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/領域番号: 12217099
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 徳島大学
• 研究代表者: 曽根 三郎 徳島大学, 大学院・ヘルスバイオサイエンス研究部, 教授 (40145024)
• 研究分担者: 矢野 聖二 徳島大学, 医学部・歯学部附属病院, 講師 (30294672) ; 埴淵 昌毅 徳島大学, 医学部・歯学部附属病院, 講師 (80335794) ; 山本 昭彦 徳島大学, 医学部附属病院, 助手 (10332818) ; 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)
• 研究期間 (年度): 2000 – 2004
• 研究課題ステータス: 完了 (2004年度)
• 配分額: 69,200千円 (直接経費: 69,200千円); 2004年度: 12,000千円 (直接経費: 12,000千円); 2003年度: 12,200千円 (直接経費: 12,200千円); 2002年度: 12,000千円 (直接経費: 12,000千円); 2001年度: 13,500千円 (直接経費: 13,500千円); 2000年度: 19,500千円 (直接経費: 19,500千円)
• キーワード: 肺癌 / 血管新生 / PTHrP / VEGF / 癌性胸水 / VEGF受容体 / 骨転移 / 血管標的薬 / 多臓器転移 / 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 / 浸潤 / 樹状細胞 / 免疫遺伝子治療 / KAI1 / CD82 / ガングリオシド / 抗体療法 / 免疫療法

研究概要

肺癌の転移・血管新生分子を標的とした治療開発に向けた検討を行い、以下の成果を得た。
1、ヒト小細胞肺癌株SBC-5が、悪性腫瘍の高カルシウム血症の原因物質Parathyroid hormone related peptide(PTHrP)を過剰発現していることを確認した。また、SBC-5をNK細胞除去SCIDマウスに静注することで骨転移を含む多臓器転移が形成されることを明らかにした。さらに、抗PTHrP中和抗体が骨転移形成を特異的に抑制したことから、SBC-5の骨転移形成にPTHrPが必須の因子であることが明らかとなった。
2、VEGFを過剰発現する高転移性ヒト肺腺癌株PC14PE6をヌードマウスに静注し肺転移と癌性胸水を形成するモデルにおいて、VEGF受容体(VEGFR)阻害薬ZD6474が肺転移巣の増大を抑制し、さらに癌性胸水形成をほぼ完全に阻害することを明らかにした。その機序はZD6474が腫瘍血管内皮細胞のVEGFR2リン酸化阻害により肺転移巣で血管新生を阻害することに加え、ZD6474がVEGFにより誘導される血管透過性を抑制した可能性も考えられた。
3、チュブリン阻害薬であるZD6126が、PC14PE6の肺転移巣において、投与24時間以内に腫瘍血管内皮細胞選択的にアポトーシスを誘導すること、抗癌剤(CDDP)を併用することによりZD6126のアポトーシス誘導が増強されること、ZD6126とCDDPの併用療法がPC14PE6の肺転移形成を抑制することを明らかにした。

