The anti-tumour effect of low-dose continuous chemotherapy may partly be mediated by thrombospondin
The anti-tumour effect of low-dose continuous chemotherapy may partly be mediated by thrombospondin
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DOI：
10.1007/s00280-005-0163-8
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发表时间：
2006-09-01
影响因子：
3
通讯作者：
Norrby, K
中科院分区：
文献类型：
--
作者：
Damber, JE;Vallbo, C;Norrby, K
背景：肿瘤的生长依赖于血管生成。抗血管生成化疗，即连续或节律性低剂量化疗，是一种以低且耐受性良好的浓度施用细胞抑制剂而不长时间中断的方法。目标是在肿瘤血管生成中起关键作用的遗传稳定的内皮细胞。不同介质可介导节律化疗的抗血管生成作用。其中一种介质可能是血栓反应蛋白（TSP）。TSP是一种有效的血管生成抑制剂，因此可能在控制肿瘤生长方面很重要。本研究旨在评估低剂量连续或中剂量灌注化疗对肿瘤生长和肿瘤中TSP表达的影响。材料和方法：采用环磷酰胺、阿霉素或紫杉醇联合环磷酰胺和阿霉素联合治疗不表达TSP的恶性前列腺肿瘤（Dunning AT-1）大鼠。在治疗期间测量肿瘤生长和体重。研究人员还分析了TSP的主要受体之一CD36。采用免疫组织化学和Western blot方法研究TSP-1、TSP-2和CD36的表达模式。Q-PCR检测TSP-1 mRNA表达。结果：低剂量环磷酰胺和紫杉醇可再次诱导肿瘤组织中TSP的表达。然而，在大剂量阿霉素后，肿瘤未显示TSP的表达。与对照相比，环磷酰胺和阿霉素治疗均使肿瘤重量降低了60%以上。当环磷酰胺和阿霉素联合使用时，肿瘤重量减少了47%，而紫杉醇使肿瘤重量减少了18%。结论：环磷酰胺和紫杉醇系统低剂量连续治疗大鼠前列腺癌模型可诱导肿瘤组织中TSP的表达，抑制肿瘤生长。这些发现支持了一种假设，即低剂量节律化疗的抗肿瘤作用，至少在某些化疗药物中，部分是由内源性抗血管生成因子的诱导介导的。
Background: Tumour growth is dependent on angiogenesis. Antiangiogenic chemotherapy, i.e. continuous or metronomic low-dose chemotherapy, is a method for administrating cytostatics at a low and well-tolerated concentration without prolonged breaks. The target is the genetically stable endothelial cells playing a pivotal role in angiogenesis within the tumour. Different mediators could mediate the antiangiogenic effect of metronomic chemotherapy. One of these mediators could be thrombospondin (TSP). TSP is a potent inhibitor of angiogenesis and might therefore be important in controlling tumour growth. This study was designed to evaluate the effects of low-dose continuous or moderate-dose bolus chemotherapy on tumour growth and on tumour expression of TSP. Materials and methods: Rats bearing a malignant prostate tumour (Dunning AT-1) not expressing TSP were treated systemically with cyclophosphamide, doxorubicin or paclitaxel and the combination of cyclophosphamide and doxorubicin. Tumour growth and body weight were measured during the treatment. CD36, one of TSP's main receptors, was also analysed. The expression pattern of TSP-1, TSP-2 and CD36 was investigated using immunohistochemistry and Western blot analyses. Q-PCR was used to analyse TSP-1 mRNA expression. Results: Low-dose cyclophosphamide and paclitaxel re-induced the expression of TSP in the tumours. However, following a bolus dose of doxorubicin, tumours showed no expression of TSP. Both cyclophosphamide and doxorubicin treatments decreased the tumour weight by more than 60% compared with vehicle controls. When cyclophosphamide and doxorubicin were combined the tumour weight was reduced by 47%, while paclitaxel reduced the tumour weight by 18% compared to the vehicle controls. Conclusions: Systemic low-dose continuous treatment of a rat prostate cancer model with cyclophosphamide and paclitaxel induced the expression of TSP in tumour tissue and inhibited tumour growth. These findings support the hypothesis that the anti-tumour effect of low-dose metronomic chemotherapy, at least with certain chemotherapeutics, is partly mediated by induction of endogenous antiangiogenic factors.