1992 年度実績報告書

がんに対する細胞移植/遺伝子治療の基礎的研究

研究課題

研究課題/領域番号	04151017
研究機関	東京大学
研究代表者	浅野茂隆東京大学, 医科学研究所, 教授 (50134614)
研究分担者	小澤敬也東京大学, 医科学研究所, 助教授 (30137707) 渡部好彦京都大学, 薬学部, 教授 (90109075) 新津洋司郎札幌医科大学, 教授 (10045502) 斉藤英彦名古屋大学, 医学部, 教授 (20153819) 内山卓京都大学, ウイルス研, 教授 (80151900)
キーワード	がん / 遺伝子治療 / 遺伝子導入 / レトロウイルスベクター / アデノウイルスベクター / 細胞移植 / 抗腫瘍免疫 / bispecific抗体
研究概要	遺伝子治療に用いるベクターの開発では、レトロウイルスベクター系については、標的細胞の特異性を変換する方法としてエンベロープの改変を試みた。また、導入効率の高いアデノウイルスベクター系の改良を行い、組換えアデノウイルスの作製効率を数十倍高めることに成功した。その他の遺伝子導入法としては、liposome法およびトランスフェリン受容体を介した方法の開発を進めた。特に後者は、in vivo投与で腫瘍細胞に遺伝子導入を行うことが可能であることを動物実験で確認した。遺伝子導入細胞の制御法については、HSV-1-TK遺伝子を予め導入しておくことによりガンシンクロビルによる殺細胞効果が得られ、その応用が可能であることを実験的に示した。白血病細胞の増殖抑制を目的としたin vitroの実験では、アンチセンスmybRNA発現ベクターの導入や、慢性骨髄性白血病に対してはBCR/ABLキメラmRNAの融合部分を狙ったアンチセンスオリコヌクレオチド処理の検討などを進めた。また、p53遺伝子異常を有する白血病細胞株に正常p53遺伝子を導入したところ、増殖抑制効果が観察された。遺伝子治療法の癌免疫療法への応用では、GM-CSF,IFN-γ,TNFなどのサイトカイン遺伝子を導入した腫瘍細胞をマウスに移植することによる、強い抗腫瘍免疫能が誘導され、治療効果ならびに再発・転移の予防効果が得られることを実験的に示した。その他、遺伝子ターゲッティングのメカニズムに関する基礎研究、造血幹細胞の増殖機構の解析、bispecific抗体によるLAK細胞のターゲッティング、SCIDマウスを用いた成人T細胞白血病細胞のin vivo増殖モデルの確立などを行った。以上、遺伝子治療に関する研究を多面的に実施し、我が国におけるがんに対する遺伝子治療の基盤づくりを行うことができた。

研究成果
(21件)

すべてその他

すべて文献書誌 (21件)

