The transcription factor HIF-1α is overexpressed in chronic lymphocytic leukaemia (CLL), where it promotes leukaemia progression by favouring the interaction of leukaemic cells with protective tissue microenvironments. Here, we tested the hypothesis that a pharmacological compound previously shown to inhibit HIF-1α may act as a chemosensitizer by interrupting protective microenvironmental interactions and exposing CLL cells to fludarabine-induced cytotoxicity. We found that the camptothecin-11 analogue EZN-2208 sensitizes CLL cells to fludarabine-induced apoptosis in cytoprotective in vitro cultures; in vivo EZN-2208 improves fludarabine responses, especially in early phases of leukaemia expansion, and exerts significant anti-leukaemia activity, thus suggesting that this or similar compounds may be considered as effective CLL therapeutic approaches.

中文翻译：

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EZN-2208治疗可通过干扰环境保护来抑制慢性淋巴细胞性白血病并增加对氟达拉滨的反应。

转录因子HIF-1α在慢性淋巴细胞性白血病（CLL）中过表达，通过促进白血病细胞与保护性组织微环境的相互作用来促进白血病进展。在这里，我们测试了一种假设，即先前显示出抑制HIF-1α的药理化合物可以通过中断保护性微环境相互作用并将CLL细胞暴露于氟达拉滨诱导的细胞毒性中而充当化学增敏剂。我们发现喜树碱11类似物EZN-2208在细胞保护性体外培养物中使CLL细胞对氟达拉滨诱导的细胞凋亡敏感。体内的EZN-2208可改善氟达拉滨的反应，尤其是在白血病扩展的早期阶段，并具有显着的抗白血病活性，