研究者詳細 - 石田　穣治

論文 - 石田　穣治

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Integrin inhibitor suppresses bevacizumab-induced glioma invasion. 国際誌

Joji Ishida, Manabu Onishi, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Kentaro Fujii, Yosuke Shimazu, Tetsuo Oka, Isao Date

Translational oncology 7 ( 2 ) 292 - 302 2014年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Glioblastoma is known to secrete high levels of vascular endothelial growth factor (VEGF), and clinical studies with bevacizumab, a monoclonal antibody to VEGF, have demonstrated convincing therapeutic benefits in glioblastoma patients. However, its induction of invasive proliferation has also been reported. We examined the effects of treatment with cilengitide, an integrin inhibitor, on bevacizumab-induced invasive changes in glioma. U87ΔEGFR cells were stereotactically injected into the brain of nude mice or rats. Five days after tumor implantation, cilengitide and bevacizumab were administered intraperitoneally three times a week. At 18 days after tumor implantation, the brains were removed and observed histopathologically. Next, the bevacizumab and cilengitide combination group was compared to the bevacizumab monotherapy group using microarray analysis. Bevacizumab treatment led to increased cell invasion in spite of decreased angiogenesis. When the rats were treated with a combination of bevacizumab and cilengitide, the depth of tumor invasion was significantly less than with only bevacizumab. Pathway analysis demonstrated the inhibition of invasion-associated genes such as the integrin-mediated cell adhesion pathway in the combination group. This study showed that the combination of bevacizumab with cilengitide exerted its anti-invasive effect. The elucidation of this mechanism might contribute to the treatment of bevacizumab-refractory glioma.

DOI： 10.1016/j.tranon.2014.02.016

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Gene expression profiling of the anti-glioma effect of Cilengitide. 国際誌

Manabu Onishi, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Hiroyuki Michiue, Kentaro Fujii, Joji Ishida, Yosuke Shimazu, E Antonio Chiocca, Balveen Kaur, Isao Date

SpringerPlus 2 ( 1 ) 160 - 160 2013年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cilengitide (EMD121974), an inhibitor of the adhesive function of integrins, demonstrated preclinical efficacy against malignant glioma. It is speculated that cilengitide can inhibit tumor growth, invasion, and angiogenesis. However, the effects of cilengitide on these processes have not been sufficiently examined. In this study, we investigated the anti-glioma effect of cilengitide using DNA microarray analysis. U87ΔEGFR cells (human malignant glioma cell line) were used for this experiment. The cells were harvested after 16 h of cilengitide treatment, and mRNA was extracted. Gene expression and pathway analyses were performed using a DNA microarray (CodeLink™Human Whole Genome Bioarray). The expression of 265 genes was changed with cilengitide treatment. The expression of 214 genes was up-regulated by more than 4-fold and the expression of 51 genes was down-regulated by more than 4-fold compared to the controls. In pathway analysis, "apoptotic cleavage of cellular proteins" and "TNF receptor signaling pathway" were over-represented. Apoptotic-associated genes such as caspase 8 were up-regulated. Gene expression profiling revealed more detailed mechanism of the anti-glioma effect of cilengitide. Genes associated with apoptosis were over-represented following cilengitide treatment.

DOI： 10.1186/2193-1801-2-160

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ANALYSIS OF COMBINATION THERAPY OF THE ADENOVIRUS VECTOR CARRYING REIC/Dkk-3 (Ad-REIC) AND THE INTEGRIN ANTAGONIST CILENGITIDE

Yosuke Shimazu, Kazuhiko Kurozumi, Tomotsugu Ichikawa, Kentaro Fujii, Manabu Onishi, Joji Ishida, Tetsuo Oka, Masami Watanabe, Yasutomo Nasu, Hiromi Kumon, Isao Date

NEURO-ONCOLOGY 15 58 - 58 2013年11月

The integrin inhibitor cilengitide enhances the anti-glioma efficacy of vasculostatin-expressing oncolytic virus. 国際誌

K Fujii, K Kurozumi, T Ichikawa, M Onishi, Y Shimazu, J Ishida, E A Chiocca, B Kaur, I Date

