2001 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	山本昭彦徳島大学, 医学部・附属病院, 助手 (10332818) 矢野聖二徳島大学, 医学部・附属病院, 講師 (30294672)
キーワード	肺癌 / 多臓器転移 / 骨転移 / 血管新生 / 浸潤 / 樹状細胞 / 免疫遺伝子治療 / KAI1 / CD82
研究概要	肺癌克服には多臓器転移の分子機構解明と臓器微小環境条件を考慮した新たな分子標的の探索、さらに生物学的制御法の開発に関する基礎研究が必要である。QOLを阻害する骨転移の病態解明および新規治療法開発を目的に、ヒト肺癌細胞の骨転移を含む多臓器転移モデルを確立した。また、P糖蛋白質を発現した多剤耐性小細胞肺癌の多臓器転移形成に対し、多剤耐性克服薬MS-209が抗癌剤との併用にて転移抑制効果を増強することを明らかにした。一方、ganglioside GM2は小細胞癌をはじめとした肺癌細胞株に高発現しており、抗体治療の格好の標的となる。in vitroにおいてヒト化抗ganglioside GM2抗体が肺癌患者の単核球の抗体依存性細胞障害反応を介し小細胞肺癌を障害することを明らかにした。また、転移抑制遺伝子として同定されたKAI1/CD82をヒト肺癌細胞に遺伝子導入する接着分子として原発巣からの腫瘍細胞の遊離を抑制する反面、血中からの腫瘍細胞の排除が不十分な場合には遠隔臓器での転移形成を促進することを明らかにした。宿主側細胞の機能を利用した生物学的療法として、樹状細胞に着目しTリンパ球に対する抗原提示細胞である樹状細胞が、NK活性を増強することを明らかにした。また、遺伝子導入樹状細胞を用いた癌免疫遺伝子療法の確立も試みており、ex vivoでのアデノウイルスヴェクターを使った樹状細胞への遺伝子導入に際し、遠心力を併用することにより細胞毒性もなく遺伝子導入効率を格段に上昇させることに成功した。本法の利用によりIL-12遺伝子を樹状細胞へ効率よく導入し抗原提示能が増強することを明らかにし、他のサイトカイン遺伝子導入効果の検討も含めて効果的な遺伝子修飾樹状細胞の調整方法を検討していく予定である。

研究成果

(21件)

すべてその他

すべて文献書誌 (21件)

