2003 年度実績報告書

肺がんの転移・血管新生分子を標的とした生物学的制御法開発

研究課題

研究課題/領域番号	12217099
研究機関	徳島大学
研究代表者	曽根三郎徳島大学, 医学部, 教授 (40145024)
研究分担者	埴淵昌毅徳島大学, 医学部・歯学部附属病院, 講師 (80335794) 矢野聖二徳島大学, 医学部・歯学部附属病院, 講師 (30294672)
キーワード	肺癌 / 多臓器転移 / 骨転移 / 分子標的治療 / EGF受容体 / MMP / 臓器微小環境 / cDNAマイクロアレイ
研究概要	肺癌の転移・血管新生分子を標的とした生物学的治療法開発に向けた検討を行い、転移臓器特異的な新規標的分子の探索とその作用機構の解析を進め、以下の成果を得た。QOL阻害要因として重要な骨転移については、ヒト小細胞肺癌株の転移モデルにおいて第三世代のビスフォスフォネートYM529が骨転移を特異的に抑制すること、さらに抗癌剤を併用することによりマウスの生存期間を有意に延長することを明らかにした。また、宿主から産生される転移関連因子としてMatrix metalloproteinase(MMP)とInterleukin-1(IL-1)に着目し、第三世代MMP阻害薬ONO-4817がMMP-2,9を高発現しているヒト肺腺癌細胞株の肺転移形成を抑制し、抗癌剤との併用にてマウスの生存期間を有意に延長すること、遺伝子導入実験にてIL-Iが細胞増殖、浸潤、血管新生を促進することにより転移形成を促進することを明らかにした。さらに、NK細胞除去SCIDマウスにヒト小細胞肺癌株SBC-5を静注し形成された肝、肺、腎、骨の転移巣かちマイクロダイセクション法で癌細胞を回収し、その遺伝子発現をcDNAマイクロアレイで解析し、臓器毎に比較した結果、臓器特異的に発現が亢進している約400遺伝子を同定した。今後は、それぞれの遺伝子を過剰発現またはノックアウトした実験系にて真の臓器特異的転移関連因子を同定し、新たな治療の分子標的となりうるか否かを検討する予定である。臨床研究としても、非小細胞肺癌患者の癌組織のEGF受容体関連因子発現および活性化状態を検討し、EGF受容体蛋白の過剰発現ではなくリン酸化EGF受容体(活性型)と予後が逆相関することを報告した。

研究成果

(22件)

すべてその他

すべて文献書誌 (22件)

