Department of Radiation Oncology and Experimental Therapeutics, H Lee Moffitt Cancer Center and Research Institute, SRB3, 12902 Magnolia Drive, Tampa, FL 33612, USA.
J Neurooncol. 2010 Sep;99(2):201-7. doi: 10.1007/s11060-010-0127-7. Epub 2010 Feb 5.
Histone deacetylase (HDAC) inhibitors represent a promising class of anti-cancer agents that are actively being evaluated in the context of clinical trials in solid tumors, including glioblastoma. What makes these agents particularly attractive is their capacity to enhance the activity of commonly used cytotoxics in cancer therapy, including both chemotherapy and ionizing radiation. As recent investigations suggest HDAC inhibitors may potentiate the cytotoxicity of topoisomerase inhibitors, which continue to be a commonly used class of agents in the treatment of glioblastoma, we performed preclinical studies to determine if this combination may be a promising strategy in glioblastoma. The effects of the HDAC inhibitor vorinostat and SN38, which is the active metabolite of the topoisomerase I inhibitor CPT-11, was evaluated using the clonogenic assay. Various treatment schedules were tested to determine optimum drug sequencing. Induction of DNA double strand breaks (DSBs) with the combination of vorinostat and SN38 was evaluated using the neutral comet assay, and their subsequent repair was evaluated by gammaH2AX foci kinetics using immunofluorescent cytochemistry. Vorinostat enhanced the cytotoxicity of SN38 in glioblastoma cell lines. Optimal treatment schedules involved maximal concurrent administration of agents. Pretreatment with either agent did not enhance cytotoxicity. Vorinostat potentiated SN38-induced DNA DSBs and attenuated their subsequent repair. These results indicate vorinostat enhances the cytotoxicity of SN38 in glioblastoma cell lines, suggesting this combination may be a worthwhile strategy to test in the context of a clinical trial.
组蛋白去乙酰化酶（HDAC）抑制剂是一类很有前途的抗癌药物，目前正在各种实体肿瘤的临床试验中进行评估，包括胶质母细胞瘤。这些药物的独特之处在于，它们能够增强癌症治疗中常用细胞毒素的活性，包括化疗药物和电离辐射。最近的研究表明，HDAC 抑制剂可能增强拓扑异构酶抑制剂的细胞毒性，而拓扑异构酶抑制剂仍然是治疗胶质母细胞瘤的常用药物类别之一，因此我们进行了临床前研究，以确定这种联合用药是否是胶质母细胞瘤的一种有前途的治疗策略。我们使用集落形成试验评估了 HDAC 抑制剂伏立诺他（vorinostat）和 SN38（拓扑异构酶 I 抑制剂 CPT-11 的活性代谢物）的作用。测试了各种治疗方案，以确定最佳的药物序贯。使用中性彗星试验评估了伏立诺他和 SN38 联合诱导 DNA 双链断裂（DSBs）的情况，并通过免疫荧光细胞化学法评估γH2AX 焦点动力学来评估其随后的修复情况。伏立诺他增强了胶质母细胞瘤细胞系中 SN38 的细胞毒性。最佳的治疗方案涉及同时最大程度地使用药物。两种药物的预处理均不能增强细胞毒性。伏立诺他增强了 SN38 诱导的 DNA DSBs 并减弱了其随后的修复。这些结果表明，伏立诺他增强了胶质母细胞瘤细胞系中 SN38 的细胞毒性，提示这种联合用药可能是临床试验中值得测试的一种策略。
