Sensitization of tumor-associated endothelial cell apoptosis by the novel vascular-targeting agent ZD6126 in combination with cisplatin
Sensitization of tumor-associated endothelial cell apoptosis by the novel vascular-targeting agent ZD6126 in combination with cisplatin
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DOI：
10.1158/1078-0432.ccr-04-1171
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发表时间：
2004-11-15
影响因子：
11.5
通讯作者：
Sone, S
中科院分区：
文献类型：
--
作者：
Goto, H;Yano, S;Sone, S
目的：ZD6126是一种新型血管靶向剂，可选择性破坏内皮细胞的微管蛋白细胞骨架。在肿瘤脉管系统的未成熟血管特征中，这会导致内皮细胞收缩、血管充血，从而导致肿瘤细胞死亡。 ZD6126 已被证明可以在一系列异种移植模型中延迟肿瘤生长。 ZD6126与顺铂或放射治疗联合使用可以增强抗肿瘤作用，尽管这种增强的确切机制尚未得到证实。 ZD6126治疗也被证明可以抑制肺转移，本研究探索了ZD6126与顺铂联用增强抗转移作用的潜力，并对其潜在机制进行了研究。 实验设计：将人肺腺癌PC14PE6细胞注射到裸鼠的尾静脉中。注射五周后，用 ZD6126（200 mg/kg i.p.）、顺铂（6 mg/kg i.v.）或两种药物的组合治疗动物。 24小时后处死动物，评估肺转移的范围和凋亡细胞的存在。结果：组织学分析显示，与单独治疗相比，ZD6126/顺铂组合导致肿瘤相关凋亡细胞总数增加2至4倍。 ZD6126单独诱导肿瘤中肿瘤相关内皮细胞凋亡，与顺铂联合使用时凋亡程度增加2倍。联合治疗组肺重量明显减轻，转移结节数量明显低于对照组。结论：这些数据表明，血管靶向剂ZD6126与顺铂联合使用可以增强抗转移作用，从而增加内皮细胞凋亡的发生率。
Purpose: ZD6126 is a novel vascular-targeting agent that selectively disrupts the tubulin cytoskeleton of endothelial cells. In the immature vessels characteristic of tumor vasculature, this leads to endothelial cell contraction, blood vessel congestion, and, consequently, tumor cell death. ZD6126 has been shown to delay tumor growth in a range of xenograft models. The antitumor effect of ZD6126 can be increased in combination with cisplatin or radiation therapy, although the precise mechanism of this enhancement has not been demonstrated. ZD6126 treatment has also been shown to inhibit lung metastasis, and the present study has explored the potential to increase the antimetastatic effect of ZD6126 by combining with cisplatin, and the underlining mechanism has been investigated.Experimental Design: Human lung adenocarcinoma PC14PE6 cells were injected into the tail vein of nude mice. Five weeks after injection animals were treated with ZD6126 (200 mg/kg i.p.), cisplatin (6 mg/kg i.v.), or a combination of the two agents. The animals were sacrificed 24 hours later, and the extent of lung metastases and the presence of apoptotic cells were assessed.Results: Histologic analysis revealed that the ZD6126/ cisplatin combination resulted in a 2 to 4-fold increase in the total number of tumor-associated apoptotic cells compared with either treatment alone. ZD6126 alone induced apoptosis of tumor-associated endothelial cells in tumors, and the extent of apoptosis was increased 2-fold in combination with cisplatin. The lung weight was significantly reduced, and the number of metastatic nodules significantly was lower in the combined treatment group than in the control group.Conclusions: These data suggest that the antimetastatic effect of the vascular-targeting agent ZD6126 can be increased by use in combination with cisplatin, which increases the incidence of endothelial cell apoptosis.