Brain Tumor Research Center, Department of Neurosurgery, Massachusetts General Hospital, Boston, USA.
Clin Cancer Res. 2011 Dec 1;17(23):7383-93. doi: 10.1158/1078-0432.CCR-11-1762. Epub 2011 Oct 5.
Glioblastoma (GBM) inevitably recurs despite surgery, radiation, and chemotherapy. A subpopulation of tumor cells, GBM stem cells (GSC), has been implicated in this recurrence. The chemotherapeutic agent etoposide is generally reserved for treating recurrent tumors; however, its effectiveness is limited due to acute and cumulative toxicities to normal tissues. We investigate a novel combinatorial approach of low-dose etoposide with an oncolytic HSV to enhance antitumor activity and limit drug toxicity.
In vitro, human GBM cell lines and GSCs were treated with etoposide alone, oncolytic herpes simplex virus (oHSV) G47Δ alone, or the combination. Cytotoxic interactions were analyzed using the Chou-Talalay method, and changes in caspase-dependent apoptosis and cell cycle were determined. In vivo, the most etoposide-resistant human GSC, BT74, was implanted intracranially and treated with either treatment alone or the combination. Analysis included effects on survival, therapy-associated adverse events, and histologic detection of apoptosis.
GSCs varied in their sensitivity to etoposide by over 50-fold in vitro, whereas their sensitivity to G47Δ was similar. Combining G47Δ with low-dose etoposide was moderately synergistic in GSCs and GBM cell lines. This combination did not enhance virus replication, but significantly increased apoptosis. In vivo, the combination of a single cycle of low-dose etoposide with G47Δ significantly extended survival of mice-bearing etoposide-insensitive intracranial human GSC-derived tumors.
The combination of low-dose etoposide with G47Δ increases survival of mice-bearing intracranial human GSC-derived tumors without adverse side effects. These results establish this as a promising combination strategy to treat resistant and recurrent GBM.
尽管进行了手术、放疗和化疗，胶质母细胞瘤（GBM）仍不可避免地复发。肿瘤细胞的一个亚群，GBM 干细胞（GSC），与这种复发有关。化疗药物依托泊苷通常用于治疗复发性肿瘤；然而，由于对正常组织的急性和累积毒性，其效果有限。我们研究了一种新的联合治疗方法，即用低剂量依托泊苷联合溶瘤单纯疱疹病毒（oHSV），以增强抗肿瘤活性并限制药物毒性。
在体外，用人 GBM 细胞系和 GSCs 单独用依托泊苷、溶瘤单纯疱疹病毒（oHSV）G47Δ 或联合治疗。用 Chou-Talalay 法分析细胞毒性相互作用，测定 caspase 依赖性细胞凋亡和细胞周期的变化。在体内，最耐受依托泊苷的人 GSC BT74 被植入颅内，并单独或联合接受治疗。分析包括对生存、治疗相关不良反应和组织学检测凋亡的影响。
在体外，GSCs 对依托泊苷的敏感性差异超过 50 倍，而对 G47Δ 的敏感性相似。在 GSCs 和 GBM 细胞系中，将 G47Δ 与低剂量依托泊苷联合使用具有中度协同作用。这种联合治疗并没有增强病毒复制，但显著增加了细胞凋亡。在体内，低剂量依托泊苷与 G47Δ 的单次循环联合治疗显著延长了携带对依托泊苷不敏感的颅内人 GSC 源性肿瘤的小鼠的生存时间。
低剂量依托泊苷与 G47Δ 的联合使用可提高携带颅内人 GSC 源性肿瘤小鼠的生存率，且无不良反应。这些结果确立了这种联合治疗策略有希望用于治疗耐药和复发性 GBM。
