Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., Novosibirsk 630090, Russia.
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk 630090, Russia.
Int J Mol Sci. 2023 Mar 17;24(6):5781. doi: 10.3390/ijms24065781.
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an important repair enzyme that removes various covalent adducts from the 3' end of DNA. Particularly, covalent complexes of topoisomerase 1 (TOP1) with DNA stabilized by DNA damage or by various chemical agents are an examples of such adducts. Anticancer drugs such as the TOP1 poisons topotecan and irinotecan are responsible for the stabilization of these complexes. TDP1 neutralizes the effect of these anticancer drugs, eliminating the DNA adducts. Therefore, the inhibition of TDP1 can sensitize tumor cells to the action of TOP1 poisons. This review contains information about methods for determining the TDP1 activity, as well as describing the inhibitors of these enzyme derivatives of natural biologically active substances, such as aminoglycosides, nucleosides, polyphenolic compounds, and terpenoids. Data on the efficiency of combined inhibition of TOP1 and TDP1 in vitro and in vivo are presented.
酪氨酰-DNA 磷酸二酯酶 1（TDP1）是一种重要的修复酶，可从 DNA 的 3' 端去除各种共价加合物。特别是，拓扑异构酶 1（TOP1）与 DNA 的共价复合物通过 DNA 损伤或各种化学试剂稳定，是此类加合物的示例。拓扑异构酶 1 抑制剂如托泊替康和伊立替康等抗癌药物负责稳定这些复合物。TDP1 中和这些抗癌药物的作用，消除 DNA 加合物。因此，TDP1 的抑制可以使肿瘤细胞对 TOP1 抑制剂的作用敏感。本综述包含有关 TDP1 活性测定方法的信息，以及描述了天然生物活性物质的这些酶衍生物的抑制剂，如氨基糖苷类、核苷、多酚化合物和萜类化合物。还介绍了在体外和体内联合抑制 TOP1 和 TDP1 的效率的数据。
