2001 Fiscal Year Annual Research Report

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

Research Project

Project/Area Number	12217099
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)	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)
Keywords	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
Research Abstract	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。

Research Products

(21 results)

All Other

All Publications (21 results)

[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] Tanaka, H. et al.: "CD4O and IFN-gamma dependent T cell activation by human bronchial epithelial cells"J. Med. Invest.. 48. 109-117 (2001)
[Publications] 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)
[Publications] 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)
[Publications] Sone, S. et al.: "Molecular pathogenesis of lung cancer and its molecular targeted therapy"Internal Med.. 40(2). 167-170 (2001)
[Publications] Huang, L. et al.: "Thrombin promotes fibroblast proliferation during the early stages of experimental radiation pneumonitis"Radiation Res.. 156. 45-52 (2001)
[Publications] 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)
[Publications] Ogushi, F. et al.: "Autoantibodies to IL-Iα in sera from rapidly progressive idiopathic pulmonary fibrosis"J. Med. Invest.. 48. 181-189 (2001)
[Publications] Tani, K. et al.: "Protease-induced leukocyte chemotaxis and activation : Roles in host defense and inflammation"J. Med. Invest.. 48. 133-141 (2001)
[Publications] Hase, K. et al.: "Increased CCR4 expression in active systemic lupus erythematosus"J. Leukoc. Biol.. 70. 749-755 (2001)
[Publications] 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 Fiscal Year Annual Research Report

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

Principal Investigator

曽根 三郎 徳島大学, 医学部, 教授 (40145024)

Research Products

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

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

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

[Publications] 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)

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

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

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

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

曽根三郎徳島大学, 医学部, 教授 (40145024)