Damber Jan-Erik, Vallbo Christina, Albertsson Per, Lennernäs Bo, Norrby Klas
Department of Urology, Institute of Surgical Sciences, Sahlgrenska Academy, Göteborg University, Sahlgrenska University Hospital, Sweden.
Cancer Chemother Pharmacol. 2006 Sep;58(3):354-60. doi: 10.1007/s00280-005-0163-8. Epub 2005 Dec 7.
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.
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.
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.
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.
肿瘤生长依赖于血管生成。抗血管生成化疗，即持续或节拍性低剂量化疗，是一种以低且耐受性良好的浓度给药细胞抑制剂且无长时间中断的方法。其靶点是在肿瘤血管生成中起关键作用的基因稳定的内皮细胞。不同的介质可能介导节拍性化疗的抗血管生成作用。其中一种介质可能是血小板反应蛋白（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中起重要作用。本研究旨在评估低剂量持续或中等剂量推注化疗对肿瘤生长及肿瘤组织中TSP表达的影响。
对携带不表达TSP的恶性前列腺肿瘤（邓宁AT-1）的大鼠进行全身环磷酰胺、阿霉素或紫杉醇以及环磷酰胺与阿霉素联合治疗。在治疗期间测量肿瘤生长和体重。还分析了TSP的主要受体之一CD36。使用免疫组织化学和蛋白质印迹分析研究TSP-1、TSP-2和CD36的表达模式。采用实时定量聚合酶链反应（Q-PCR）分析TSP-1 mRNA表达。
低剂量环磷酰胺和紫杉醇可重新诱导肿瘤组织中TSP的表达。然而，推注剂量的阿霉素后，肿瘤组织未显示TSP表达。与溶剂对照组相比，环磷酰胺和阿霉素治疗均使肿瘤重量减轻超过60%。环磷酰胺与阿霉素联合使用时，肿瘤重量降低了47%，而紫杉醇使肿瘤重量比溶剂对照组降低了18%。
对大鼠前列腺癌模型进行全身低剂量持续环磷酰胺和紫杉醇治疗可诱导肿瘤组织中TSP的表达并抑制肿瘤生长。这些发现支持以下假设：低剂量节拍性化疗的抗肿瘤作用，至少对于某些化疗药物而言，部分是由内源性抗血管生成因子的诱导介导的。
