Metronomic low-dose chemotherapy boosts CD95-dependent antiangiogenic effect of the thrombospondin peptide ABT-510: a complementation antiangiogenic strategy.
Metronomic low-dose chemotherapy boosts CD95-dependent antiangiogenic effect of the thrombospondin peptide ABT-510: a complementation antiangiogenic strategy.
复制标题
节拍式低剂量化疗可增强血小板反应蛋白肽 ABT-510 的 CD95 依赖性抗血管生成作用：一种补充性抗血管生成策略。
DOI：
10.1158/1078-0432.ccr-05-0621
复制
发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Volpert,OlgaV
中科院分区：
文献类型：
--
作者：
Yap,Ronald;Veliceasa,Dorina;Emmenegger,Urban;Kerbel,RobertS;McKay,LauraM;Henkin,Jack;Volpert,OlgaV
阻断血管生成是癌症治疗中有前途的方法。血管生成的天然抑制剂及其衍生物诱导受体介导的信号，这通常导致内皮细胞死亡。低剂量化疗，在短时间内定期给予，没有长时间的休息（节拍化疗），也通过消除增殖的内皮细胞和循环内皮细胞前体靶向血管生成。ABT-510是一种血小板反应蛋白的肽衍生物，通过增加CD 95死亡受体的配体CD 95 L杀死内皮细胞。然而，CD 95表达本身不受ABT-510的影响，并限制了其疗效。我们发现，多种化疗药物，环磷酰胺（环磷酰胺），顺铂和多西他赛，诱导内皮细胞CD 95在体外和体内低剂量不能杀死内皮细胞（环磷酰胺>顺铂>多西他赛）。因此，我们得出结论，这些药物中的一些可能相互补充，并一起阻断血管生成的最大功效。作为原理的证明，我们设计了一种抗血管生成鸡尾酒，将ABT-510与环磷酰胺或顺铂结合。环磷酰胺和顺铂协同增加ABT-510对内皮细胞凋亡和血管抑制的作用。这种协同作用需要CD 95，因为它与CD 95诱饵受体是可逆的。在小鼠模型中，ABT-510和环磷酰胺以低剂量一起应用，协同作用以延迟肿瘤摄取，稳定已建立肿瘤的生长，并导致PC-3前列腺癌的长期进展延迟。这些抗肿瘤作用伴随着微血管密度的显著降低和伴随的血管CD 95、CD 95 L和细胞凋亡的增加。因此，我们的研究显示了抗血管生成肽和节拍化疗的最佳癌症治疗的“互补”设计。
Blocking angiogenesis is a promising approach in cancer therapy. Natural inhibitors of angiogenesis and derivatives induce receptor-mediated signals, which often result in the endothelial cell death. Low-dose chemotherapy, given at short regular intervals with no prolonged breaks (metronomic chemotherapy), also targets angiogenesis by obliterating proliferating endothelial cells and circulating endothelial cell precursors. ABT-510, a peptide derivative of thrombospondin, kills endothelial cell by increasing CD95L, a ligand for the CD95 death receptor. However, CD95 expression itself is unaffected by ABT-510 and limits its efficacy. We found that multiple chemotherapy agents, cyclophosphamide (cytoxan), cisplatin, and docetaxel, induced endothelial CD95in vitroandin vivoat low doses that failed to kill endothelial cells (cytoxan > cisplatin > docetaxel). Thus, we concluded that some of these agents might complement each other and together block angiogenesis with maximal efficacy. As a proof of principle, we designed an antiangiogenic cocktail combining ABT-510 with cytoxan or cisplatin. Cyclophosphamide and cisplatin synergistically increasedin vivoendothelial cell apoptosis and angiosuppression by ABT-510. This synergy required CD95, as it was reversible with the CD95 decoy receptor. In a mouse model, ABT-510 and cytoxan, applied together at low doses, acted in synergy to delay tumor take, to stabilize the growth of established tumors, and to cause a long-term progression delay of PC-3 prostate carcinoma. These antitumor effects were accompanied by major decreases in microvascular density and concomitant increases of the vascular CD95, CD95L, and apoptosis. Thus, our study shows a “complementation” design of an optimal cancer treatment with the antiangiogenic peptide and a metronomic chemotherapy.