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KAKEN_25670195seika.pdf
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Title |
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ヒト化モノクローナル抗体の核内移行による新規分子標的療法の開発
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ヒトカ モノクローナル コウタイ ノ カクナイ イコウ ニ ヨル シンキ ブンシ ヒョウテキ リョウホウ ノ カイハツ
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Hitoka monokuronaru kotai no kakunai iko ni yoru shinki bunshi hyoteki ryoho no kaihatsu
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Development of molecular targeting therapy using nuclear-transpoted humanized monoclonal antibody
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山田, 健人
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ヤマダ, タケト
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Yamada, Taketo
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慶應義塾大学・医学部・准教授
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Research team head
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科研費研究者番号 : 60230463
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林, 睦
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ハヤシ, ムツミ
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Hayashi, Mutsumi
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慶應義塾大学・医学部・特任助教
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Research team member
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科研費研究者番号 : 60327575
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2014
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科学研究費補助金研究成果報告書
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2013
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CD26は広汎なヒトがんに発現している。ヒト化抗CD26抗体(Ab)でがん細胞を処理するとがん細胞の増殖抑制と共にCD26とAbは細胞質内から核内に移行した。クロマチン免疫沈降法にてCD26とPOLR2Aの転写調節領域が特異的に会合することを同定した。Abに抗がん分子Xを結合させたところ、X結合Abが、Abのみよりも極めて高効率にCD26依存性にがん細胞の増殖能の極度の低下を誘導した。一方、CD26を発現する正常ヒト内皮細胞やTリンパ球では、Ab核内移行はなく増殖抑制は認められなかった。X結合Ab-Xをマウスへ投与したところ、異種移植したヒトがんの増殖抑制能は、Abよりも強い効果が得られた。
CD26 is on cell surface of various types of cancers. It was shown humanized anti-CD26 monoclonal antibody(Ab) inhibited cancer cell growth and the Ab treatment induced nuclear translocation of both CD26 and YS110. In response to Ab treatment, it was revealed nuclear CD26 interacted with a genomic flanking region of POLR2A gene, a subunit of RNA polymerase II, using a chromatin immunoprecipitation assay. This interaction with nuclear CD26 and POLR2A gene consequently led to transcriptional repression of the POLR2A gene, resulting in retarded cell proliferation of cancer cells. Anti-cancer reagent X was conjugated with Ab, as a result X-Ab inhibited severely cancer cell growth as compaired with Ab only. It was revealed that Ab or X-Ab did not impair cell growth of normal human endothelial cell and T lymphocyte with CD26 expression. Xenografted human carcinomas were reduced significantly by X-Ab treatment as compared with Ab treatment.
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研究種目 : 挑戦的萌芽研究
研究期間 : 2013~2013
課題番号 : 25670195
研究分野 : 医歯薬学
科研費の分科・細目 : 基礎医学・実験病理学
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