[文献書誌] Takeuchi, E. et al.: "IL-12-induced production of IL-10 and interferon-gamma by mononuclear cells in lung cancer-associated malignant pleural effusions"Lung Cancer. 35. 171-177 (2002)
[文献書誌] Shinohara, T. et al.: "NF-kB-dependent expression of metastasis suppressor KAII/CD82 gene in lung cancer cell lines expressing mutant p53"Cancer Res.. 61. 673-678 (2001)
[文献書誌] Shinohara, T. et al.: "Transduction of KAII /CD82 cDNA promotes hematogenous spread of human lung-cancer cells in natural killer cell-depleted SCID mice"Int. J. Cancer. 94. 16-23 (2002)
[文献書誌] Goto, H. et al.: "Gamma interferon-dependent induction of thymidine phosphorylase/platelet-derived endothelial growth factor through gamma-activated sequence-like element in human macrophages"Cancer Res.. 61. 469-473 (2001)
[文献書誌] Nishimura, N. et al.: "Enhanced efficiency by centrifugal manupulation of adenovirus-mediated interleukin 12 gene transduction into human monocyte-derived dendritic cells"Hum. Gene Ther.. 12. 333-346 (2001)
[文献書誌] Nishimura, N. et al.: "Novel centrifugal method for simple and highly efficient adenovirus-mediated green fluorescence protein gene transduction into human monocyte-deried dendritic cells"J. Immunological. Methods.,. 253. 113-124 (2001)
[文献書誌] Takeuchi, E. et al.: "Interleukin (IL-) 15 has less activity than IL-2 to promote type 2 cytokine predominance in tumour-associated mononuclear cells form lung cancer patients"Cytokine. 13. 119-123 (2001)
[文献書誌] Parajuli, P. et al.: "Humanized anti-ganglioside GM2 antibody is effective to induce antibody-dependent cell-mediated cytotoxicity in mononuclear cells from lung cancer patients"Cancer Lett.. 163. 179-184 (2001)
[文献書誌] Hanibuchi, M. et al.: "Immunological circumvention of multiple organ metastases of multidrug resistant human small cell lung cancer cells by mouse-human chimeric anti-ganglioside GM2 antibody KM966"Clin. Exp. Metastasis. 18. 353-360 (2001)
[文献書誌] Cui, P.et al.: "A novel bioactive 31-amino acid endothelin-1 is a potent chemotactic peptide for human neutrophils and monocytes"J. Leukoc. Biol.. 70. 306-312 (2001)
[文献書誌] Miki, T. et al.: "Bone metastasis model with multi-organ dissemination of human small cell lung cancer (SBC-5) cells in natural killer-cell depleted SCID mice"Oncol. Res.. 12. 209-217 (2001)
[文献書誌] Tanaka, H. et al.: "CD4O and IFN-gamma dependent T cell activation by human bronchial epithelial cells"J. Med. Invest.. 48. 109-117 (2001)
[文献書誌] Suzuki, Y. et al.: "Efficient generation of dendritic cells from alveolar and pleural macrophages as well as blood monocytes in patients with lung cancer"Lung Cancer. 34. 195-205 (2001)
[文献書誌] Ge, N.et al.: "Interferon-gamma activates outwardly rectifying chloride channels in the human bronchial epithelial cell line BEAS-2B"J. Med. Invest.. 48. 97-101 (2001)
[文献書誌] Sone, S. et al.: "Molecular pathogenesis of lung cancer and its molecular targeted therapy"Internal Med.. 40(2). 167-170 (2001)
[文献書誌] Huang, L. et al.: "Thrombin promotes fibroblast proliferation during the early stages of experimental radiation pneumonitis"Radiation Res.. 156. 45-52 (2001)
[文献書誌] Nokihara, H. et al.: "A new quinoline derivative MS-209 reverses multidrug resistance and inhibits multiorgan metastases by P-glycoprotein-expressing human small cell lung cancer cells"Jpn.J.Cancer Res.. 92. 785-792 (2001)
[文献書誌] Ogushi, F. et al.: "Autoantibodies to IL-Iα in sera from rapidly progressive idiopathic pulmonary fibrosis"J. Med. Invest.. 48. 181-189 (2001)
[文献書誌] Tani, K. et al.: "Protease-induced leukocyte chemotaxis and activation : Roles in host defense and inflammation"J. Med. Invest.. 48. 133-141 (2001)
[文献書誌] Hase, K. et al.: "Increased CCR4 expression in active systemic lupus erythematosus"J. Leukoc. Biol.. 70. 749-755 (2001)
[文献書誌] Nishioka, Y. et al.: "Human monocyte-derived and CD83+ blood dendritic cells enhance NK cell-mediated cytotoxicity"Eur. J. Immunol.. 31. 2633-2641 (2001)

2001 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] Takeuchi, E. et al.: "IL-12-induced production of IL-10 and interferon-gamma by mononuclear cells in lung cancer-associated malignant pleural effusions"Lung Cancer. 35. 171-177 (2002)

[文献書誌] Shinohara, T. et al.: "NF-kB-dependent expression of metastasis suppressor KAII/CD82 gene in lung cancer cell lines expressing mutant p53"Cancer Res.. 61. 673-678 (2001)

[文献書誌] Shinohara, T. et al.: "Transduction of KAII /CD82 cDNA promotes hematogenous spread of human lung-cancer cells in natural killer cell-depleted SCID mice"Int. J. Cancer. 94. 16-23 (2002)

[文献書誌] Goto, H. et al.: "Gamma interferon-dependent induction of thymidine phosphorylase/platelet-derived endothelial growth factor through gamma-activated sequence-like element in human macrophages"Cancer Res.. 61. 469-473 (2001)

