薬剤感受性と耐性克服の分子生物学的研究

• 研究課題/領域番号: 12217165
• 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: 国立がんセンター(研究所)
• 研究代表者: 西尾 和人 国立がんセンター(研究所), 薬効試験部, 室長 (10208134)
• 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: 50,800千円 (直接経費: 50,800千円); 2004年度: 10,800千円 (直接経費: 10,800千円); 2003年度: 9,800千円 (直接経費: 9,800千円); 2002年度: 10,000千円 (直接経費: 10,000千円); 2001年度: 10,200千円 (直接経費: 10,200千円); 2000年度: 10,000千円 (直接経費: 10,000千円)
• キーワード: 遺伝子発現解析 / 分子標的薬 / EGFR / 臨床第I相試験 / 血管新生阻害剤 / チロシンキナーゼ阻害剤 / ゲフィチニブ / 臨床付随研究 / 薬理学 / トランスレーショナルリサーチ / マクロアレイ / 薬剤反応性 / シグナル伝達 / 相乗効果 / ZD1839 / ファルネシルトランスフェラーゼ / アポトーシス / Ras / MAPK / cDNAアレイ / 細胞周期制御薬 / ヒートショック / バイオマーカー / 抗がん剤

研究概要

各種分子標的薬の抗腫瘍効果規定因子の検討をおこなった。
(1)EGFR特異的チロシンキナーゼ阻害剤ゲフィチニブの感受性はがん細胞のEGFRの発現の有無、自己リン酸化に相関することを示した。
(2)大腸がんおよび肺がんにおけるゲフィチニブとCPT-11の併用の有用性をin vitro, in vivoでしめした。EGFRの各リン酸化欠損株の樹立をおこない、EGFRリン酸化(特にTyr1068)が併用効果のバイオマーカであることを示した。
(3)抗がん剤併用療法におけるcDNAアレイを用いた評価方法の確立を試みた。
(4)細胞周期作用薬E7070に対する耐性細胞を樹立し、同薬剤の感受性マーカーとしてcyclin B2等を選択した。
(5)血管新生阻害薬はVEGFあるいはオステオポンチンの過剰発現細胞による血管新生をより効果的に抑制することを示した。
(6)細胞株レベルで各種がん細胞に薬剤接触し、遺伝子発現の変化をcDNAアレイで検討することで、薬剤特異的なバイオマーカーの選択をおこなった。また同法によって遺伝子発現変動に基づく微小管作用薬の分類をおこなった。
(7)各種臨床検体のRNA抽出、保存、増幅、統計解析等の基礎的な検討をおこなった。統計解析では、再現性評価のためサンプルを測定し級内相関などによりアレイの評価をおこない、日間変動より日内変動が大きいことをしめし、必要なサンプル数が設定できた。また統計解析法、データの標準化の工夫をおこなった。
(8)分子標的薬(各種チロシンキナーゼ阻害剤)の臨床第1相試験における薬物投与前後の患者末梢血単核球における遺伝子発現プロファイルをcDNA遺伝子発現アレイを用いて検討し薬剤が生物学的に適切と考えられる分子に作用している原理の証明が達成できた。有害事象に相関するバイオマーカを選択した。

