2002 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, 助手 (80335794) 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 / 分子標的治療 / 血管新生 / MMP / 臓器微小環境 / 血管標的薬
研究概要	臨床を反映した肺癌の多臓器転移モデルを用い、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、以下の成果を得た。 FIZ法を用いてマウス正常臓器のMMP(gelatinase)活性を検討し、MMP活性は、肺では全く検出されなかったが、肝では高く、腎で低かったことから、MMP活性の発現には臓器間格差があることを明らかとなった。また、その由来に関わらず腫瘍病巣でMMPが発現されている場合には、MMP阻害薬は転移形成を阻害しうることを明らかにした。さらに、抗癌剤との併用により、MMP阻害薬の肺微小転移巣に対する増大阻害効果を増強できることを示した。 Tubulin阻害薬であるZD6126が、投与24時間以内に腫瘍血管内皮細胞特異的にアポトーシスを誘導すること、連日投与により非小細胞肺癌株の肺転移形成を阻害することを明らかにした。ZD6126は、血管新生阻害薬とは異なり既存の腫瘍血管に作用するため血管標的薬に分類されるが、その効果を増強するためには既存の抗癌剤や血管新生阻害薬、非小細胞肺癌に対し腫瘍縮小効果が期待できる上皮成長因子(EGF)受容体阻害薬などとの併用が必要であり、現在併用療法の効果を検討中である。骨転移は肺癌において高頻度にみられ、患者のQOLを阻害する重大な問題である。ヒト小細胞肺癌株を用いた骨転移を含む多臓器転移モデルにおいて、第三世代ビスフォスフォネート(Minodronate)が破骨細胞数を減少させ骨転移形成を選択的に抑制することを示した。今後は、既存の抗癌剤との併用や新規分子標的治療同士の併用のみならず、分子標的治療と癌免疫遺伝子療法の併用療法の可能性も検討していく予定である。

研究成果

(20件)

すべてその他

すべて文献書誌 (20件)

[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)

2002 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] 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)

2002 年度実績報告書

曽根三郎徳島大学, 医学部, 教授 (40145024)