Revacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy
Revacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy
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DOI：
10.1158/1078-0432.ccr-07-0278
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发表时间：
2007-07-01
影响因子：
11.5
通讯作者：
Davidoff, Andrew M.
中科院分区：
文献类型：
--
作者：
Dickson, Paxton V.;Hamner, John B.;Davidoff, Andrew M.
目的：功能障碍的肿瘤血管可能是有效癌症治疗的重要障碍。然而，越来越多的证据表明，血管内皮生长因子（VEGF）抑制可以影响肿瘤血管系统的短暂“正常化”，从而改善肿瘤灌注，并因此，全身化疗的交付。我们试图检查肿瘤血管功能对抗VEGF抗体（贝伐单抗）的反应的时间变化。实验设计：在一系列时间点评价用贝伐单抗治疗的已建立的原位神经母细胞瘤异种移植瘤的瘤内血管生理学、全身给药化疗的渗透性和联合治疗的疗效的治疗相关变化。在单次贝伐单抗剂量后，在7天内观察到肿瘤微血管密度逐渐降低至对照的< 30%。肿瘤微环境的评估显示，肿瘤血管通透性和肿瘤间质液压力均快速持续下降，而通过超声造影评估的肿瘤内灌注得到改善，尽管后者的变化在1周后减弱。肿瘤内给药反映了这些变化;与两种药物同时给药或间隔7天给药相比，贝伐珠单抗给药后1 - 3天化疗的渗透率提高了81%。最后，在贝伐单抗后3天给予荷瘤小鼠拓扑替康，导致更大的肿瘤生长抑制（36%的对照大小）比单药治疗（88%贝伐单抗，54%托泊替康）或同时给予两种药物（44%）。贝伐珠单抗介导的VEGF阻断影响肿瘤血管生理学的改变，其允许改善化疗的递送和功效，尽管需要仔细考虑药物调度以优化抗肿瘤活性。
Purpose: Dysfunctional tumor vessels can be a significant barrier to effective cancer therapy. However, increasing evidence suggests that vascular endothelial growth factor (VEGF) inhibition can effect transient "normalization" of the tumor vasculature, thereby improving tumor perfusion and, consequently, delivery of systemic chemotherapy. We sought to examine temporal changes in tumor vascular function in response to the anti-VEGF antibody, bevacizumab.Experimental Design: Established orthotopic neuroblastoma xenografts treated with bevacizumab were evaluated at serial time points for treatment-associated changes in intratumoral vascular physiology, penetration of systemically administered chemotherapy, and efficacy of combination therapy.Results: After a single bevacizumab dose, a progressive decrease in tumor microvessel density to < 30% of control was observed within 7 days. Assessment of the tumor microenvironment revealed a rapid, sustained decrease in both tumor vessel permeability and tumor interstitial fluid pressure, whereas intratumoral perfusion, as assessed by contrast-enhanced ultrasonography, was improved, although this latter change abated by 1 week. Intratumoral drug delivery mirrored these changes; penetration of chemotherapy was improved by as much as 81% when given 1 to 3 days after bevacizumab, compared with when both drugs were given concomitantly, or 7 days apart. Finally, administering topotecan to tumor-bearing mice 3 days after bevacizumab resulted in greater tumor growth inhibition (36% of control size) than with monotherapy (88% bevacizumab, 54% topotecan) or concomitant administration of the two drugs (44%).Conclusions: Bevacizumab-mediated VEGF blockade effects alterations in tumor vessel physiology that allow improved delivery and efficacy of chemotherapy, although careful consideration of drug scheduling is required to optimize antitumor activity.