2000 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
研究種目	特定領域研究(C)
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	矢野聖二徳島大学, 医学部・附属病院, 講師 (30294672) 篠原勉徳島大学, 医学部・附属病院, 講師 (70284289) 西岡安彦徳島大学, 医学部, 講師 (70274199) 齋藤政樹国立がんセンター研究所, ウイルス部, 部長 (60012762)
キーワード	肺癌 / 多臓器転移 / 血管新生 / 癌性胸水 / ガングリオシド / 抗体療法 / 分子標的治療 / 免疫療法
研究概要	難治癌とされる肺癌の転移・血管新生因子を分子標的とした制御法の開発を目的に検討を行い、以下の成果を得た。1)臨床上問題となる脳転移と骨転移について、マウスを用い、臨床に近いヒト肺癌細胞の脳転移および骨転移モデルを確立した。2)がん性胸水形成には胸膜浸潤とVEGF高発現の2つのステップが必要であることを明らかにし、さらにVEGF受容体阻害剤の投与で、癌性胸水形成が有意に抑制され、分子標的治療の一つとして臨床応用できる可能性を示した。3)肺腺癌の脳転移モデルを用い、VEGFが拡張血管形成を誘導し脳転移を促進していることを明らかにした。4)腫瘍との相互反応に関与する宿主側細胞としてNK細胞に着目し、NK細胞intactのSCIDマウスを用いてMCP-1遺伝子導入肺癌細胞の転移形成能を検討し、MCP-1により活性化されたNK細胞が転移形成の抑制に重要な役割を果たすことを明らかにした。5)肺癌細胞に比較的選択的に発現しているgangliosideGM2を腫瘍抗原としてとらえ、in vitroにおいてヒト化抗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、ヒト肺癌転移モデルにおいて抗癌剤耐性小細胞肺癌の遠隔転移を抑制することを明らかにし、抗GM2の臨床応用の可能性を示唆した。6)シアロ糖脂質分子群生合成系のキーエンザイムで、ヒト白血病細胞の分化誘導能を持つgangliosideGM3を合成する糖転移酵素(Sialyltransferase-1/ST3GalV)のゲノム構造を明らかにした。この酵素遺伝子をヒト大腸癌HCT116細胞に導入して、GM3を過剰に発現させると癌細胞のアポトーシスが誘導された。今後、転移・血管新生機構についてさらに詳細な分子生物学的解析を進めるとともに、新規分子標的治療の開発に向けた検討を行う予定である。

研究成果

(19件)

すべてその他

すべて文献書誌 (19件)

[文献書誌] Nokihara,H.: "Natural killer cell-dependent suppression of systemic spread of human lung adenocarcinoma cells by monocyte chemoattractant protein-1 gene transfection in severe combined immunodeficient mice."Cancer Res.. 60. 7002-7007 (2000)
[文献書誌] Shinohara,T: "NF-kB-dependent expression of metastasis suppressor KAI1/CD82 gene in lung cancer cell lines expressing mutant p53."Cancer Res.. 61. 673-678 (2001)
[文献書誌] Goto,H.: "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.: "Enhanced efficiency by centrifugal manipulation of adeno virus-mediated interleukin-12 gene transduction into human monocyte-derived dendritic cells."Human Gene Therapy. (発表予定). (2001)
[文献書誌] Hanibuchi,M.: "Human interferon enhances expression of ganglioside GM2 on human lung cancer cells and their susceptibility for anti-ganglioside GM2 monoclonal antibody-dependent cellular cytotoxicity."Oncol.Res.. (発表予定). (2001)
[文献書誌] Parajuli,P.: "Humanized anti-ganglioside GM2 antibody is effective to induce antibody-dependent cell-mediated cytotoxicity in mononuclear cells from lung cancer patients."Cancer Letters. (発表予定). (2001)
[文献書誌] Hanibuchi,M.: "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. (発表予定). (2001)
[文献書誌] Takeuchi,E.: "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. 199-123 (2001)
[文献書誌] Tani,K.: "CD13/aminopeptidase N, a novel chemoattractant for T lymphocytes in pulmonary sarcoidosis."Am.J.Respir.Crit.Care Med.. 161. 1636-1642 (2000)
[文献書誌] Nishimura,N.: "Down-regulation by a new anti-inflammatory compound, FR167653, of differentiation and maturation of human monocytes and bone marrow CD34+ cells to dendritic cells."Int.J.Immunopharmacol.. 22. 501-514 (2000)
[文献書誌] Iwano,J.: "Synergistic effect of combining theophylline and drugs that potentially elevate serum creatine kinase."J.Med.Invest.. 47. 9-13 (2000)
[文献書誌] Yanagawa,H.: "Intrapleural therapy with MDP-Lys (L18), a synthetic derivative of muramyl dipeptide, against malignant pleurisy associated with lung cancer."Lung Cancer. 27. 67-73 (2000)
[文献書誌] Miki,T.: "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. (発表予定). (2001)
[文献書誌] Singh,S.M.: "Augmentation by interleukin-18 of MHC-nonrestricted killer activity of human peripheral blood mononuclear cells in response to interleukin-12."Int.J.Immunopharmacol.. 22. 35-43 (2000)
[文献書誌] Sumitomo,K.: "Expression of a TGF-beta1 inducible gene, TSC-36, causes growth inhibition in human lung cancer cell lines."Cancer lett.. 155. 37-46 (2000)
[文献書誌] Torisu,H.: "Macrophage infiltration correlates with tumjor stage and angiogenesis in human malignant melanoma : possible involvement of TNFalpha and IL-1alpha."Int.J.Cancer. 85. 182-188 (2000)
[文献書誌] Yano,S.: "Production of experimental malignant pleural effusions is dependent on invasion of the pleura and expression of vascular endothelial growth factor/vascular permeability factor by...."Am.J.Pathol.. 157. 1893-1903 (2000)
[文献書誌] Yano,S.: "Treatment for malignant pleural effusion of human lung adenocarcinoma by inhibition of vascular endothelial growth factor receptor tyrosine kinase phosphorylation."Clin.Cancer Res.. 6. 957-965 (2000)
[文献書誌] Yano,S.: "Expression of vascular endothelial growth factor is essential but not sufficient for production and growth of brain metastasis."Cancer Res.. 60. 4959-4967 (2000)

