Glisson B S, Ross W E
Pharmacol Ther. 1987;32(2):89-106. doi: 10.1016/0163-7258(87)90054-4.
Based on the weight of evidence accrued in the past eight years, there is little question that the nuclear enzyme, topoisomerase II, serves as a common intracellular target for the cytotoxic effect of drugs of widely varying structure. The enzyme appears to be unique as a chemotherapy target in that it is recruited into a lethal process under the influence of drug. Its role contrasts sharply with other more classical chemotherapy targets, such as dihydrofolate reductase, whose activity must be successfully inhibited for the expression of cytotoxicity. Resistance to inhibitors of this enzyme frequently results from marked elevations in intracellular enzyme content. In contrast, the presence of topoisomerase is required for drug effect, and, in general, the greater the cellular content of the enzyme, the more sensitive the cell will be to these agents. However, important issues remain unresolved. The biochemical events that are initiated by cleavable complex formation and result in cell death must be more fully defined. It is likely a better understanding of the drug-enzyme interaction will be required for rational drug development. Finally, those aspects of the drug-topoisomerase interaction that confer therapeutic selectivity and/or clinical resistance are of paramount importance if the phenomenon is ever to be fully exploited.
基于过去八年积累的证据权重，毫无疑问，核酶拓扑异构酶II是结构差异很大的药物细胞毒性作用的常见细胞内靶点。作为化疗靶点，该酶似乎具有独特性，因为它在药物影响下被纳入致死过程。其作用与其他更经典的化疗靶点形成鲜明对比，如二氢叶酸还原酶，其活性必须被成功抑制才能表现出细胞毒性。对这种酶抑制剂的耐药性通常源于细胞内酶含量的显著升高。相比之下，药物发挥作用需要拓扑异构酶的存在，一般来说，细胞中该酶的含量越高，细胞对这些药物就越敏感。然而，重要问题仍未得到解决。由可裂解复合物形成引发并导致细胞死亡的生化事件必须得到更全面的界定。合理的药物开发可能需要对药物与酶的相互作用有更好的理解。最后，如果要充分利用这一现象，药物与拓扑异构酶相互作用中赋予治疗选择性和/或临床耐药性的那些方面至关重要。
