriaki Tanaka

DIGESTIVE DISEASES AND SCIENCES 52 ( 11 ) 3184 - 3187 2007年11月

Knock down of hSNF5/Ini1 causes cell cycle arrest and apoptosis in a p53-dependent manner

Hiroyuki Kato, Reiko Honma, Takaomi Sanda, Toshiyoshi Fujiwara, Emi Ito, Yuka Yanagisawa, Jun-ichi Imai, Takashi Okamoto, Shinya Watanabe

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 361 ( 3 ) 580 - 585 2007年9月

記述言語：英語出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

hSNF5/Inil is a core component of the SWI/SNF complex and the gene is frequently mutated in aggressive pediatric rhabdoid tumors. Mechanisms of the malignant transformation, however, remain poorly understood. We analyzed HeLa cells treated with siRNA to the hSNF5/Inil mRNA. The resulting efficient and long-term suppression caused characteristic cell enlargement, cell cycle arrest in G1 phase, and subsequent modest apoptosis. Gene expression profiling of the hSNF5-down-regulated cells by cDNA microarray analysis revealed that a limited number of p53-responsive genes, especially p21, were up-regulated. The p53 protein level was also greatly enhanced, suggesting that loss of hSNF5/Inil induces a p53 signaling pathway irrelevant to the chk1/2 phosphorylation pathway. Some rhabdoid tumors with very low or no ARF expression were induced to undergo cell enlargement, growth arrest, and, in one case, apoptosis by ectopic expression of the p14ARF protein. These results may in part account for molecular mechanisms of rhabdoid tumor formation. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2007.07.035

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Clonality and heterogeneity of pulmonary blastoma from the viewpoint of genetic alterations: A case report

Kenji Takahashi, Takashi Kohno, Shingo Matsumoto, Yukihiro Nakanishi, Yasuhito Arai, Toshiyoshi Fujiwara, Noriaki Tanaka, Jun Yokota

LUNG CANCER 57 ( 1 ) 103 - 108 2007年7月

記述言語：英語出版者・発行元：ELSEVIER IRELAND LTD

Biphasic pulmonary blastoma is a rare lung tumor with epithelia[ and mesenchymal components. Genetic alterations in this tumor are largely unknown, except for the presence of beta-catenin and p53 mutations and the absence of KRAS mutation. To understand the molecular process of histogenesis of this tumor, a whole genome allelic imbalance (Al) scanning using a high-resolution single nucleotide polymorphism array as well as mutational analysis of the p53, EGFR, KRAS and beta-catenin genes were performed against the epithelial and mesenchymal components in the primary tumor and a metastatic tumor in a case of pulmonary blastoma. Al at chromosome regions 14q24-q32 and 17p11-p13 and beta-catenin mutation were commonly detected in all tumors. On the other hand, Al at chromosome regions 3p11-p14 and 9p21-p24 and p53 mutation were detected only in the mesenchymal component in the primary tumor but not in the epithelial component in the primary tumor and the brain metastasis. Likewise, Al at chromosome regions 6p24-p25 and 6q14-q27 was detected in the epithelial. component in the primary tumor and the brain metastasis but not in the mesenchymal component in the primary tumor. Furthermore, the genetic alterations detected in the metastatic tumor were completely the same as those in the epithelial component in the primary tumor, indicating that a tumor cell(s) in the epithelial component in the primary tumor selectively metastasized to the brain. These results indicate that this biphasic tumor is of monoclonal origin and the phenotypic heterogeneity of the tumor is due to the differences in the accumulated genetic alterations in each component of the tumor. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2007.01.026

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Immunological evaluation of personalized peptide vaccination in combination with a 5-fluorouracil derivative (TS-1) for advanced gastric or colorectal carcinoma patients

Yuji Sato, Toshiyoshi Fujiwara, Takashi Mine, Hiroki Shomura, Shigenori Homma, Yoshiaki Maeda, Naoyuki Tokunaga, Yoshihiro Ikeda, Yuki Ishihara, Akira Yamada, Noriaki Tanaka, Kyogo Itoh, Mamoru Harada, Satoru Todo

CANCER SCIENCE 98 ( 7 ) 1113 - 1119 2007年7月

記述言語：英語出版者・発行元：BLACKWELL PUBLISHING

The aim of the present study was to investigate the safety and immunological responses of personalized peptide vaccination in combination with oral administration of a 5-fluorouracil derivative (TS-1) in advanced gastric or colorectal carcinoma patients. Eleven patients (four with gastric cancer and seven with colorectal cancer) who failed to improve by prior TS-1-based chemotherapies were enrolled in this study. Peptides to be administered to patients were determined based on the presence of peptide-specific cytotoxic T lymphocyte (CTL) precursors in peripheral blood mononuclear cells and peptide-specific IgG in the plasma of cancer patients. Patients were vaccinated with peptides (a maximum of four) biweekly in combination with or without three different doses of TS-1 (20, 40 and 80 mg/m(2)/day). Although grade 3 toxicity, including anemia (one patient) and neutropenia (one patient) were observed, the combination therapy was generally well tolerated. An increase in peptide-specific IgG after the sixth vaccination was observed in the vast majority of patients irrespective of the dose of TS-1 used. In contrast, an increase in peptide-specific interferon-gamma production by CTL was most evident in patients who were administered the highest dose of TS-1. Furthermore, in the patients who received 80 mg/m(2)/day TS-1, CTL-mediated cytotoxicity against cancer cells was maintained at the prevaccination level. These results indicate that administration of the standard dose (80 mg/m(2)/day) of TS-1 in combination with a personalized peptide vaccination does not necessarily impede immunological responses in cancer patients, and could actually maintain or augment them.

DOI： 10.1111/j.1349-7006.2007.00498.x

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