Li Haiqing, Raia Valentina, Bertolini Francesco, Price Douglas K, Figg William D
Molecular Pharmacology Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
BJU Int. 2008 Apr;101(7):884-8. doi: 10.1111/j.1464-410X.2007.07342.x. Epub 2007 Dec 5.
To investigate how thalidomide confers its survival benefit in prostate cancer, by assessing its effect on circulating endothelial cells (CECs) and progenitors (CEPs) in a combined therapy of thalidomide and chemotherapy drugs in a human prostate cancer xenograft model, as in clinical trials patients treated with both thalidomide and docetaxel had a >50% decrease in prostate-specific antigen (PSA) levels and longer median overall survival than those treated with docetaxel monotherapy.
A human prostate cancer xenograft model was used to evaluate the effect of either thalidomide, docetaxel or a combination of the two drugs on circulating ECs. Drug treatment was continued for 17 days, and tumours were measured two or three times a week. Blood samples were taken at three different time points: before the treatments, 4 days and 17 days into the treatments, and CECs and CEPs were measured by flow cytometry analysis.
There was an increased level of apoptotic/dead CECs shortly after the intravenous injection of docetaxel, and the addition of thalidomide further increased the apoptotic/dead CEC level, showing that thalidomide enhances the cytotoxicity of docetaxel against tumour vascular ECs.
Thalidomide increased the apoptotic/dead CEC level and enhanced the cytotoxicity of docetaxel against tumour vascular ECs, confirming its antiangiogenic property in vivo in combined anticancer treatments. In addition, there was a correlation between the increased apoptotic/dead CEC levels early in the treatment and antitumour efficacy later, suggesting that the apoptotic/dead CEC level could be used as a marker, at an early stage, to predict tumour response to antiangiogenic therapies.
在人前列腺癌异种移植模型中，通过评估沙利度胺与化疗药物联合治疗对循环内皮细胞（CECs）和祖细胞（CEPs）的影响，研究沙利度胺在前列腺癌中如何发挥其生存获益作用。因为在临床试验中，同时接受沙利度胺和多西他赛治疗的患者前列腺特异性抗原（PSA）水平下降超过50%，且中位总生存期比接受多西他赛单药治疗的患者更长。
使用人前列腺癌异种移植模型评估沙利度胺、多西他赛或两种药物联合使用对循环内皮细胞的影响。持续药物治疗17天，每周测量肿瘤两到三次。在三个不同时间点采集血样：治疗前、治疗第4天和第17天，通过流式细胞术分析测量CECs和CEPs。
静脉注射多西他赛后不久，凋亡/死亡的CECs水平升高，加入沙利度胺后进一步提高了凋亡/死亡的CECs水平，表明沙利度胺增强了多西他赛对肿瘤血管内皮细胞的细胞毒性。
沙利度胺提高了凋亡/死亡的CECs水平，增强了多西他赛对肿瘤血管内皮细胞的细胞毒性，证实了其在体内联合抗癌治疗中的抗血管生成特性。此外，治疗早期凋亡/死亡的CECs水平升高与后期抗肿瘤疗效之间存在相关性，表明凋亡/死亡的CECs水平可在早期用作预测肿瘤对抗血管生成治疗反应的标志物。
