Differentiation Therapy for Myeloblastic Leukemia-Establishment of New Strategy

粒细胞白血病的分化治疗-新策略的制定

• 批准号: 07672380
• 负责人: TAKEDA Ken
• 金额: $ 1.47万
• 依托单位: SCIENCE UNIVERSITY OF TOKYO
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07672380/
• 关键词: retinoic acid; GM-CSF; human myeloblastic leukemia cells; differentiation; granulocytes; cell cycle; oncogene; Bcl-2; bcl-2; ヒト骨髄性白血病; サイトカイン; 細胞死; レチノイン酸誘導体

The effects of all-trans retinoic acid (ATRA), either alone in combination with GM-CSF, on the induction of differentiation of a human myeloblastic leukemia cell line, ML-1, were investigated. ATRA alone caused only slight induction of NBT-reducing activity even at a high concentration (10-7M), but when combined with GM-CSF, it led to remarkable increase in the induction NBT reducing activity. Synergistic effect of both agents was also observed on morphological changes, the inhibition of cell proliferation and granulocytic characteristics such as esterase activity and expression of surface antigens. When ATRA pr GM-CSF was used alone, neither parameter was changed substantially for long periods of up to 9 days. However, the combination of both agents induced remarkable morphological changes with segmented nuclei and also suppressed DNA-synthesizing activity. The hypophosphorylated form of pRB during this differentiation process was observed. The expression of cyclin D3 cdc25A was markedly down regulated during differentiation. In contrast, Cdk2, Cdk4, Cdk6 and cyclins (A, D2, E) showed almost the same level of expression of CKIs (p21,p27,p57,p15,p16,p18 and p19) that inhibit cdk activity did not change during differentiation. These data suggest that change to the hypophosphorylated form of pRB is attributable to the repression of cyclin D3 and cdc25A genes.

研究了全反式维甲酸（ATRA）单独或与GM-CSF联合对人髓性白血病细胞系ML-1的诱导分化作用。ATRA单独使用时，即使在高浓度（10 ~（-7）M）下，也仅能诱导少量的NBT还原活性，但当与GM-CSF联合使用时，可显著提高NBT还原活性。还观察到这两种药物在形态学变化、细胞增殖抑制和粒细胞特性（如酯酶活性和表面抗原表达）方面的协同作用。当单独使用ATRA pr GM-CSF时，两个参数在长达9天的长时间内均未发生实质性变化。然而，这两种药物的组合诱导显着的形态学变化与分段核，也抑制DNA合成活性。在此分化过程中观察到pRB的低磷酸化形式。细胞周期蛋白D3 cdc 25 A的表达在分化过程中明显下调。相比之下，Cdk 2、Cdk 4、Cdk 6和细胞周期蛋白（A、D2、E）显示出几乎相同水平的抑制cdk活性的CKI（p21、p27、p57、p15、p16、p18和p19）表达，在分化过程中没有变化。这些数据表明，pRB低磷酸化形式的变化归因于细胞周期蛋白D3和cdc 25 A基因的抑制。

项目成果

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Oka,Y.: "Retinoic acid combined with GM-CSF induces morpho-logical changes with segmented nuclei in human myeloblastic leukemia ML-1 cells." Anticancer Res.17(印刷中). (1997)

Oka, Y.：“视黄酸与 GM-CSF 结合可诱导人成髓细胞白血病 ML-1 细胞中分节细胞核的形态变化。”Anticancer Res.17（出版中）。

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