1999 Fiscal Year Annual Research Report

肺がんの薬剤耐性と転移因子を分子標的とした免疫遺伝子治療

Research Project

Project/Area Number	08266242
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)	篠原勉徳島大学, 医学部・附属病院, 助手 (70284289) 西岡安彦徳島大学, 医学部, 講師 (70274199) 清水英治徳島大学, 医学部, 講師 (50187449)
Keywords	肺がん / 転移 / 多剤耐性 / P糖蛋白質 / 遺伝子治療 / 免疫療法 / SCIDマウス
Research Abstract	多剤耐性(MDR)癌細胞が発現するP糖蛋白質(P-gp)に対する抗体MRK16はマクロファージ(MΦ)の抗体依存性細胞障害反応(ADCC)を誘導し、MDR癌細胞を障害する。本年度は、肺癌の遠隔転移とMDRの克服を目的に、MDR肺癌細胞の多臓器転移に対する抗P-gp抗体の治療効果を検討し、更にMΦのADCCを強化すべくMDR肺癌細胞へMΦ活性化因子M-CSFまたはMΦ遊走因子MCP-1の遺伝子導入を行い、抗P-gp抗体との併用効果を検討し、以下の成果を得た。1、ヒト小細胞肺癌株H69及びP-gp陽性MDR株H69/VPはNK細胞除去SCIDマウスに静注した場合、多臓器(肝、腎、リンパ節)転移を形成した。ビンデシン治療はH69の転移形成を抑制したがH69/VPのそれを全く抑制せず、H69/VPの転移巣での抗癌剤耐性を確認した。2、抗P-gp抗体(マウス抗体MRK16とキメラ抗体MH162)は用量依存性にH69/VPの多臓器転移形成を抑制した。3、H69/VPにM-CSFまたはMCP-1遺伝子を導入し生物活性を有するM-CSFまたはMCP-1産生株を得た。これらの株を用い上記転移モデルにてMRK16治療の転移抑制効果を検討した。(1)H69/VPに対する遺伝子導入はin vitroでの増殖能及びP-gp発現に影響しなかった。(2)M-CSF遺伝子導入はMΦ活性化により肝及びリンパ節転移を抑制したが腎転移には影響しなかった。しかし、MRK16併用にて各臓器の転移形成が完全に抑制された。(3)MCP-1遺伝子導入は転移形成に影響しなかったが、MRK16併用において転移抑制効果を有意に増強した。その機序として、転移巣で産生されたMCP-1がMΦ集積を促進しADCCを増強させたと考えられた。以上より、MDR肺癌に対する抗転移療法を開発する上で、免疫エフェクター細胞の転移局所への動員と活性化を試みるアプローチの重要性が示唆された。

Research Products

(19 results)

All Other

All Publications (19 results)

[Publications] Sone.S.,: "Heterogeneity of multiorgan metastases of human lung cancer cells genetically engineered to produce cytokines and reversal using chimeric monoclonal antibodies in natural killer cell-depleted severe combined immunodeficient mice"Cancer Chemother.Pharmacol.,. 43. S26-31 (1999)
[Publications] Nokihara,H.,: "Monocyte chemoattractant protein-1 gene modification of multidrug-resistant human lung cancer enhances antimetastatic effect of therapy with anti-P-glycoprotein antibody in SCID mice"Int.J.Cancer,. 80. 773-780 (1999)
[Publications] Yano,S.,: "Combined therapy with anti-P-glycoprotein antibody and macrophage colony-stimulating factor gene transduction for multiorgan metastases of multidrug-resistant human small cell lung cancer in NK cell-depleted SCID mice"Int.J.Cancer,. 82. 105-111 (1999)
[Publications] Nakamura,K.,: "Apoptosis induction of human lung cancer cell line in multicellular heterospheroids with humanized antiganglioside GM2 monoclonal antibody"Cancer Res.,. 59. 5323-2330 (1999)
[Publications] 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)
[Publications] Yanagawa,H.,: "Vascular endothelial growth factor in malignant pleural effusion associated with lung cancer"Cancer Immunol.Immunother.,. 48. 396-400 (1999)
[Publications] Parajuli,P.,: "Cytolysis of human dendritic cells by autologous lymphokine-activated killer cells : participation of both T cells and NK cells in the killing"J.Leukoc.Biol.,. 65. 764-770 (1999)
[Publications] Kawano,T.: "Comparison of suppressive effects of a new anti-inflammatory compound, FR167653, on production of PGE2 and inflammatory cytokines, human monocytes, and alveolar macrophages in response to endotoxin"J.Leukoc.Biol.,. 65. 80-86 (1999)
[Publications] Yamamoto,A.,: "Infrequent presence of anti-c-Myc antibodies and absence of c-Myc oncoprotein in sera from lung cancer patients"Oncology,. 56. 129-133 (1999)
[Publications] Sumitomo,K.,: "Activation of RB tumor suppressor protein and growth suppression of small cell lung carcinoma cells by reintroduction of p16INK4A gene"Int.J.Oncol.,. 14. 1075-1080 (1999)
[Publications] Yanagawa,H.,: "Presence and potent immunosuppressive role of interleukin-10 in malignant pleural effusion due to lung cancer"Cancer Lett.,. 136. 27-32 (1999)
[Publications] Parajuli,P.,: "Therapeutic efficacy of a new topoisomerase I and II inhibitor TAS-103, against both P-glycoprotein-expressing and -nonexpressing drug-resistant human small-cell lung cancer"Oncol.Res.,. 11. 219-224 (1999)
[Publications] Namikawa,O.,: "Analysis of antibodies to p16INK4A tumor suppressor gene products in lung cancer patients"Int.J.Oncol.,. 14. 681-685 (1999)
[Publications] Ichikawa,W.,: "Characterization of immunoglobulin binding factor in sputum from patients with chronic airway diseases"Respirology,. 4. 375-381 (1999)
[Publications] Yanagawa,H.,: "Production of interleukin-10 by alveolar macrophages from lung cancer patients"Respir.Med.,. 93. 666-671 (1999)
[Publications] Yanagawa,H.,: "A case of resectable lung adenocarcinoma associated with sarcoidosis"Med.Oncol.,. 16. 216-220 (1999)
[Publications] Ogushi,F.,: "Decreased prostaglandin E2 synthesis by lung fibroblasts isolated from rats with bleomycin-induced lung fibrosis"Int.J.Exp.Pathol.,. 80. 41-49 (1999)
[Publications] Nishimura,N.,: "Down-regulation by a new anti-inflammatory compound, FR167653, of differentiation and maturation of human monocytes and bone marrow CD34+ cells to dentritic cells"Int.J.Immunopharmacol.. (in press).
[Publications] Sumitomo,K.,: "Expression of a TGF-b1 inducible gene, TSC-36, causes growth inhibition in human lung cancer cell lines"Cancer Letters. (in press).

