DNA topoisomerase II alpha expression is associated with alkylating agent resistance.
DNA topoisomerase II alpha expression is associated with alkylating agent resistance.
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DOI：
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发表时间：
1995
期刊：
影响因子：
11.2
通讯作者：
J. Eder;V. Chan;S. Ng;N. Rizvi;S. Zacharoulis;B. Teicher;L. Schnipper
中科院分区：
文献类型：
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作者：
J. Eder;V. Chan;S. Ng;N. Rizvi;S. Zacharoulis;B. Teicher;L. Schnipper
DNA拓扑异构酶II α的表达增加与对某些DNA损伤性烷化剂的耐药性有关，但尚未建立因果关系或机制。为了研究这一观察结果，我们通过将全长中国仓鼠卵巢拓扑异构酶II α转染到EMT 6小鼠乳腺癌中，建立了拓扑异构酶II过表达的模型。拓扑异构酶II α转染的细胞系在稳定期（G 0-G1）表现出拓扑异构酶II α mRNA和蛋白质的持续表达，这在仅载体系中是检测不到的。拓扑异构酶II转染子对烷化剂顺铂和氮芥的抗性约为5-10倍。从G 0-G1释放后，拓扑异构酶II转染子表现出更快的胸苷掺入和更短的细胞倍增时间比对照细胞。纯化的拓扑异构酶II和具有拓扑异构酶II-decatenating活性的核提取物与顺铂处理的DNA结合，其亲和力显著高于未处理的DNA，呈顺铂浓度依赖性。这些观察结果表明，拓扑异构酶II α的表达可能在细胞对烷化剂的耐药性中起作用。其机制可能涉及拓扑异构酶II α与烷化剂损伤的DNA的结合增加。
Increased expression of DNA topoisomerase II alpha has been associated with resistance to certain DNA-damaging alkylating agents, but no causal relationship or mechanism has been established. To investigate this observation, we developed a model of topoisomerase II overexpression by transfecting a full-length Chinese hamster ovary topoisomerase II alpha into EMT6 mouse mammary carcinoma. Topoisomerase II alpha-transfected cell lines demonstrated continued topoisomerase II alpha mRNA and protein expression, which were undetectable in vector-only lines, in stationary phase (G0-G1). The topoisomerase II transfectants were approximately 5-10-fold resistant to the alkylating agents cisplatin and mechlorethamine. Upon release from G0-G1, the topoisomerase II transfectants demonstrated more rapid thymidine incorporation and shorter cell-doubling times than control cells. Purified topoisomerase II and nuclear extracts with topoisomerase II-decatenating activity bound to cisplatin-treated DNA with significantly greater affinity than to untreated DNA in a cisplatin concentration-dependent manner. These observations suggest that expression of topoisomerase II alpha may have a role in cellular resistance to antineoplastic alkylating agents. The mechanism for this may involve increased binding of topoisomerase II alpha to alkylating agent-damaged DNA.