Cancer gene therapy 20 ( 8 ) 437 - 44 2013年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Oncolytic viral (OV) therapy has been considered as a promising treatment modality for brain tumors. Vasculostatin, the fragment of brain-specific angiogenesis inhibitor-1, shows anti-angiogenic activity against malignant gliomas. Previously, a vasculostatin-expressing oncolytic herpes simplex virus-1, Rapid Antiangiogenesis Mediated By Oncolytic virus (RAMBO), was reported to have a potent antitumor effect. Here, we investigated the therapeutic efficacy of RAMBO and cilengitide, an integrin inhibitor, combination therapy for malignant glioma. In vitro, tube formation was significantly decreased in RAMBO and cilengitide combination treatment compared with RAMBO or cilengitide monotherapy. Moreover, combination treatment induced a synergistic suppressive effect on endothelial cell migration compared with the control virus. RAMBO, combined with cilengitide, induced synergistic cytotoxicity on glioma cells. In the caspase-8 and -9 assays, the relative absorption of U87ΔEGFR cell clusters treated with cilengitide and with RAMBO was significantly higher than that of those treated with control. In addition, the activity of caspase 3/7 was significantly increased with combination therapy. In vivo, there was a significant increase in the survival of mice treated with combination therapy compared with RAMBO or cilengitide monotherapy. These results indicate that cilengitide enhanced vasculostatin-expressing OV therapy for malignant glioma and provide a rationale for designing future clinical trials combining these two agents.

DOI： 10.1038/cgt.2013.38

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内視鏡下経鼻的経蝶形骨洞手術後の遅発性鼻出血に対し塞栓術が有効であった1例

岡哲生, 杉生憲志, 石田穣治, 菱川朋人, 小野成紀, 徳永浩司, 伊達勲

Neurological Surgery 40 ( 1 ) 55 - 60 2012年1月

記述言語：日本語出版者・発行元：(株)医学書院

66歳男。頭部MRIで下垂体腺腫を指摘された。半年後のMRIで増大傾向を示し、手術目的で入院した。手術は右鼻腔から神経内視鏡を使用してアプローチした、腫瘍を肉眼的にほぼ全摘出した。動脈性の出血を含めmassiveな出血は術中に認めなかった。術後経過は良好で、術後10日目に自宅に退院した。退院14日後、自宅で突然鼻出血を来し、止血困難であった。耳鼻咽喉科医によりボスミンガーゼを挿入され、いったん止血した。自宅で経過をみていたが、再度鼻出血を来し緊急入院した。左外頸動脈造影にて左顎動脈末梢のsphenopalatine arteryより鼻咽頭への血液の流出を確認し、出血点と診断した。塞栓術を施行した。sphenopalatine arteryを血管損傷部とともに完全に閉塞した。再度外頸動脈撮影で完全止血を確認し、手技を終了とした。術後経過は良好で再出血もなく、塞栓術後2週間で退院となった。

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J01228&link_issn=&doc_id=20120124070013&doc_link_id=10.11477%2Fmf.1436101628&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1436101628&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

[Usefulness of endovascular treatment for delayed massive epistaxis following endoscopic endonasal transsphenoidal surgery: a case report].

Tetsuo Oka, Kenji Sugiu, Joji Ishida, Tomohito Hishikawa, Shigeki Ono, Koji Tokunaga, Isao Date

No shinkei geka. Neurological surgery 40 ( 1 ) 55 - 60 2012年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）

We report here a case of massive nasal bleeding from the sphenopalatine artery three weeks after endonasal transsphenoidal surgery. This 66-year-old male suffered from massive nasal bleeding with the status of hypovolemic shock. Under general anesthesia, an emergent angiography revealed an extravasation from the sphenopalatine artery. Trans-arterial embolization using coil and n-butyl-cyanoacrylate (NBCA) was performed following the diagnostic angiography. Complete occlusion of the injured artery was achieved. The patient showed good recovery from general anesthesia. Delayed nasal bleeding after endonasal transsphenoidal surgery is a rare but important complication. The sphenopalatine artery and its branch are located in the hidden inferior lateral corner of the sphenoid sinus and may be injured during enlargement of the sphenoid opening. When massive delayed nasal bleeding follows transsphenoidal surgery and damage of the internal carotid artery has been ruled out, endovascular treatment of the external carotid artery should be considered.

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