Research on DNA biosynthesis in human hematologic malignant cells.

人类血液恶性肿瘤细胞DNA生物合成的研究。

• 批准号: 59570399
• 负责人: TAKEDA Eiji
• 金额: $ 0.83万
• 依托单位: University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1984
• 资助国家: 日本
• 起止时间: 1984 至 1986
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-59570399/
• 关键词: Human hematologic malignancies; Cellular proliferation; DNA biosynthesis; Ribonucleotide reductase; Thymidine kinase; de novo pathway; salvage pathway

The role of de novo and salvage pathways for DNA biosynthesis in human hematologic malignant cells was investigated to provide further informations for appropriate chemotherapy. The activities of ribonucleotide reductase and thymidine kinase, and the thymidine incorporation rate were measured in 16 cultured human hematologic malignant cell lines with different cell proliferation rates. A close correlation was found between the cell proliferation rate and ribonucleotide reductase activity, but not thymidine kinase activity or the thymidine incorporation rate. These results indicate that in cultured human malignant cells a high potential for proliferation may depend mainly on the de novo pyrimidine pathway of DNA biosynthesis. Then, the extent of use and role of the salvage pathway of pyrimidine metabolism for DNA biosynthesis in the growth of human hematologic malignant cells were studied by examining the effect of dipyridamole, an effective blocker of this salvage pathway on their growth. The data indicate that the salvage pathway for deoxynucleotide supply is more important in peroxidase-positive non-lymphoid cell lines than in lymphoid cell lines. Blockers of salvage pathway like dipyridamole which has not been used might be useful clinically. Next, the component of ribonucleotide reductase was investigated. Ribonucleotide reductase is concisted of M1-subunit "effector binding subunit" and M2-subunit "nonhem iron subunit". It became clear that the amount of M1-subunit was more than that of M2-subunit in any hematologic malignant cells. Therefore, the use of specific inhibitor of M2-subunit might provide more potential inhibitory effect of cellular proliferation.

本研究旨在探讨恶性血液病细胞DNA合成的从头途径和补救途径，为临床合理化疗提供依据。本文测定了16个不同增殖率的人血液恶性肿瘤细胞株的核苷酸还原酶、胸苷激酶活性和胸苷掺入率。细胞增殖率与核苷酸还原酶活性密切相关，但与胸苷激酶活性或胸苷掺入率无关。这些结果表明，在培养的人类恶性肿瘤细胞增殖的高潜力可能主要取决于从头嘧啶途径的DNA生物合成。然后，使用的程度和作用的补救途径嘧啶代谢的DNA生物合成在人类血液恶性肿瘤细胞的生长进行了研究，通过检查双嘧达莫，这种补救途径的有效阻断剂对他们的生长的影响。这些数据表明，补救途径的脱氧核苷酸供应是更重要的过氧化物酶阳性的非淋巴细胞系比淋巴细胞系。补救途径阻断剂如双嘧达莫可能在临床上有一定的应用价值。接下来，研究了核糖核苷酸还原酶的组分。核糖核苷酸还原酶由M1亚基“效应子结合亚基”和M2亚基“非血红素铁亚基”组成。结果表明，在所有恶性血液病细胞中，M1亚基的含量均高于M2亚基。因此，使用M2-亚基特异性抑制剂可能提供更潜在的细胞增殖抑制作用。

项目成果

広瀬政雄,武田英二,二宮恒夫,黒田泰弘,宮尾益英: 医学のあゆみ. 137. 145-146 (1986)

Masao Hirose、Eiji Takeda、Tsuneo Ninomiya、Yasuhiro Kuroda、Masuhide Miyao：医学史 137。 145-146 (1986)。

Hirose・Masao;Takeda・Eiji;Ninomiya・Tsuneo;Kuroda・Yasuhiro;Miyao・Masuhide: Tokushima J.of Exp.Med.(1987)

广濑·正夫；武田·英二；二宫·恒夫；黑田·康弘；宫尾·增秀：德岛实验医学杂志（1987）

Takeda Eiji, Hirose Masao, Kuroda Yasuhiro, Ninomiya Tsuneo, Toshima Kenji, Watanabe Toshiyuki, Ito Michinori, Naito Etsuo, Miyao Masuhide: "Ribonucleotide reductase and thymidine kinase activities in various cultured cell lines derived from hematologic m

Takeda Eiji、Hirose Masao、Kuroda Yasuhiro、Ninomiya Tsuneo、Toshima Kenji、Watanabe Toshiyuki、Ito Michinori、Naito Etsuo、Miyao Masuhide：“源自血液学的各种培养细胞系中的核糖核苷酸还原酶和胸苷激酶活性

Hirose Masao, Takeda Eiji, Ninomiya Tsuneo, Kuroda Yasuhiro, Miyao Masuhide: "Inhibitory effect of dipyridamole on the growth of human cultured cell lines derived from hematologic malignancies.(in Japanese)" Igakunoayumi. 137. 145-146 (1986)

Hirose Masao、Takeda Eiji、Ninomiya Tsuneo、Kuroda Yasuhiro、Miyao Masuhide：“双嘧达莫对源自血液恶性肿瘤的人类培养细胞系生长的抑制作用。（日语）”Igakunoayumi。

Hirose Masao, Takeda Eiji, Ninomiya Tsuneo, Kuroda Yasuhiro, Miyao Masuhide: "Inhibitory effect of dipyridamole on the growth of various human hematologic malignant cell lines." Tokushima J. of Exp. Med.in press. (1987)

Hirose Masao、Takeda Eiji、Ninomiya Tsuneo、Kuroda Yasuhiro、Miyao Masuhide：“双嘧达莫对多种人类血液恶性细胞系生长的抑制作用。”