Inhibition of growth of estrogen receptor positive and estrogen receptor negative breast cancer cells in culture by AA-etherA, a stable 2-5A derivative.
Inhibition of growth of estrogen receptor positive and estrogen receptor negative breast cancer cells in culture by AA-etherA, a stable 2-5A derivative.
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发表时间：
1996-02
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影响因子：
8
通讯作者：
K. Latham;S. Cosenza;R. Nl;E. Mordechai;Adelson Me;N. Kon;S. Horvath;R. Charubala;Mikhaĭlov Sn;W. Pfeiderer;Suhadolnik Rj
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作者：
K. Latham;S. Cosenza;R. Nl;E. Mordechai;Adelson Me;N. Kon;S. Horvath;R. Charubala;Mikhaĭlov Sn;W. Pfeiderer;Suhadolnik Rj
本发明涉及一种抗核酸酶、无毒的生物活性2-5A衍生物AA-醚A [即，腺苷酰-（2 ′-5 ′）-腺苷酰-（2 ′-2 ″）-9-[（2 ′-羟基乙氧基）-甲基]腺嘌呤]被描述为抑制乳腺癌细胞生长的新方法。AA-etherA以剂量依赖性方式抑制培养物中雌激素受体阳性（MCF-7）和雌激素受体阴性（BT-20）乳腺癌细胞的DNA复制和细胞分裂。在MCF-7和BT-20细胞中，在处理4天后用100 μ M AA-etherA获得最大抑制，GI 50分别为58和37 μ M。AA-醚A在细胞质中是稳定的。经处理的细胞在细胞周期的G1晚期/S早期内积累，然后仅非常缓慢地通过S期。AA-醚A不激活RNase L，2-5A和其他2-5A衍生物也不激活RNase L，也不增加细胞的p68激酶（PKR）含量。高分辨率、二维蛋白质凝胶电泳显示，在682种蛋白质中，有92种蛋白质的合成受到两倍或更大的抑制，这些蛋白质在未处理细胞中可重复地检测为高质量斑点，平均合成速率>或= 20 p. p.m.。AA-etherA对选择蛋白的作用的特异性及其不能激活RNase L表明AA-etherA不通过对mRNA翻译或稳定性的一般作用起作用，而是通过阻断DNA复制来抑制细胞增殖，同时减少特定蛋白的合成，其中一些蛋白可能是细胞周期转运所需的。解释AA-etherA抑制DNA复制的两个可能的靶点是DNA拓扑异构酶I和胸苷激酶，DNA拓扑异构酶I在其他细胞系中被AA-etherA抑制，胸苷激酶可以以类似于阿昔洛韦的作用的方式被抑制。这些数据表明，2-5A类似物，特别是双功能2-5A类似物如AA-醚A，将可用于控制癌细胞生长。这种2-5A类似物的进一步开发可提供用于化学疗法和化学预防的高度特异性化合物。
The design, chemical synthesis and biological activities of a nuclease-resistant, nontoxic bioactive 2-5A derivative, AA-etherA [i.e., adenylyl-(2'-5')-adenylyl-(2'-2")-9-[(2'-hydroxyethoxy)-methyl]adenine], are described as a new approach to the inhibition of breast cancer cell growth. AA-etherA inhibits DNA replication and cell division of both estrogen receptor positive (MCF-7) and estrogen receptor negative (BT-20) breast cancer cells in culture in a dose-dependent manner. Maximal inhibition in MCF-7 and BT-20 cells was obtained with 100 microM AA-etherA after four days of treatment, with an GI50 of 58 and 37 microM, respectively. AA-etherA is stable in the cytoplasm. Treated cells accumulate within the late G1/early S phase of the cell cycle and then progress only very slowly through S phase. AA-etherA does not activate RNase L, as do 2-5A and other 2-5A derivatives, nor does it increase p68 kinase (PKR) content of the cells. High resolution, two-dimensional protein gel electrophoresis reveals twofold or greater inhibition of synthesis of 92 proteins out of 682 proteins that were reproducibly detected as high quality spots with average rates of synthesis of > or = 20 p.p.m. in untreated cells. The specificity of the effects of AA-etherA on select proteins and its failure to activate RNase L indicate that AA-etherA does not act through a general effect on mRNA translation or stability, but rather inhibits cell proliferation through a block to DNA replication, with a concommitant reduction in the synthesis of specific proteins, some of which may be required for cell cycle transit. Two likely targets to account for the AA-etherA inhibition of DNA replication are DNA topoisomerase I, which is inhibited by AA-etherA in other cell lines, and thymidine kinase, which could be inhibited in a manner similar to the effect of acyclovir. These data indicate that 2-5A analogs, particularly bifunctional 2-5A analogs like AA-etherA, will be useful for controlling cancer cell growth. Further development of such 2-5A analogs may provide highly specific compounds for chemotherapy and chemoprevention.