研究成果

• [雑誌論文] Synthesis and secretion of interleukin-15 by freshly isolated human bronchial epithelial cells. (2004)
  • 著者名/発表者名: Ge, N.
  • 雑誌名: Int Arch Allergy Immunol. 135・3 ページ: 235-242
• [雑誌論文] Sensitization of tumor-associated endothelial cell apoptosis by the novel vascular-targeting agent ZD6126 in combination with cisplatin. (2004)
  • 著者名/発表者名: Goto, H.
  • 雑誌名: Clip Cancer Res. 10・22 ページ: 7671-7676
• [雑誌論文] Prediction of sensitivity of advanced non-small cell lung cancers to gefitinib (Iressa, ZD1839). (2004)
  • 著者名/発表者名: Kakiuchi, S.
  • 雑誌名: Hum Mol Genet. 13・24 ページ: 3029-3043
• [雑誌論文] A case of early-stage lung cancer detected by autofluorescence bronchoscopy. (2004)
  • 著者名/発表者名: Hasnibuchi, M.
  • 雑誌名: J Med Invest. 51・3,4 ページ: 234-237
• [雑誌論文] 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. (2004)
  • 著者名/発表者名: Miki, T.
  • 雑誌名: Int J Cancer. 108・4 ページ: 511-515
• [雑誌論文] Expression of toll-like receptor 4 on dendritic cells is significiant for anticancer effect of dendritic cell-based immunotherapy in combination with an active component of OK-432, a streptococcal preparation. (2004)
  • 著者名/発表者名: Okamoto, M.
  • 雑誌名: Cancer Res, 64・15 ページ: 5461-5470
• [雑誌論文] Atimulation of human bronchial epithelial cells by IgE-dependent histamine-releasing factor. (2004)
  • 著者名/発表者名: Yoneda, K.
  • 雑誌名: Am J Physil Lung Cell Mol Physiol. 286・1 ページ: 174-181
• [雑誌論文] Ebselen inhibits tumor necrosis factor-a-induced c-Jun N-terminal kinase activation and adhesion molecule expression in endothelial cells. (2004)
  • 著者名/発表者名: Yoshizumi, M.
  • 雑誌名: Exp Cell Res. 292・1 ページ: 1-10
• [雑誌論文] Re-treatment of lung adenocarcinoma patients with gefitinib who had experienced favorable results from their initial treatment with this selective epidermalgrowth factor receptor inhibitor : a report of three cases.
  • 著者名/発表者名: Yano, S.
  • 雑誌名: Oncol Res. (in press)
• [雑誌論文] Imatinib as a novel anti-fibrotic agent in bleomycin-induced pulmonary fibrosis in mice.
  • 著者名/発表者名: Aono, Y.
  • 雑誌名: Am J Respir Crit Care Med. (in press)
• [雑誌論文] ZD6474, an inhibitor of vascular endothelial growth factor receptortyrosine kinase with additional activity against epidermal growth factor receptor tyrosine kinase, inhibits growth of lung metastases in a non-small cell lung cancer model.
  • 著者名/発表者名: Matsumori, Y.
  • 雑誌名: Clin Exp Metastasis (in press)
• [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)
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• [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)
• [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 expressing 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. (in press).
• [文献書誌] Mitani, K.: "Soluble Fas in malignant pleural effusion and its expression in lung cancer calls"Cancer Science. (in press).
• [文献書誌] Nishioka, Y.: "Differential effects of IL-12 on the generation of alloreactive CTL mediated by murine and human dendritic cells : A critical role for nitric oxide"J. Leukoc. Biol.. (in press).
• [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-a angiogenesis-related molecules"Cancer Science. (in press).
• [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 Science. (in press).
• [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.. (in press).
• [文献書誌] Motoki, Y.: "The expression of chemokine receptor CXCR3 : relevance to disease activity of rheumatoid arthritis"Mod. Rhematol.. (in press).
• [文献書誌] Tada, H.: "Increased binding and chemotactic capacities of PDGF-BB on fibroblasts in radiation pneumonitis"Radiat. Res.. (in press).
• [文献書誌] Dan, H.: "Tani, K., Hase, K., Shimizu, T., Tamiya, H., Biraa, Y., Huang, L., Yanagawa, H., Sone, S. : CD13/aminopeptidase N in collagen vascular diseases"Rheumatol. Int.. (in press).
• [文献書誌] Goto, H.: "Activity of a new vascular targeting agent, ZD6126, in pulmonary metastases by human lung adenocarcinoma in nude mice"Cancer Res.. 62. 3711-3715 (2002)
• [文献書誌] Shiraga, M.: "Organ heterogeneity of host-derived matrix metalloproteinase expression and its involvement in multiple-organ metastasis by lung cancer cell lines"Cancer Res.. 62. 5967-5973 (2002)
• [文献書誌] Nishioka, M.: "MYO18B, a candidate tumor suppressor gene at chromosome 22q12.1, deleted, mutated, and methylated in human lung cancer"Proc Natl Acad Sci USA. 99. 12269-12274 (2002)
• [文献書誌] Shimizu, T.: "CD13/aminopeptidase N-induced lymphocyte involvement in inflamed joints of patients with rheumatoid arthritis"Arthritis Rheum. 46. 2330-2338 (2002)
• [文献書誌] Takeuchi, E.: "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] Sei, H.: "Age-related changes in control of blood pressure and heart rate"Sleep. 25. 279-285 (2002)
• [文献書誌] Ogawa, H.: "Interleukin(IL)-12 gene transduction and its functional expression into human bronchial epithelial cells(BEAS-2B) by adenovirus vector"J. Med. Invest. 49. 74-82 (2002)
• [文献書誌] Nishioka, Y.: "Genetic modification of dendritic cells and its application for cancer immunotherapy"J. Med. Invest. 49. 7-17 (2002)
• [文献書誌] Itokawa T.: "Antiangiogenic effect by SU5416 is partly attributable to inhibition of Flt-1 receptor signaling"Mol. Cancer Therapeu.. 5. 295-302 (2002)
• [文献書誌] Huang, L.: "Tani, K., Ogushi, F., Ogawa, H., Shimizu, T., Motoki, Y., Moriguchi, H., Sone, S.: Role of CD13/aminopeptidase N in rat lymphocytic alveolitis caused by thoracic irradiation. 157 : 191-198, 2002"Radiat. Res.. 157. 191-198 (2002)
• [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)
• [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)