[文献書誌] Miki, T.: "Parathyroid hormone-related protein (PTHrP) is responsible for production of bone metastasis, but not visceral metastasis, by human small cell lung cancer SBC-5 cells in natural killer cell-depleted SCID mice."Int.J.Cancer. 108. 511-515 (2004)
[文献書誌] Yoneda, K.: "Atimulation of human bronchial epithelial cells by IgE-dependent histamine-releasing factor."Am.J.Physil.Lung Cell Mol.Physiol.. 286. 174-181 (2004)
[文献書誌] Yamamoto, A.: "A third generation matrix metalloproteinase (MMP) Inhibitor (ONO-4817) combined with docetaxel suppresses progression of lung-micrometastasis of MMP exoressing tumor cells in nude mice."Int.J.Cancer. 103. 822-828 (2003)
[文献書誌] Zhang, H.: "A novel bisophosphonate minodronate (YM529) specifically inhibites osteolytic bone metastasis produced by human small cell lung cancer cells in NK-cell depleted SCID mice."Clin.Exp.Metastasis. 20. 153-159 (2003)
[文献書誌] Yano, S.: "Multifunctional interleukin-1 β promotes metastasis of human lung cancer cells in SCID mice via enhanced expression of adhesion-, invasion- and angiogenesis-related molecules."Cancer Sci.. 94. 244-252 (2003)
[文献書誌] Yano, S.: "A report of two bronchioloalveolar carcinoma cases which were rapidly improved by treatment with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 ('Iressa')."Cancer Sci.. 94. 453-458 (2003)
[文献書誌] Kanematsu, T.: "Phosphorylation, but not overexpression of epidermal growth factor receptor is associated with poor prognosis of non-small cell lung cancer patients."Oncol.Res.,. 13. 289-298 (2003)
[文献書誌] Fukuoka, M.: "Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer."J.Clin.Oncol.. 21. 2237-2246 (2003)
[文献書誌] Kakiuchi, S.: "Genome-wide analysis of organ-preferential metastasis of human small cell lung cancer in mice."Mol.Cancer Res.. 1. 458-499 (2003)
[文献書誌] Yano, S.: "Combined therapy by a new bisphosphonate, minodronate (YM529), with chemotherapy for multiple organ metastases of small cell lung cancer cells in SCID mice."Glin.Cancer Res.. 9. 5380-5385 (2003)
[文献書誌] Yano, S.: "Molecular mechanisms of angiogenesis in non-small cell lung cancer, and therapeutics targeting related molecules."Cancer Sci.. 94. 479-485 (2003)
[文献書誌] Yano, S., Goto, H., Yamamoto, A., Kanematsu, T., Sone, S.: "Angiogenesis in the progression of lung cancer."Intern.Med.. 42. 305-309 (2003)
[文献書誌] Yanagawa, H.: "Inhead steroid therapy and hospitalization for bronchial asthma : trend in Tokushima University Hospital."J.Med.Invest.. 50. 72-77 (2003)
[文献書誌] Miki, M.: "Effect on human airway trypsin-like protease on intracellular free Ca^<2+> concentration in human bronchial epithelial cells."J.Med.Invest.. 50. 95-107 (2003)
[文献書誌] Mitani, K.: "Soluble Fas in malignant pleural effusion and its expression in lung cancer cells."Cancer Sci.. 94. 302-307 (2003)
[文献書誌] Nishioka, Y.: "Differential effects ofIL-2 on the generation of alloreactive CTL mediated by murine and human dendritic cells : a critical role for nitric oxide."J Leukocyte Biol.. 73. 621-629 (2003)
[文献書誌] Tada, H.: "Increased binding and chemotactic capacities of PDGF-BB on fibroblasts in radiation pneumonitis."Ratiat.Res.. 159. 805-811 (2003)
[文献書誌] Ogawa, H.: "Adenoviral interleukin-12 gene transduction into human bronchial epithelial cells : up-regulation of pro-inflammatory cytokines and its prevention by corticosteroids."Clin.Exp.Allergy. 33. 921-929 (2003)
[文献書誌] Sano, T.: "Add-on effects of suplatast tosilate in bronchial asthma patients treated with inhaled corticosteroids."Lung,. 181. 227-235 (2003)
[文献書誌] Motoki, Y.: "The expression of chemokine receptor CXCR3 : relevance to disease activity of rheumatoid arthritis."Mod.Rheumatol.. 13. 114-120 (2003)
[文献書誌] Asano, T.: "Increased macrophage inflammatory protein-1 α and -1 β in BAL fluid of bronchiolitis obliterans organizing pneumonia."Respirology. 8. 461-466 (2003)
[文献書誌] Yano, S.: "Methods Mol.Med."Humana Press. 594 (2003)

2003 年度 実績報告書

肺がんの転移・血管新生分子を標的とした生物学的制御法開発

研究代表者

曽根 三郎 徳島大学, 医学部, 教授 (40145024)

研究成果

[文献書誌] Miki, T.: "Parathyroid hormone-related protein (PTHrP) is responsible for production of bone metastasis, but not visceral metastasis, by human small cell lung cancer SBC-5 cells in natural killer cell-depleted SCID mice."Int.J.Cancer. 108. 511-515 (2004)

[文献書誌] Yoneda, K.: "Atimulation of human bronchial epithelial cells by IgE-dependent histamine-releasing factor."Am.J.Physil.Lung Cell Mol.Physiol.. 286. 174-181 (2004)

[文献書誌] Yamamoto, A.: "A third generation matrix metalloproteinase (MMP) Inhibitor (ONO-4817) combined with docetaxel suppresses progression of lung-micrometastasis of MMP exoressing tumor cells in nude mice."Int.J.Cancer. 103. 822-828 (2003)

