Dings Ruud P M, Loren Melissa, Heun Hanke, McNiel Elizabeth, Griffioen Arjan W, Mayo Kevin H, Griffin Robert J
Department of Biochemistry, University of Minnesota, Minneapolis, USA.
Clin Cancer Res. 2007 Jun 1;13(11):3395-402. doi: 10.1158/1078-0432.CCR-06-2441.
To test whether a direct antiangiogenic peptide (anginex) and a vascular endothelial growth factor antibody (bevacizumab, Avastin) can transiently normalize vasculature within tumors to improve oxygen delivery, alleviate hypoxia, and increase the effect of radiation therapy.
Tumor oxygenation levels, microvessel density and pericyte coverage were monitored in three different solid tumor models (xenograft human ovarian carcinoma MA148, murine melanoma B16F10, and murine breast carcinoma SCK) in mice. Multiple treatment schedules were tested in these models to assess the influence on the effect of radiation therapy.
In all three tumor models, we found that tumor oxygenation levels, monitored daily in real time, were increased during the first 4 days of treatment with both anginex and bevacizumab. From treatment day 5 onward, tumor oxygenation in treated mice decreased significantly to below that in control mice. This "tumor oxygenation window" occurred in all three tumor models varying in origin and growth rate. Moreover, during the treatment period, tumor microvessel density decreased and pericyte coverage of vessels increased, supporting the idea of vessel normalization. We also found that the transient modulation of tumor physiology caused by either antiangiogenic therapy improved the effect of radiation treatment. Tumor growth delay was enhanced when single dose or fractionated radiotherapy was initiated within the tumor oxygenation window as compared with other treatment schedules.
The results are of immediate translational importance because the clinical benefits of bevacizumab therapy might be increased by more precise treatment scheduling to ensure radiation is given during periods of peak radiosensitivity. The oxygen elevation in tumors by non-growth factor-mediated peptide anginex suggests that vessel normalization might be a general phenomenon of agents directed at disrupting the tumor vasculature by a variety of mechanisms.
测试一种直接抗血管生成肽（血管抑素）和一种血管内皮生长因子抗体（贝伐单抗，阿瓦斯汀）能否使肿瘤内的脉管系统暂时正常化，以改善氧气输送、缓解缺氧并增强放射治疗的效果。
在小鼠的三种不同实体瘤模型（人卵巢癌MA148异种移植瘤、小鼠黑色素瘤B16F10和小鼠乳腺癌SCK）中监测肿瘤氧合水平、微血管密度和周细胞覆盖率。在这些模型中测试了多种治疗方案，以评估其对放射治疗效果的影响。
在所有三种肿瘤模型中，我们发现，在使用血管抑素和贝伐单抗治疗的前4天，实时每日监测的肿瘤氧合水平均有所升高。从治疗第5天起，治疗小鼠的肿瘤氧合显著下降，低于对照小鼠。这种“肿瘤氧合窗口”在所有三种起源和生长速率不同的肿瘤模型中均出现。此外，在治疗期间，肿瘤微血管密度降低，血管的周细胞覆盖率增加，支持血管正常化的观点。我们还发现，抗血管生成治疗引起的肿瘤生理的短暂调节改善了放射治疗的效果。与其他治疗方案相比，在肿瘤氧合窗口内开始单剂量或分次放疗时，肿瘤生长延迟增强。
这些结果具有直接的转化意义，因为通过更精确的治疗计划，确保在放射敏感性峰值期进行放疗，可能会增加贝伐单抗治疗的临床益处。非生长因子介导的肽血管抑素使肿瘤内氧气升高，这表明血管正常化可能是通过多种机制破坏肿瘤脉管系统的药物的普遍现象。
