がん増殖環境修飾物質の研究

• 研究課題/領域番号: 12217157
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 独立行政法人理化学研究所 (2003-2004); (財)微生物化学研究会 (2000-2002)
• 研究代表者: 長田 裕之 (2003-2004) 独立行政法人理化学研究所, 長田抗生物質研究室, 主任研究員 (80160836); 石塚 雅章 (2000-2002) 財団法人微生物化学研究会, 化学療法研究所, 所長 (80159722)
• 研究分担者: 川田 学 財団法人微生物化学研究会, 微生物化学研究センター・沼津創薬医科学研究所・創薬基盤研究ユニット, ユニット長 (20300808) ; 長田 裕之 理化学研究所, 抗生物質研究室, 主任研究員 (80160836)
• 研究期間 (年度): 2000 – 2004
• 研究課題ステータス: 完了 (2004年度)
• 配分額: 100,500千円 (直接経費: 100,500千円); 2004年度: 20,800千円 (直接経費: 20,800千円); 2003年度: 20,300千円 (直接経費: 20,300千円); 2002年度: 20,000千円 (直接経費: 20,000千円); 2001年度: 20,400千円 (直接経費: 20,400千円); 2000年度: 19,000千円 (直接経費: 19,000千円)
• キーワード: ヘパラナーゼ / VEGF / 血管新生 / がん細胞 / 化学生物学 / アクチン / Hsp60 / 血管新生阻害剤 / 分子標的 / PP2A / Bcl-2 / アポトーシス / 転移 / 血管内皮細胞遊走阻害 / 血管内皮細胞増殖阻害 / がん-間質相互作用 / PP2A阻害剤 / 前立腺がん / アンドロゲン受容体 / p53 / p21WAF1 / 乳がん / PTHrP(副甲状腺類縁タンパク) / 破骨細胞 / 骨転移 / 間質細胞 / Cuvularol / NK細胞活性化 / 15-deoxyspergualin / 癌増悪化 / 上皮-間質細胞間反応

研究概要

新規抗がん剤の探索研究として、血管内皮細胞増殖因子(VEGF)の作用を阻害する抗血管新生物質の探索を行い、epoxytwinol Aや新規フマギリン誘導体などの新規化合物を見出した。また、ヘパラン硫酸を模倣する化合物の探索を行った結果、RK-682から合成展開した4-Bn-RK682を高い特異性を有する抗ヘパラナーゼ物質として得た。さらに、がん細胞と間質細胞との共培養系によるがん細胞増殖阻害物質の探索を行ったところ、カビの培養液から一連のthielavin類を得た。
抗がん剤の化学生物学的手法による分子標的研究として、発見した化合物をビオチンや安定同位体で標識し結合タンパク質を同定した結果、amphidinolide Hはアクチンの200番目のチロシン残基に、またepolactaeneはHsp60の442番目のシステイン残基にそれぞれ細胞内で結合していることが示された。さらに、低分子化合物を官能基非依存的にビーズに固定化する技術を確立し、化合物に結合している内在性のタンパク質をマススペクトルにより同定することに成功した。
動物実験系での抗がん剤標的研究としては、ヘパラナーゼ阻害剤を検討した。ヘパラナーゼ阻害剤の4-Bn-RK-682およびKI-105はin vitroにおいてがん細胞の遊走・浸潤を阻害するだけではなく、in vivoにおいてもマウス腹腔内から注射したがん細胞の肺転移を経口投与で抑制した。

研究成果

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  • NAID: 10012685872
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