Dingemans A M, Pinedo H M, Giaccone G
Department of Medical Oncology, University Hospital Vrije Universiteit, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
Biochim Biophys Acta. 1998 Oct 1;1400(1-3):275-88. doi: 10.1016/s0167-4781(98)00141-9.
This review describes topoisomerase (topo)-mediated drug resistance and topo expression in human tissues and cancers. In some in vitro studies a relation has been observed between topo I, IIalpha or IIbeta expression and sensitivity to topo inhibitors. Drug resistance to topo inhibitors may, however, be multifactorial. Several topo inhibitors are substrates for drug membrane transporters. As most topo inhibitors are cell cycle specific, disturbances in cell cycle regulation can also confer resistance, and downstream events following DNA damage induced by topo inhibitors may be involved in regulating cell death or survival. Several studies in patient specimens have shown a relation between topo IIalpha expression and the proliferative state of the tumor, higher topo IIalpha levels being seen in more highly proliferating tumor types. In contrast, topo IIbeta appears to be expressed in both proliferating and quiescent cells. Furthermore, higher topo I levels were observed in some tumors when compared to their normal counterparts. In some studies a reduced topo IIalpha level was seen in samples taken after chemotherapy treatment, as compared with specimens prior to treatment. No unequivocal relation was observed, however, between expression or activity of the topo genes and response to chemotherapy; nonetheless only a few studies have properly addressed this question. This review summarizes the results of the clinical studies performed so far, and analyzes the critical issues in performing studies on patient material.
本综述描述了拓扑异构酶（topo）介导的耐药性以及拓扑异构酶在人体组织和癌症中的表达情况。在一些体外研究中，已观察到拓扑异构酶I、IIα或IIβ的表达与对拓扑异构酶抑制剂的敏感性之间存在关联。然而，对拓扑异构酶抑制剂的耐药性可能是多因素的。几种拓扑异构酶抑制剂是药物膜转运蛋白的底物。由于大多数拓扑异构酶抑制剂具有细胞周期特异性，细胞周期调控的紊乱也可导致耐药性，并且拓扑异构酶抑制剂诱导的DNA损伤后的下游事件可能参与调节细胞死亡或存活。对患者标本的多项研究表明，拓扑异构酶IIα的表达与肿瘤的增殖状态之间存在关联，在增殖程度更高的肿瘤类型中观察到更高的拓扑异构酶IIα水平。相比之下，拓扑异构酶IIβ似乎在增殖细胞和静止细胞中均有表达。此外，与正常对应组织相比，在一些肿瘤中观察到更高的拓扑异构酶I水平。在一些研究中，与治疗前的标本相比，化疗治疗后采集的样本中拓扑异构酶IIα水平降低。然而，在拓扑异构酶基因的表达或活性与化疗反应之间未观察到明确的关联；尽管如此，只有少数研究恰当地解决了这个问题。本综述总结了迄今为止进行的临床研究结果，并分析了对患者材料进行研究的关键问题。
