Bevacizumab-Induced Normalization of Blood Vessels in Tumors Hampers Antibody Uptake
Bevacizumab-Induced Normalization of Blood Vessels in Tumors Hampers Antibody Uptake
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DOI：
10.1158/0008-5472.can-12-3518
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发表时间：
2013-06-01
期刊：
影响因子：
11.2
通讯作者：
de Vries, Elisabeth G. E.
中科院分区：
文献类型：
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作者：
Arjaans, Marlous;Munnink, Thijs H. Oude;de Vries, Elisabeth G. E.
在实体瘤中，血管生成发生在血管缺陷和淋巴引流受损的情况下，这与血管通透性增加和肿瘤通透性增强有关。肿瘤微环境的这些普遍方面可能对肿瘤内药物递送具有显著影响，这可能经常被低估。在这项研究中，我们研究了抗血管生成药物贝伐单抗对肿瘤抗体摄取的影响。在人卵巢癌和食管癌（SKOV-3和OE 19）的小鼠异种移植模型中，我们在注射Zr-89-曲妥珠单抗（SKOV-3和OE 19）、Zr-89-贝伐珠单抗（SKOV-3）或Zr-89-IgG（SKOV-3）后24和144小时，在贝伐珠单抗治疗前或治疗后，通过正电子发射断层扫描成像评价了肿瘤中的抗体摄取。肿瘤内分布通过荧光显微镜沿着平均血管密度（MVD）和血管标准化进行评估。值得注意的是，与对照组相比，贝伐珠单抗治疗降低了肿瘤模型的肿瘤摄取和肿瘤内蓄积。贝伐单抗治疗还降低了肿瘤中的MVD，并增加了血管周细胞覆盖。这些发现具有临床重要性，提示在设计治疗性抗体的组合试验时应谨慎，因为贝伐珠单抗联合治疗可能会减少肿瘤蓄积。(C)2013年AACR。
In solid tumors, angiogenesis occurs in the setting of a defective vasculature and impaired lymphatic drainage that is associated with increased vascular permeability and enhanced tumor permeability. These universal aspects of the tumor microenvironment can have a marked influence on intratumoral drug delivery that may often be underappreciated. In this study, we investigated the effect of blood vessel normalization in tumors by the antiangiogenic drug bevacizumab on antibody uptake by tumors. In mouse xenograft models of human ovarian and esophageal cancer (SKOV-3 and OE19), we evaluated antibody uptake in tumors by positron emission tomographic imaging 24 and 144 hours after injection of Zr-89-trastuzumab (SKOV-3 and OE19), Zr-89-bevacizumab (SKOV-3), or Zr-89-IgG (SKOV-3) before or after treatment with bevacizumab. Intratumor distribution was assessed by fluorescence microscopy along with mean vessel density (MVD) and vessel normalization. Notably, bevacizumab treatment decreased tumor uptake and intratumoral accumulation compared with baseline in the tumor models relative to controls. Bevacizumab treatment also reduced MVD in tumors and increased vessel pericyte coverage. These findings are clinically important, suggesting caution in designing combinatorial trials with therapeutic antibodies due to a possible reduction in tumoral accumulation that may be caused by bevacizumab cotreatment. (C) 2013 AACR.