A novel gene therapy against human leukemias : suppression of protein-tyrosine kinase activities

一种针对人类白血病的新型基因疗法：抑制蛋白酪氨酸激酶活性

• 批准号: 05807092
• 负责人: MANO Hiroyuki
• 金额: $ 1.15万
• 依托单位: Jichi Medical School (1994)The University of Tokyo (1993)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05807092/
• 关键词: Protein-tyrosine kinase; Anti-sense; 遺伝子治療; レトロウィルス

Protein-tyrosine kinase(PTK)is known to be directly involved in the mechanisms of cell growth or differentiation. As in the case of the Bcr-Abl kinase in chronic myeloid leukemia(CML), activated PTKs have been identified in some human malignancies and shown to participate in the process of oncogenesis. In this study, we have investigated if suppression of such PTK-activities may block the deregulated growth of cancer cells. Tec PTK is known to transduce mitogenic stimuli of cytokines. Addition of antisense oligonucleotides against Tec to culture medium was demonstrated to suppress the cytokine-dependent growth of both leukemia cells and normal bone marrow mononuclear cells. Also, antisense oligonucleotides against Abl could block the growth of CML cell line in a sequence-specific manner.Taken together, suppression of PTK activities should be a novel approach of gene therapy against a broad range of malignancies.

蛋白酪氨酸激酶（PTK）是已知的直接参与细胞生长或分化的机制。与慢性髓性白血病（CML）中Bcr-Abl激酶的情况一样，已在某些人类恶性肿瘤中鉴定出活化的PTK，并显示其参与肿瘤发生过程。在这项研究中，我们研究了抑制这种PTK活性是否可以阻断癌细胞的失调生长。已知Tec PTK是细胞因子的促分裂刺激物。在培养液中加入Tec的反义寡核苷酸，可以抑制白血病细胞和正常骨髓单个核细胞依赖于嘌呤的生长。Abl的反义寡核苷酸能以序列特异性的方式抑制CML细胞株的生长，抑制PTK活性有望成为一种新的基因治疗方法。

项目成果

Mano, H.al.: "Tec protein-tyrosine kinase is involved in IL-3 signaling pathway." Blood. 85. 343-350 (1995)

Mano, H.al.：“Tec 蛋白酪氨酸激酶参与 IL-3 信号通路。”

Tang, B.et al.: "Tec kinase associates with c-Kit and is tyrosine phosphorylated and activated following stem cell factor binding." Mol.Cell.Biol.14. 8432-8437 (1994)

Tang, B. 等人：“Tec 激酶与 c-Kit 相关，在干细胞因子结合后被酪氨酸磷酸化并激活。”

Sato, K.et al.: "Molecular cloning and analysis of the human Tec protein-tyrosine kinase." Leukemia. 8. 1663-1672 (1994)

Sato, K. 等人：“人类 Tec 蛋白酪氨酸激酶的分子克隆和分析。”

Sasaki, K.et al.: "Coordinate expression of the alpha and beta chains of human granulocyte macrophage colony-stimulating factor receptor confers ligand-induced morphological transformation in mouse fibroblasts." J.Biol.Chem.268. 13697-13702 (1993)

Sasaki, K.等人：“人粒细胞巨噬细胞集落刺激因子受体的α和β链的协调表达在小鼠成纤维细胞中赋予配体诱导的形态转变。”

Matsuda, T.et al.: "Association and activation of Btk-Tec kinases by gp130, a signal transducer of the IL-6 family of cytokines." Blood. 85. 627-633 (1995)

Matsuda, T. 等人：“gp130（IL-6 细胞因子家族的信号转导器）对 Btk-Tec 激酶的关联和激活。”