The efficacy of topoisomerase II-targeted anticancer agents reflects the persistence of drug-induced cleavage complexes in cells.
The efficacy of topoisomerase II-targeted anticancer agents reflects the persistence of drug-induced cleavage complexes in cells.
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DOI：
10.1021/bi800981j
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发表时间：
2008-11-11
期刊：
影响因子：
2.9
通讯作者：
Osheroff, Neil
中科院分区：
文献类型：
--
作者：
Bandele, Omari J.;Osheroff, Neil
染料木素是一种广泛使用的生物类黄酮，在成人中具有化学预防作用，而依托泊苷是一种常用的抗癌药物，它们都是具有良好特征的拓扑异构酶II毒物。尽管这两种化合物在体外对人拓扑异构酶i α和β具有相似的效力，并在培养的人细胞中诱导相似水平的DNA切割复合物，但它们的细胞毒性和基因毒性作用存在显著差异。通过监测活性或组蛋白H2AX磷酸化的实验，发现依托泊苷对CEM细胞的毒性比染料木素大得多。进一步的研究表明，染料木素和依托泊苷同时处理细胞，这两种化合物的不同作用与染料木素对细胞过程的影响无关，除了其抗拓扑异构酶II的活性。相反，与染料木素相比，它们似乎是由于依托opo苷诱导的卵裂复合物的持久性较长。纯化II型酶的平行体外研究得出了关于切割复合体持久性的类似结论。在体外和依托泊苷处理的细胞中观察到异构体特异性差异。到目前为止，依托泊苷诱导的CEM细胞中与拓扑异构酶i - α形成的DNA切割复合物的t1/2比与拓扑异构酶i - β形成的DNA切割复合物长约5倍。依托泊苷在四个治疗-恢复周期后的细胞毒性与在同等时间内连续暴露于该药物所引起的毒性相似。综上所述，这些发现表明依托泊苷可以通过采用脉冲药物治疗-恢复周期的方案优先靶向拓扑异构酶i α。
Genistein, a widely consumed bioflavonoid with chemopreventative properties in adults, and etoposide, a commonly prescribed anticancer drug, are well-characterized topoisomerase II poisons. Although both compounds display similar potencies against human topoisomerase IIα and β in vitro and induce comparable levels of DNA cleavage complexes in cultured human cells, their cytotoxic and genotoxic effects differ significantly. As determined by assays that monitored viability or the phosphorylation of histone H2AX, etoposide was much more toxic in CEM cells than genistein. Further studies that characterized the simultaneous treatment of cells with genistein and etoposide indicate that the differential actions of the two compounds are not related to the effects of genistein on cellular processes outside of its activity against topoisomerase II. Rather, they appear to result from a longer persistence of cleavage complexes induced by etoposide as compared to genistein. Parallel in vitro studies with purified type II enzymes led to similar conclusions regarding cleavage complex persistence. Isoform-specific differences were observed in vitro and in cells treated with etoposide. To this point, the t1/2 of etoposide-induced DNA cleavage complexes formed with topoisomerase IIα in CEM cells was ∼5 times longer than those formed with topoisomerase IIβ. The cytotoxicity of etoposide following four treatment-recovery cycles was similar to that induced by continuous exposure to the drug over an equivalent time period. Taken together, these findings suggest that it may be possible to preferentially target topoisomerase IIα with etoposide by employing a schedule that utilizes pulsed drug treatment-recovery cycles.
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影响因子：
2.9
作者：
Byl, JAW;Cline, SD;Osheroff, N
通讯作者：
Osheroff, N
DOI：
10.1073/pnas.85.4.1086
发表时间：
1988-02-01
影响因子：
11.1
作者：
HECK, MMS;HITTELMAN, WN;EARNSHAW, WC
通讯作者：
EARNSHAW, WC
DOI：
10.2174/1568011054222364
发表时间：
2005-07-01
期刊：
Current Medicinal Chemistry - Anti-Cancer Agents
影响因子：
--
作者：
Baldwin, E. L.;Osheroff, N.
通讯作者：
Osheroff, N.
影响因子：
64.8
作者：
Berger, JM;Gamblin, SJ;Wang, JC
通讯作者：
Wang, JC
影响因子：
4.8
作者：
ELSEA, SH;HSIUNG, YC;OSHEROFF, N
通讯作者：
OSHEROFF, N