[文献書誌] Watanabe Y.et al.: "Transfection of interferon-γ gnene in animal tumors-a model for local cytokine production and tumor immunity." Seminars in Cancer Biology. 3. 43-46 (1992)
[文献書誌] Himeno T.et al.: "Induction of synthesis of manganous superoxide dismutase in LM(pNTnF) cells carrying an inducible TNF gene." Int Cancer. 50. 458-462 (1992)
[文献書誌] Okamoto T.et al.: "Endogenous tumor necrosis factor exerts its protective function intracellularty against the cytotoxicity of exogenous tumor necrosis factor" Cancer Res. 52. 5258-5281 (1992)
[文献書誌] Kobayashi I.et al.: "Mechanisms for gene conversion and homologous recombination:The double-strand break repair model and the successive half crossing-over model." Advances in Biophysics. 28. 81-133 (1992)
[文献書誌] Uemura N.et al.: "Acquisition of IL-3-independence in FDC-P2 cells after transfection with the actived c-H-ras gene using a bovine papillomavirus-based plasmid vector." Blood. 80. 3198-3204 (1992)
[文献書誌] Nishikawa M.et al.: "Delection mutagenesis of stem cell factor defines the C-terminal sequences essential for its biological activity." Biochem Biophys Commun. 188. 292-297 (1992)
[文献書誌] Sugimoto K.et al.: "Frequent mutation of the p53 gene in human myeloid leukemia cell lines." Blood. 79. 2378-2383 (1992)
[文献書誌] Kamano H.et al.: "E. Coli gpt gene expression effects on K562 human leukemia cell proliferation and erythroid deferentiation altered by mycophenolic acid." Biochemistry International. 26. 537-543 (1992)
[文献書誌] Imasa K.et al.: "Interleukin 2(IL-2) induces erythroid differentiation and throsine phosphorylation in ELM-I-1 cells transfected with a human IL-2 receptor β chain cDNA." Biochem Biophys Res Commun. 188. 352-357 (1992)
[文献書誌] Matsuura Y.et al.: "Expression of processed envelope protein of hepatitis C virus in mammalian and insect cells." J Virol. 66. 1425-1431 (1992)
[文献書誌] Azuma A.et al.: "Induction of intercellular adhesion molecule-1 on small cell lung cracinoma cell lines by interferon-enhances antibody-directed lymphokine-activated killer cell cytotoxicity." Cancer Res. 52. 4890-4894 (1992)
[文献書誌] Yagita H.et al.: "Role of perforin in lymhocyte-mediated cytolysis." Ady Immunol. 51. 215-242 (1992)
[文献書誌] Yuo A.et al.: "Rapid priming of human monocytes by human hematopoietic growth factors: granulocyte-mecrophage colony-stimulating factor (CSF),macrophage-CSF,and interleukin-3 selectively enhance superoxide release triggered by receptor-mediated agonists." Blood. 79. 1553-1557 (1992)
[文献書誌] Miura N.et al.: "Stem cell factor and IL-6 preferentially support the proliferation of kit-positive hemopoietic progenitors rather than their differntiation." Exp Hematol. 21. 143-149 (1993)
[文献書誌] Dranoff G.et al.: "Irradiated tumor cells secreting murine GM-CSF are unique in their ability to stimulate potent anti-tumor immunity in a nonimmunogenic tumor model." Nature. (1993)
[文献書誌] Porgador A.et al.: "Anti-metastatic vaccination of tumor-bearing mice with two types of γ IFN gene inserted tumor cells." J Immunol. (1993)
[文献書誌] Sugimoto K.et al.: "Mutations of the p53 gene in myelodysplastic syndromes and HDS-derived leukemia." Blood. (1993)
[文献書誌] Watanabe S.et al.: "Reconstituted human granulocyte-macrophage colony-stimulating factor receptor transduces growth-promoting signals in mouse NIH3T3 cells:comparison with signalling in BA/F3 pro-B cells." Mol Cell Biol. (1993)
[文献書誌] Tani K.et al.: "Implantation of genetically manipulated fibroblasts into mice as a model of cytokine supplementation gene therapyusing human G-CSF and IFN-alpha cDNAs In,Molecular approaches to the study and treatment of human deseases." Elsevier Science Publishers B.V., 419-428 (1992)
[文献書誌] Uchiyama T.et al.: "Interleukin-2 receptor chain expression in ATL.IN,Gann Monograph om Cancer Research No39 “Advances in adult T-cell leukemia and HTLV-I research"" Japan Scientific Societies,Tokyo, 107-118 (1992)
[文献書誌] Yagita H.et al.: "Bispecific antibody as a potentiation of tumor cell killing IL-2-activated lymphocytes.IN,Gann Monograph" Japan Scientific Societies,Tokyo, (1993)

1992 年度 実績報告書

がんに対する細胞移植/遺伝子治療の基礎的研究

研究代表者

浅野 茂隆 東京大学, 医科学研究所, 教授 (50134614)

研究成果

[文献書誌] Watanabe Y.et al.: "Transfection of interferon-γ gnene in animal tumors-a model for local cytokine production and tumor immunity." Seminars in Cancer Biology. 3. 43-46 (1992)

[文献書誌] Himeno T.et al.: "Induction of synthesis of manganous superoxide dismutase in LM(pNTnF) cells carrying an inducible TNF gene." Int Cancer. 50. 458-462 (1992)

