DNA topoisomerases as targets for the anticancer drug TAS-103: DNA interactions and topoisomerase catalytic inhibition
DNA topoisomerases as targets for the anticancer drug TAS-103: DNA interactions and topoisomerase catalytic inhibition
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DOI：
10.1021/bi991792g
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发表时间：
1999-11-23
期刊：
影响因子：
2.9
通讯作者：
Osheroff, N
中科院分区：
文献类型：
--
作者：
Fortune, JM;Velea, L;Osheroff, N
TAS-103是一种新型抗癌药物，通过增加拓扑异构酶II介导的DNA切割水平来杀死细胞。虽然大多数刺激拓扑异构酶II介导的DNA断裂的药物（即拓扑异构酶II毒药）也抑制酶的催化活性，但它们通常只有在浓度高于临床范围时才能起作用。TAS-103的不寻常之处在于，据报道它抑制拓扑异构酶I和拓扑异构酶II的催化活性，并且在生理上相关的浓度下起作用[Utsugi， T., et al. (1997) Jpn]。[j]中华医学杂志，1999,19(2):391 - 391。如果没有拓扑异构酶活性来缓解累积的扭转应力，那么促进TAS-103作为拓扑异构酶II毒性作用的DNA跟踪系统将被破坏。因此，表征了TAS-103对拓扑异构酶I和拓扑异构酶II的催化活性的影响。DNA结合和解绕实验表明，药物插入DNA的表观解离常数与2.2 μ m相似。此外，与哺乳动物拓扑异构酶I的DNA链传代实验表明，TAS-103不会抑制I型酶的催化活性。相反，先前报道的拓扑异构酶i催化的DNA松弛的抑制是由药物诱导的核酸底物表面拓扑结构的改变引起的。TAS-103确实抑制了人拓扑异构酶II α的催化活性，显然是通过阻断酶的DNA还原反应。TAS-103缺乏对拓扑异构酶I催化活性的抑制解释了该药物如何能够在处理细胞中作为拓扑异构酶II毒药发挥作用。
TAS-103 is a novel anticancer drug that kills cells by increasing levels of DNA cleavage mediated by topoisomerase II. While most drugs that stimulate topoisomerase II-mediated DNA scission (i.e., topoisomerase II poisons) also inhibit the catalytic activity of the enzyme, they typically do so only at concentrations above the clinical range. TAS-103 is unusual in that it reportedly inhibits the catalytic activity of both topoisomerase I and II and does so at physiologically relevant concentrations [Utsugi, T., et al. (1997) Jpn. J. Cancer Res. 88, 992-1002]. Without a topoisomerase activity to relieve accumulating torsional stress, the DNA tracking systems that promote the action of TAS-103 as a topoisomerase II poison would be undermined. Therefore, the effects of TAS-103 on the catalytic activity of topoisomerase I and II were characterized. DNA binding and unwinding assays indicate that the drug intercalates into DNA with an apparent dissociation constant of similar to 2.2 mu M. Furthermore, DNA strand passage assays with mammalian topoisomerase I indicate that TAS-103 does not inhibit the catalytic activity of the type I enzyme. Rather, the previously reported inhibition of topoisomerase I-catalyzed DNA relaxation results from a drug-induced alteration in the apparent topology of the nucleic acid substrate. TAS-103 does inhibit the catalytic activity of human topoisomerase II alpha, apparently by blocking the DNA religation reaction of the enzyme. The lack of inhibition of topoisomerase I catalytic activity by TAS-103 explains how the drug is able to function as a topoisomerase II poison in treated cells.