Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Cancer Chemother Pharmacol. 2014 Mar;73(3):639-49. doi: 10.1007/s00280-014-2395-y. Epub 2014 Jan 30.
Glioblastomas are amongst the most highly vascularised tumours, and the pursuit of anti-angiogenic approaches such as bevacizumab has provided short-term benefits. The purpose of this study was to determine whether the vascular-disrupting agent, dimethylxanthenone-4-acetic acid (DMXAA), could provide longer-lasting therapeutic benefits in a murine model of glioblastoma.
Luciferase-expressing murine GL261 glioma cells were inoculated subcutaneously or intracranially into C57Bl/6 mice. Mice with tumours were administered DMXAA, and tumours measured using callipers or by optical imager. Concentrations of DMXAA in plasma and brain were measured by LC-MS/MS.
DMXAA (25 mg/kg) caused widespread necrosis at 24 h, a 9-day growth delay and complete regressions in 50 % of the mice with subcutaneous GL261 tumours. Co-administered lenalidomide (100 mg/kg) increased the growth delay to 20 days and the percentage of cures to 83 %. The same dose of DMXAA with or without lenalidomide had minimal effects on intracranial GL261 tumours. Concentrations of DMXAA extracted from brain tissue were approximately 25-fold lower than those measured in plasma 15 min to 4 h after DMXAA administration. The presence of intracranial GL261 tumours did not alter the concentrations of DMXAA entering the brain.
DMXAA does not appear to cross the blood-brain barrier efficiently. Thus, whilst excellent activity was obtained against subcutaneous GL261 gliomas, minimal effects were observed against intracranial GL261 tumours. These results emphasise the need to use appropriate orthotopic models for the evaluation of new approaches for the treatment of brain cancers.
胶质母细胞瘤是血管化程度最高的肿瘤之一，采用贝伐单抗等抗血管生成方法已带来短期获益。本研究旨在确定血管破坏剂二甲氧黄酮酸（DMXAA）是否能在胶质母细胞瘤的小鼠模型中提供更持久的治疗益处。
将表达荧光素酶的 GL261 鼠胶质瘤细胞皮下或颅内接种到 C57Bl/6 小鼠中。在有肿瘤的小鼠中给予 DMXAA，并用卡尺或光学成像仪测量肿瘤。用 LC-MS/MS 测量血浆和脑内 DMXAA 的浓度。
DMXAA（25mg/kg）在 24 小时内引起广泛坏死，皮下 GL261 肿瘤的小鼠生长延迟 9 天，50%的小鼠完全消退。联合给予来那度胺（100mg/kg）将生长延迟增加到 20 天，治愈率增加到 83%。相同剂量的 DMXAA 联合或不联合来那度胺对颅内 GL261 肿瘤的影响很小。DMXAA 从脑组织中提取的浓度在 DMXAA 给药后 15 分钟至 4 小时，比血浆中的浓度低约 25 倍。颅内 GL261 肿瘤的存在并未改变进入大脑的 DMXAA 浓度。
DMXAA 似乎不能有效地穿过血脑屏障。因此，尽管在皮下 GL261 胶质瘤中获得了极好的活性，但在颅内 GL261 肿瘤中观察到的效果很小。这些结果强调了在评估新的脑癌治疗方法时，需要使用适当的原位模型。