1999 Fiscal Year Annual Research Report

肺がんの薬剤耐性と転移因子を分子標的とした免疫遺伝子治療

Principal Investigator

曽根 三郎 徳島大学, 医学部, 教授 (40145024)

Research Products

[Publications] Nokihara,H.,: "Monocyte chemoattractant protein-1 gene modification of multidrug-resistant human lung cancer enhances antimetastatic effect of therapy with anti-P-glycoprotein antibody in SCID mice"Int.J.Cancer,. 80. 773-780 (1999)

[Publications] Yano,S.,: "Combined therapy with anti-P-glycoprotein antibody and macrophage colony-stimulating factor gene transduction for multiorgan metastases of multidrug-resistant human small cell lung cancer in NK cell-depleted SCID mice"Int.J.Cancer,. 82. 105-111 (1999)

[Publications] Nakamura,K.,: "Apoptosis induction of human lung cancer cell line in multicellular heterospheroids with humanized antiganglioside GM2 monoclonal antibody"Cancer Res.,. 59. 5323-2330 (1999)

[Publications] 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)

[Publications] Yanagawa,H.,: "Vascular endothelial growth factor in malignant pleural effusion associated with lung cancer"Cancer Immunol.Immunother.,. 48. 396-400 (1999)

[Publications] Parajuli,P.,: "Cytolysis of human dendritic cells by autologous lymphokine-activated killer cells : participation of both T cells and NK cells in the killing"J.Leukoc.Biol.,. 65. 764-770 (1999)

[Publications] Kawano,T.: "Comparison of suppressive effects of a new anti-inflammatory compound, FR167653, on production of PGE2 and inflammatory cytokines, human monocytes, and alveolar macrophages in response to endotoxin"J.Leukoc.Biol.,. 65. 80-86 (1999)

[Publications] Yamamoto,A.,: "Infrequent presence of anti-c-Myc antibodies and absence of c-Myc oncoprotein in sera from lung cancer patients"Oncology,. 56. 129-133 (1999)

[Publications] Sumitomo,K.,: "Activation of RB tumor suppressor protein and growth suppression of small cell lung carcinoma cells by reintroduction of p16INK4A gene"Int.J.Oncol.,. 14. 1075-1080 (1999)

[Publications] Yanagawa,H.,: "Presence and potent immunosuppressive role of interleukin-10 in malignant pleural effusion due to lung cancer"Cancer Lett.,. 136. 27-32 (1999)

[Publications] Parajuli,P.,: "Therapeutic efficacy of a new topoisomerase I and II inhibitor TAS-103, against both P-glycoprotein-expressing and -nonexpressing drug-resistant human small-cell lung cancer"Oncol.Res.,. 11. 219-224 (1999)

[Publications] Namikawa,O.,: "Analysis of antibodies to p16INK4A tumor suppressor gene products in lung cancer patients"Int.J.Oncol.,. 14. 681-685 (1999)

[Publications] Ichikawa,W.,: "Characterization of immunoglobulin binding factor in sputum from patients with chronic airway diseases"Respirology,. 4. 375-381 (1999)

[Publications] Yanagawa,H.,: "Production of interleukin-10 by alveolar macrophages from lung cancer patients"Respir.Med.,. 93. 666-671 (1999)

[Publications] Yanagawa,H.,: "A case of resectable lung adenocarcinoma associated with sarcoidosis"Med.Oncol.,. 16. 216-220 (1999)

[Publications] Ogushi,F.,: "Decreased prostaglandin E2 synthesis by lung fibroblasts isolated from rats with bleomycin-induced lung fibrosis"Int.J.Exp.Pathol.,. 80. 41-49 (1999)

[Publications] Nishimura,N.,: "Down-regulation by a new anti-inflammatory compound, FR167653, of differentiation and maturation of human monocytes and bone marrow CD34+ cells to dentritic cells"Int.J.Immunopharmacol.. (in press).

[Publications] Sumitomo,K.,: "Expression of a TGF-b1 inducible gene, TSC-36, causes growth inhibition in human lung cancer cell lines"Cancer Letters. (in press).

曽根三郎徳島大学, 医学部, 教授 (40145024)