[文献書誌] Zhang, H.: "A novel bisophosphonate minodronate (YM529) specifically inhibites osteolytic bone metastasis produced by human small cell lung cancer cells in NK-cell depleted SCID mice."Clin.Exp.Metastasis. 20. 153-159 (2003)

[文献書誌] Yano, S.: "Multifunctional interleukin-1 β promotes metastasis of human lung cancer cells in SCID mice via enhanced expression of adhesion-, invasion- and angiogenesis-related molecules."Cancer Sci.. 94. 244-252 (2003)

[文献書誌] Yano, S.: "A report of two bronchioloalveolar carcinoma cases which were rapidly improved by treatment with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 ('Iressa')."Cancer Sci.. 94. 453-458 (2003)

[文献書誌] Kanematsu, T.: "Phosphorylation, but not overexpression of epidermal growth factor receptor is associated with poor prognosis of non-small cell lung cancer patients."Oncol.Res.,. 13. 289-298 (2003)

[文献書誌] Fukuoka, M.: "Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer."J.Clin.Oncol.. 21. 2237-2246 (2003)

[文献書誌] Kakiuchi, S.: "Genome-wide analysis of organ-preferential metastasis of human small cell lung cancer in mice."Mol.Cancer Res.. 1. 458-499 (2003)

[文献書誌] Yano, S.: "Combined therapy by a new bisphosphonate, minodronate (YM529), with chemotherapy for multiple organ metastases of small cell lung cancer cells in SCID mice."Glin.Cancer Res.. 9. 5380-5385 (2003)

[文献書誌] Yano, S.: "Molecular mechanisms of angiogenesis in non-small cell lung cancer, and therapeutics targeting related molecules."Cancer Sci.. 94. 479-485 (2003)

[文献書誌] Yano, S., Goto, H., Yamamoto, A., Kanematsu, T., Sone, S.: "Angiogenesis in the progression of lung cancer."Intern.Med.. 42. 305-309 (2003)

[文献書誌] Yanagawa, H.: "Inhead steroid therapy and hospitalization for bronchial asthma : trend in Tokushima University Hospital."J.Med.Invest.. 50. 72-77 (2003)

[文献書誌] Miki, M.: "Effect on human airway trypsin-like protease on intracellular free Ca^<2+> concentration in human bronchial epithelial cells."J.Med.Invest.. 50. 95-107 (2003)

[文献書誌] Mitani, K.: "Soluble Fas in malignant pleural effusion and its expression in lung cancer cells."Cancer Sci.. 94. 302-307 (2003)

[文献書誌] Nishioka, Y.: "Differential effects ofIL-2 on the generation of alloreactive CTL mediated by murine and human dendritic cells : a critical role for nitric oxide."J Leukocyte Biol.. 73. 621-629 (2003)

[文献書誌] Tada, H.: "Increased binding and chemotactic capacities of PDGF-BB on fibroblasts in radiation pneumonitis."Ratiat.Res.. 159. 805-811 (2003)

[文献書誌] Ogawa, H.: "Adenoviral interleukin-12 gene transduction into human bronchial epithelial cells : up-regulation of pro-inflammatory cytokines and its prevention by corticosteroids."Clin.Exp.Allergy. 33. 921-929 (2003)

[文献書誌] Sano, T.: "Add-on effects of suplatast tosilate in bronchial asthma patients treated with inhaled corticosteroids."Lung,. 181. 227-235 (2003)

[文献書誌] Motoki, Y.: "The expression of chemokine receptor CXCR3 : relevance to disease activity of rheumatoid arthritis."Mod.Rheumatol.. 13. 114-120 (2003)

[文献書誌] Asano, T.: "Increased macrophage inflammatory protein-1 α and -1 β in BAL fluid of bronchiolitis obliterans organizing pneumonia."Respirology. 8. 461-466 (2003)

[文献書誌] Yano, S.: "Methods Mol.Med."Humana Press. 594 (2003)

2003 年度実績報告書

曽根三郎徳島大学, 医学部, 教授 (40145024)