[文献書誌] Nishimura, N. et al.: "Enhanced efficiency by centrifugal manupulation of adenovirus-mediated interleukin 12 gene transduction into human monocyte-derived dendritic cells"Hum. Gene Ther.. 12. 333-346 (2001)

[文献書誌] Nishimura, N. et al.: "Novel centrifugal method for simple and highly efficient adenovirus-mediated green fluorescence protein gene transduction into human monocyte-deried dendritic cells"J. Immunological. Methods.,. 253. 113-124 (2001)

[文献書誌] Takeuchi, E. et al.: "Interleukin (IL-) 15 has less activity than IL-2 to promote type 2 cytokine predominance in tumour-associated mononuclear cells form lung cancer patients"Cytokine. 13. 119-123 (2001)

[文献書誌] Parajuli, P. et al.: "Humanized anti-ganglioside GM2 antibody is effective to induce antibody-dependent cell-mediated cytotoxicity in mononuclear cells from lung cancer patients"Cancer Lett.. 163. 179-184 (2001)

[文献書誌] Hanibuchi, M. et al.: "Immunological circumvention of multiple organ metastases of multidrug resistant human small cell lung cancer cells by mouse-human chimeric anti-ganglioside GM2 antibody KM966"Clin. Exp. Metastasis. 18. 353-360 (2001)

[文献書誌] Cui, P.et al.: "A novel bioactive 31-amino acid endothelin-1 is a potent chemotactic peptide for human neutrophils and monocytes"J. Leukoc. Biol.. 70. 306-312 (2001)

[文献書誌] Miki, T. et al.: "Bone metastasis model with multi-organ dissemination of human small cell lung cancer (SBC-5) cells in natural killer-cell depleted SCID mice"Oncol. Res.. 12. 209-217 (2001)

[文献書誌] Tanaka, H. et al.: "CD4O and IFN-gamma dependent T cell activation by human bronchial epithelial cells"J. Med. Invest.. 48. 109-117 (2001)

[文献書誌] Suzuki, Y. et al.: "Efficient generation of dendritic cells from alveolar and pleural macrophages as well as blood monocytes in patients with lung cancer"Lung Cancer. 34. 195-205 (2001)

[文献書誌] Ge, N.et al.: "Interferon-gamma activates outwardly rectifying chloride channels in the human bronchial epithelial cell line BEAS-2B"J. Med. Invest.. 48. 97-101 (2001)

[文献書誌] Sone, S. et al.: "Molecular pathogenesis of lung cancer and its molecular targeted therapy"Internal Med.. 40(2). 167-170 (2001)

[文献書誌] Huang, L. et al.: "Thrombin promotes fibroblast proliferation during the early stages of experimental radiation pneumonitis"Radiation Res.. 156. 45-52 (2001)

[文献書誌] Nokihara, H. et al.: "A new quinoline derivative MS-209 reverses multidrug resistance and inhibits multiorgan metastases by P-glycoprotein-expressing human small cell lung cancer cells"Jpn.J.Cancer Res.. 92. 785-792 (2001)

[文献書誌] Ogushi, F. et al.: "Autoantibodies to IL-Iα in sera from rapidly progressive idiopathic pulmonary fibrosis"J. Med. Invest.. 48. 181-189 (2001)

[文献書誌] Tani, K. et al.: "Protease-induced leukocyte chemotaxis and activation : Roles in host defense and inflammation"J. Med. Invest.. 48. 133-141 (2001)

[文献書誌] Hase, K. et al.: "Increased CCR4 expression in active systemic lupus erythematosus"J. Leukoc. Biol.. 70. 749-755 (2001)

[文献書誌] Nishioka, Y. et al.: "Human monocyte-derived and CD83+ blood dendritic cells enhance NK cell-mediated cytotoxicity"Eur. J. Immunol.. 31. 2633-2641 (2001)

2001 年度実績報告書

曽根三郎徳島大学, 医学部, 教授 (40145024)