新規天然制癌物質の探索とその作用機序の解明

• 研究課題/領域番号: 09255105
• 研究種目: 特定領域研究(A)
• 配分区分: 補助金
• 研究機関: (財)微生物化学研究会
• 研究代表者: 石塚 雅章 財団法人 微生物化学研究会, 化学療法研究所, 副所長 (80159722)
• 研究分担者: 上村 大輔 名古屋大学, 大学院・理学研究科, 教授 (00022731) ; 伏谷 伸宏 東京大学, 大学院・農学生命科学研, 教授 (70012010) ; 瀬戸 治男 東京大学, 分子細胞生物学研, 教授 (10013335) ; 長田 裕之 理化学研究所, 抗生物質, 主任研究員 (80160836) ; 小林 淳一 北海道大学, 大学院・薬学研究科, 教授 (90221241) ; 林 正彦 (社)北里研究所, 基礎研究所, 室長 (20164965)
• 研究期間 (年度): 1999
• 研究課題ステータス: 完了 (1999年度)
• 配分額: 111,000千円 (直接経費: 111,000千円); 1999年度: 37,000千円 (直接経費: 37,000千円); 1998年度: 37,000千円 (直接経費: 37,000千円); 1997年度: 37,000千円 (直接経費: 37,000千円)
• キーワード: テロメラーゼ阻害剤 / 海洋生物由来細胞毒物質 / 細胞接着阻害剤 / 血管新生阻害剤 / 神経突起伸長 / アポトーシス誘導物質 / 細胞接着阻害物質 / 細胞周期阻害物質 / PP2A / 微小管重合 / caspase-3 / DNAポリメラーゼβ阻害物質 / チロシンキナーゼ阻害物質 / 多剤耐性克服物質 / IL-6阻害物質 / TGF-β活性調節物質 / サイトカイン調節物質 / 消化管毒性軽減物質

研究概要

1.細胞増殖阻害物質:微生物代謝産物よりきわめて選択性に優れたテロメラーゼ阻害活性を示す新規物質GM95物質を発見した。本物質による癌細胞ならびに宿主におけるテロメラーゼ機能の解明が期待される。TGF-β様活性を指標にヒト癌細胞に制癌活性を示す新規物質Q71576 AおよびB物質を発見した。植物由来物質として、微小管脱重合阻害活性を示す新規タキサン化合物Taxezopidine KおよびL、環状ペプチドMoroidin、タンパク合成阻害物質で細胞毒性を示すCephalezomine A-F、海洋生物由来細胞毒性物質、Theopederin類、Hterumalide、Attenol類などの新規物質を発見した。これらの物質については制癌活性の検討が行われる。
2.作用機構の解明:a)微生物生産物より接着因子ビトロネクチンの受容体でヒト血管内皮細胞に分布するαVβ3結合阻害物質としてPyrrothine群抗生物質が同定され、Thiolutinが接着シグナルに深く関与するパキシリンの減少に作用することを示した。b)ヒト腫瘍細胞のG1ならびにG2期特異的停止作用を有するHerboxidineがP27の翻訳を上昇させ、CDK結合活性を持つP27フラグメントを蓄積させることを明らかにした。c)液胞型プロトンポンプATPsaseの阻害剤DestruxinがPC12神経芽腫細胞のカテプシンB活性を阻害して神経突起伸長を誘導することを見出した。神経芽腫ならびに神経線維の研究への展開が期待される。

研究成果

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