Murphy Susan, Davey Ross A, Gu Xiao-Qing, Haywood Miriam C, McCann Lauren A, Mather Laurence E, Boyle Frances M
Bill Walsh Cancer Research Laboratories, Royal North Shore Hospital, University of Sydney, St Leonards, NSW, 2065, Australia.
J Neurooncol. 2007 Nov;85(2):181-9. doi: 10.1007/s11060-007-9406-3. Epub 2007 May 30.
With the aim of improving the treatment of glioblastoma multiforme, we investigated the potential of thalidomide to enhance the effectiveness of cisplatin chemotherapy in a rat glioma model. Female F344 rats were implanted with 9L gliosarcoma tumors either intracranially or subcutaneously and treated with 1 mg/kg cisplatin injected i.p. or with 1% thalidomide in the food or with these treatments combined. Cisplatin in combination with thalidomide significantly reduced both the subcutaneous tumor volume at 30 days to 22 +/- 5% (mean +/- SEM, P < 0.001) and the intracranial tumor volume at 18 days to 44 +/- 15% (P < 0.05) of that with cisplatin alone. Thalidomide selectively increased the cisplatin concentration 10-fold in intracranial tumors (P < 0.05) and 2-fold in the subcutaneous tumors (P < 0.05) without increasing its concentration in major organs including brain and kidney. Cisplatin combined with thalidomide caused a significant decrease in vascular endothelial growth factor (VEGF) levels by 73% in intracranial tumors (P < 0.05) and by 50% in subcutaneous tumors (P < 0.05) and caused the level of active hepatic growth factor (a-HGF) to double in both the subcutaneous and intracranial tumors (P < 0.05), suggesting this treatment altered the vasculature in these tumors. We conclude the increased efficacy of cisplatin in the presence of thalidomide was due to the selective increase in cisplatin concentration within the tumors and speculate that this is the result of thalidomide or the cisplatin/thalidomide combination, selectively altering the tumor vasculature. Based on the selective effects of thalidomide on tumor cisplatin concentrations and the resulting increase in efficacy, thalidomide may also increase the efficacy of other drugs that are presently considered ineffective against glioma.
为了改善多形性胶质母细胞瘤的治疗效果，我们在大鼠胶质瘤模型中研究了沙利度胺增强顺铂化疗效果的潜力。将雌性F344大鼠颅内或皮下植入9L胶质肉瘤肿瘤，腹腔注射1mg/kg顺铂，或在食物中添加1%沙利度胺，或联合使用这些治疗方法。顺铂与沙利度胺联合使用显著降低了30天时皮下肿瘤体积至单独使用顺铂时的22±5%（平均值±标准误，P<0.001），以及18天时颅内肿瘤体积至单独使用顺铂时的44±15%（P<0.05）。沙利度胺选择性地使颅内肿瘤中顺铂浓度增加10倍（P<0.05），皮下肿瘤中增加2倍（P<0.05），而不会增加其在包括脑和肾在内的主要器官中的浓度。顺铂与沙利度胺联合使用使颅内肿瘤中血管内皮生长因子（VEGF）水平显著降低73%（P<0.05），皮下肿瘤中降低50%（P<0.05），并使皮下和颅内肿瘤中活性肝生长因子（a-HGF）水平翻倍（P<0.05），表明这种治疗改变了这些肿瘤的血管系统。我们得出结论，在沙利度胺存在下顺铂疗效增加是由于肿瘤内顺铂浓度的选择性增加，并推测这是沙利度胺或顺铂/沙利度胺组合选择性改变肿瘤血管系统的结果。基于沙利度胺对肿瘤顺铂浓度的选择性作用以及由此导致的疗效增加，沙利度胺也可能增加目前认为对胶质瘤无效的其他药物的疗效。
