肺がんの薬剤耐性と転移因子を分子標的とした免疫遺伝子治療

• Project/Area Number: 08266242
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (A)
• Allocation Type: Single-year Grants
• Research Institution: The University of Tokushima
• Principal Investigator: 曽根 三郎 徳島大学, 医学部, 教授 (40145024)
• Co-Investigator(Kenkyū-buntansha): 篠原 勉 徳島大学, 医学部・附属病院, 助手 (70284289) ; 西岡 安彦 徳島大学, 医学部, 講師 (70274199) ; 清水 英治 徳島大学, 医学部, 講師 (50187449) ; 楊河 宏章 徳島大学, 医学部附属病院, 助手 (50263827)
• Project Period (FY): 1996 – 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥39,000,000 (Direct Cost: ¥39,000,000); Fiscal Year 1999: ¥10,000,000 (Direct Cost: ¥10,000,000); Fiscal Year 1998: ¥10,000,000 (Direct Cost: ¥10,000,000); Fiscal Year 1997: ¥10,000,000 (Direct Cost: ¥10,000,000); Fiscal Year 1996: ¥9,000,000 (Direct Cost: ¥9,000,000)
• Keywords: 肺がん / 転移 / 多剤耐性 / P糖蛋白質 / 遺伝子治療 / 免疫療法 / SCIDマウス / 肺癌 / 転移モデル / ガンクリオシドGM2 / モノクローナル抗体 / ADCC / NK細胞 / サイトカイン / 薬剤耐性 / 免疫遺伝子治療 / 抗体治療

Research Abstract

多剤耐性(MDR)癌細胞が発現するP糖蛋白質(P-gp)に対する抗体MRK16はマクロファージ(MΦ)の抗体依存性細胞障害反応(ADCC)を誘導し、MDR癌細胞を障害する。本年度は、肺癌の遠隔転移とMDRの克服を目的に、MDR肺癌細胞の多臓器転移に対する抗P-gp抗体の治療効果を検討し、更にMΦのADCCを強化すべくMDR肺癌細胞へMΦ活性化因子M-CSFまたはMΦ遊走因子MCP-1の遺伝子導入を行い、抗P-gp抗体との併用効果を検討し、以下の成果を得た。1、ヒト小細胞肺癌株H69及びP-gp陽性MDR株H69/VPはNK細胞除去SCIDマウスに静注した場合、多臓器(肝、腎、リンパ節)転移を形成した。ビンデシン治療はH69の転移形成を抑制したがH69/VPのそれを全く抑制せず、H69/VPの転移巣での抗癌剤耐性を確認した。2、抗P-gp抗体(マウス抗体MRK16とキメラ抗体MH162)は用量依存性にH69/VPの多臓器転移形成を抑制した。3、H69/VPにM-CSFまたはMCP-1遺伝子を導入し生物活性を有するM-CSFまたはMCP-1産生株を得た。これらの株を用い上記転移モデルにてMRK16治療の転移抑制効果を検討した。(1)H69/VPに対する遺伝子導入はin vitroでの増殖能及びP-gp発現に影響しなかった。(2)M-CSF遺伝子導入はMΦ活性化により肝及びリンパ節転移を抑制したが腎転移には影響しなかった。しかし、MRK16併用にて各臓器の転移形成が完全に抑制された。(3)MCP-1遺伝子導入は転移形成に影響しなかったが、MRK16併用において転移抑制効果を有意に増強した。その機序として、転移巣で産生されたMCP-1がMΦ集積を促進しADCCを増強させたと考えられた。以上より、MDR肺癌に対する抗転移療法を開発する上で、免疫エフェクター細胞の転移局所への動員と活性化を試みるアプローチの重要性が示唆された。

Research Products

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• [Publications] Parajuli,P.,: "Therapeutic efficacy of a new topoisomerase I and II inhibitor TAS-103, against both P-glycoprotein-expressing and -nonexpressing drug-resistant human small-cell lung cancer"Oncol.Res.,. 11. 219-224 (1999)
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