2000 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] Nokihara,H.: "Natural killer cell-dependent suppression of systemic spread of human lung adenocarcinoma cells by monocyte chemoattractant protein-1 gene transfection in severe combined immunodeficient mice."Cancer Res.. 60. 7002-7007 (2000)

[文献書誌] Shinohara,T: "NF-kB-dependent expression of metastasis suppressor KAI1/CD82 gene in lung cancer cell lines expressing mutant p53."Cancer Res.. 61. 673-678 (2001)

[文献書誌] Goto,H.: "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.: "Enhanced efficiency by centrifugal manipulation of adeno virus-mediated interleukin-12 gene transduction into human monocyte-derived dendritic cells."Human Gene Therapy. (発表予定). (2001)

[文献書誌] Hanibuchi,M.: "Human interferon enhances expression of ganglioside GM2 on human lung cancer cells and their susceptibility for anti-ganglioside GM2 monoclonal antibody-dependent cellular cytotoxicity."Oncol.Res.. (発表予定). (2001)

[文献書誌] Parajuli,P.: "Humanized anti-ganglioside GM2 antibody is effective to induce antibody-dependent cell-mediated cytotoxicity in mononuclear cells from lung cancer patients."Cancer Letters. (発表予定). (2001)

[文献書誌] Hanibuchi,M.: "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. (発表予定). (2001)

[文献書誌] Takeuchi,E.: "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. 199-123 (2001)

[文献書誌] Tani,K.: "CD13/aminopeptidase N, a novel chemoattractant for T lymphocytes in pulmonary sarcoidosis."Am.J.Respir.Crit.Care Med.. 161. 1636-1642 (2000)

[文献書誌] Nishimura,N.: "Down-regulation by a new anti-inflammatory compound, FR167653, of differentiation and maturation of human monocytes and bone marrow CD34+ cells to dendritic cells."Int.J.Immunopharmacol.. 22. 501-514 (2000)

[文献書誌] Iwano,J.: "Synergistic effect of combining theophylline and drugs that potentially elevate serum creatine kinase."J.Med.Invest.. 47. 9-13 (2000)

[文献書誌] Yanagawa,H.: "Intrapleural therapy with MDP-Lys (L18), a synthetic derivative of muramyl dipeptide, against malignant pleurisy associated with lung cancer."Lung Cancer. 27. 67-73 (2000)

[文献書誌] Miki,T.: "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. (発表予定). (2001)

[文献書誌] Singh,S.M.: "Augmentation by interleukin-18 of MHC-nonrestricted killer activity of human peripheral blood mononuclear cells in response to interleukin-12."Int.J.Immunopharmacol.. 22. 35-43 (2000)

[文献書誌] Sumitomo,K.: "Expression of a TGF-beta1 inducible gene, TSC-36, causes growth inhibition in human lung cancer cell lines."Cancer lett.. 155. 37-46 (2000)

[文献書誌] Torisu,H.: "Macrophage infiltration correlates with tumjor stage and angiogenesis in human malignant melanoma : possible involvement of TNFalpha and IL-1alpha."Int.J.Cancer. 85. 182-188 (2000)

[文献書誌] Yano,S.: "Production of experimental malignant pleural effusions is dependent on invasion of the pleura and expression of vascular endothelial growth factor/vascular permeability factor by...."Am.J.Pathol.. 157. 1893-1903 (2000)

[文献書誌] Yano,S.: "Treatment for malignant pleural effusion of human lung adenocarcinoma by inhibition of vascular endothelial growth factor receptor tyrosine kinase phosphorylation."Clin.Cancer Res.. 6. 957-965 (2000)

[文献書誌] Yano,S.: "Expression of vascular endothelial growth factor is essential but not sufficient for production and growth of brain metastasis."Cancer Res.. 60. 4959-4967 (2000)

2000 年度実績報告書

曽根三郎徳島大学, 医学部, 教授 (40145024)