新型抗肿瘤环缩肽BE-22179对拓扑异构酶II的抑制作用
Inhibition of topoisomerase II by a novel antitumor cyclic depsipeptide, BE-22179.
作者信息
Yoshinari T, Okada H, Yamada A, Uemura D, Oka H, Suda H, Okura A
机构信息
Banyu Tsukuba Research Institute.
出版信息
Jpn J Cancer Res. 1994 May;85(5):550-5. doi: 10.1111/j.1349-7006.1994.tb02394.x.
BE-22179, a novel cyclic depsipeptide antibiotic having two 3-hydroxyquinoline moieties, inhibited the DNA-relaxing activity of L1210 topoisomerase II completely at 0.08 microM. This effect was far stronger than that of VP-16. However, it did not show any marked effect on topoisomerase II-mediated DNA cleavage. BE-22179 was ineffective in inhibiting the DNA relaxation by topoisomerase I at concentrations up to 10 microM, but showed DNA-intercalating ability (DNA unwinding) at 30 microM. The structure of BE-22179 is quite novel for a topoisomerase II inhibitor. Echinomycin, a quinoxaline antibiotic structurally related to BE-22179, interfered with DNA relaxation by topoisomerase II, though the effect was not due to inhibition of the catalytic activity of topoisomerase II but to conformational change of DNA based on its intercalation into DNA. Therefore, the potent inhibitory activity on topoisomerase II might not be a common activity of quinoxaline antibiotics, but might rather be specific to BE-22179. BE-22179 prevented DNA synthesis as well as RNA synthesis in L1210 cells and inhibited the growth of the cells. However, it remains unclear to what extent the topoisomerase II inhibition was responsible for the cytotoxicity of BE-22179.
BE-22179是一种新型环缩肽抗生素，含有两个3-羟基喹啉部分，在0.08微摩尔浓度时能完全抑制L1210拓扑异构酶II的DNA松弛活性。这种作用远比依托泊苷（VP-16）强。然而，它对拓扑异构酶II介导的DNA切割没有明显作用。BE-22179在浓度高达10微摩尔时对拓扑异构酶I介导的DNA松弛无抑制作用，但在30微摩尔时表现出DNA嵌入能力（DNA解旋）。BE-22179的结构对于拓扑异构酶II抑制剂来说相当新颖。棘霉素是一种与BE-22179结构相关的喹喔啉抗生素，它干扰拓扑异构酶II介导的DNA松弛，不过这种作用并非由于抑制拓扑异构酶II的催化活性，而是基于其嵌入DNA导致DNA构象改变。因此，对拓扑异构酶II的强效抑制活性可能不是喹喔啉抗生素的共同活性，而可能是BE-22179特有的。BE-22179可阻止L1210细胞中的DNA合成以及RNA合成，并抑制细胞生长。然而，尚不清楚拓扑异构酶II抑制在多大程度上导致了BE-22179的细胞毒性。
Zotero 插件