研究成果

• [雑誌論文] Randomized Pharmacokinetic and Pharmacodynamic Study of Docetaxel : Dosing Based on Body-Surface Area Compared With Individualized Dosing Based on Cytochrome P450 Activity Estimated Using a Urinary Metabolite of Exogenous Cortisol. (2004)
  • 著者名/発表者名: Yamamoto, N.
  • 雑誌名: J.Clin.Oncol. 23 ページ: 1-9
• [雑誌論文] Small in-frame deletion in the epidermal growth factor receptor as a target for ZD6474. (2004)
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• [雑誌論文] Anticancer effects of ZD6474, a VEGF receptor tyrosine kinase inhibitor, in gefitinib ("Iressa")-sensitive and resistant xenog raft models. (2004)
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• [雑誌論文] Synergistic interaction between gefitinib (Iressa, ZD1839) and paclitaxel against human gastric carcinoma cells. (2004)
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• [雑誌論文] The translational study for lung cancer. (2004)
  • 著者名/発表者名: Nishio, K.
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• [雑誌論文] hnRNP L enhances sensitivity of the cells to KW-2189. (2004)
  • 著者名/発表者名: Taguchi, F.
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• [雑誌論文] Synergistic interaction between the EGFR tyrosine kinase inhibitor gefitinib (‘Iressa') and the DNA topoisomerase I inhibitor CPT-11 (Irinotecan) in human colorectal cancer cells. (2004)
  • 著者名/発表者名: Koizumi, F.
  • 雑誌名: Int.J.Cancer 108 ページ: 464-472
• [雑誌論文] Development and biological analysis of peritoneal metastasis mouse models for human scirrhous stomach cancer.
  • 著者名/発表者名: Yanagihara, K.
  • 雑誌名: Cancer Sci. (印刷中)
• [雑誌論文] Gefitinib treatment affects androgen levels in non-small cell lung cancer patients.
  • 著者名/発表者名: Nishio, M.
  • 雑誌名: Br.J.Cancer (印刷中)
• [雑誌論文] The role of DNA-microarray in translational cancer research.
  • 著者名/発表者名: Korfbe, S.
  • 雑誌名: Curr.Pharmacogenomics (印刷中)
• [雑誌論文] Establishment of a human non-small cell lung cancer cell line resistant to gefitinib.
  • 著者名/発表者名: Koizumi, F.
  • 雑誌名: Int.J.Cancer (印刷中)
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• [文献書誌] Tatsumi, Y., et al.: "Enhancement of in vivo antitumor activity of a novel antimitotic 1-phenylpropenone derivative, AM-132, by tumor necrosis factor-α or interleukin-6"Jpn. J. Cancer Res.. 92・7. 768-777 (2001)
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• [文献書誌] Nakamura, T., et al.: "Reversal of cisplatin resistance by the 1,4-benzothiazepine derivative, JTV-519"Jpn. J. Cancer Res.. 92・6. 597-602 (2001)
• [文献書誌] Kanzawa, F., et al.: "In vitro synergistic interactions between the cisplatin analogue nedaplatin and the DNA topoisomerase I inhibitor irinotecan and the mechanism of this interaction"Clin. Cancer Res.. 7・1. 202-209 (2001)
• [文献書誌] Tsunoda, T., et al.: "Upregulated expression of angiogenesis genes and down regulation of cell cycle genes in human colorectal cancer tissue determined by cDNA macroarray"Anticancer Res.. 21・1A. 137-144 (2001)
• [文献書誌] Shimizu, M., et al.: "CPT-11 alters the circadian rhythm of dihydropyrimidine dehydrogenase mRNA in mouse liver"Jpn. J. Cancer Res.. 92・5. 554-561 (2001)
• [文献書誌] Suzuki, T., et al.: "The MRP family and anticancer drug metabolism current drug"Met. Curr. Drug Met.. 2・4. 367-377 (2001)
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• [文献書誌] Natsume, T., et al.: "Enhanced antitumor activities of TZT-1027 against TNF-α or IL-6 secreting Lewis lung carcinoma in vivo"Cancer Chemother. Pharmacol.. 49・1. 35-47 (2002)
• [文献書誌] Koh, Y., et al.: "Decreased expression of α2,8 sialyltransferase and increased expression of β1,4 N-acetylgalactosaminyltransferase in gastrointestinal cancers"Proc. Soc. Exp. Biol. Med.. 227・3. 196-200 (2002)
• [文献書誌] Naruse, I., et al.: "Antitumor activity of the selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)Iressa^<TM>(ZD1839) in a EGFR-expressing multidrug resistant cell line in vitro and in vivo"Int. J. Cancer. 98・2. 310-315 (2002)
• [文献書誌] Naruse, I., et al.: "Enhanced anti-tumor effect of trastuzumab in combination with cisplatin"Int. J. Cancer. (In press).
• [文献書誌] Fukuoka, K., et al.: "Mechanism of vinorelbine-induced radiosensitization of human small cell lung cancer cells"Cancer Chemother. Pharmacol.. (In press).
• [文献書誌] Takahashi, F., et al.: "Osteopontin induces angiogenesis of murine neuroblastoma cells in mice"Int. J. Cancer. (In press).
• [文献書誌] Kanzawa, F., et al.: "In vitro effects of combinations of cis-amminedichloro(2-methylpyridine)platinum (α)(ZD0473) with other novel anticancer drugs on the growth of SBC-3, a human small cell lung cancer cell line"Lung Cancer. (In press).
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• [文献書誌] Usuda,J., et al: "Molecular determinants of UCN-01 induced growth inhibition in human lung cancer cells."International Journal of Cancer. 85・2. 275-280 (2000)
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