[文献書誌] Okamoto T.et al.: "Endogenous tumor necrosis factor exerts its protective function intracellularty against the cytotoxicity of exogenous tumor necrosis factor" Cancer Res. 52. 5258-5281 (1992)

[文献書誌] Kobayashi I.et al.: "Mechanisms for gene conversion and homologous recombination:The double-strand break repair model and the successive half crossing-over model." Advances in Biophysics. 28. 81-133 (1992)

[文献書誌] Uemura N.et al.: "Acquisition of IL-3-independence in FDC-P2 cells after transfection with the actived c-H-ras gene using a bovine papillomavirus-based plasmid vector." Blood. 80. 3198-3204 (1992)

[文献書誌] Nishikawa M.et al.: "Delection mutagenesis of stem cell factor defines the C-terminal sequences essential for its biological activity." Biochem Biophys Commun. 188. 292-297 (1992)

[文献書誌] Sugimoto K.et al.: "Frequent mutation of the p53 gene in human myeloid leukemia cell lines." Blood. 79. 2378-2383 (1992)

[文献書誌] Kamano H.et al.: "E. Coli gpt gene expression effects on K562 human leukemia cell proliferation and erythroid deferentiation altered by mycophenolic acid." Biochemistry International. 26. 537-543 (1992)

[文献書誌] Imasa K.et al.: "Interleukin 2(IL-2) induces erythroid differentiation and throsine phosphorylation in ELM-I-1 cells transfected with a human IL-2 receptor β chain cDNA." Biochem Biophys Res Commun. 188. 352-357 (1992)

[文献書誌] Matsuura Y.et al.: "Expression of processed envelope protein of hepatitis C virus in mammalian and insect cells." J Virol. 66. 1425-1431 (1992)

[文献書誌] Azuma A.et al.: "Induction of intercellular adhesion molecule-1 on small cell lung cracinoma cell lines by interferon-enhances antibody-directed lymphokine-activated killer cell cytotoxicity." Cancer Res. 52. 4890-4894 (1992)

[文献書誌] Yagita H.et al.: "Role of perforin in lymhocyte-mediated cytolysis." Ady Immunol. 51. 215-242 (1992)

[文献書誌] Yuo A.et al.: "Rapid priming of human monocytes by human hematopoietic growth factors: granulocyte-mecrophage colony-stimulating factor (CSF),macrophage-CSF,and interleukin-3 selectively enhance superoxide release triggered by receptor-mediated agonists." Blood. 79. 1553-1557 (1992)

[文献書誌] Miura N.et al.: "Stem cell factor and IL-6 preferentially support the proliferation of kit-positive hemopoietic progenitors rather than their differntiation." Exp Hematol. 21. 143-149 (1993)

[文献書誌] Dranoff G.et al.: "Irradiated tumor cells secreting murine GM-CSF are unique in their ability to stimulate potent anti-tumor immunity in a nonimmunogenic tumor model." Nature. (1993)

[文献書誌] Porgador A.et al.: "Anti-metastatic vaccination of tumor-bearing mice with two types of γ IFN gene inserted tumor cells." J Immunol. (1993)

[文献書誌] Sugimoto K.et al.: "Mutations of the p53 gene in myelodysplastic syndromes and HDS-derived leukemia." Blood. (1993)

[文献書誌] Watanabe S.et al.: "Reconstituted human granulocyte-macrophage colony-stimulating factor receptor transduces growth-promoting signals in mouse NIH3T3 cells:comparison with signalling in BA/F3 pro-B cells." Mol Cell Biol. (1993)

[文献書誌] Uchiyama T.et al.: "Interleukin-2 receptor chain expression in ATL.IN,Gann Monograph om Cancer Research No39 “Advances in adult T-cell leukemia and HTLV-I research"" Japan Scientific Societies,Tokyo, 107-118 (1992)

[文献書誌] Yagita H.et al.: "Bispecific antibody as a potentiation of tumor cell killing IL-2-activated lymphocytes.IN,Gann Monograph" Japan Scientific Societies,Tokyo, (1993)

1992 年度実績報告書

浅野茂隆東京大学, 医科学研究所, 教授 (50134614)