Acute Temporal Changes of MRI-Tracked Tumor Vascular Parameters after Combined Anti-angiogenic and Radiation Treatments in a Rat Glioma Model: Identifying Signatures of Synergism.
Acute Temporal Changes of MRI-Tracked Tumor Vascular Parameters after Combined Anti-angiogenic and Radiation Treatments in a Rat Glioma Model: Identifying Signatures of Synergism.
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在大鼠神经胶质瘤模型中联合抗血管生成和放射治疗后 MRI 跟踪的肿瘤血管参数的急性时间变化：识别协同作用的特征。
DOI：
10.1667/rr14358.1
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发表时间：
2017-01
影响因子：
3.4
通讯作者：
Ewing JR
中科院分区：
文献类型：
--
作者：
Elmghirbi R;Nagaraja TN;Brown SL;Panda S;Aryal MP;Keenan KA;Bagher-Ebadian H;Cabral G;Ewing JR
在这项研究中，我们使用磁共振成像（MRI）生物标志物来监测肿瘤血管生理学的急性时间变化，目的是识别预测对联合抗血管生成和放射治疗反应的血管特征。43只植入原位U-251胶质瘤细胞的无胸腺大鼠在植入后约21天进行了研究。在治疗前和治疗后对每只动物进行两次MRI研究，以测量肿瘤血管参数。两个动物组接受由西仑吉肽（一种抗血管生成剂）和放射组成的治疗。第一组在照射前1 h接受西仑吉肽亚治疗方案，而第二组在照射前8 h接受西仑吉肽治疗方案。在预处理MRI研究后和接受20戈伊辐射剂量之前，给予西仑吉肽单次剂量（4 mg/kg;腹膜内）。照射后，在选定的时间点进行治疗后MRI研究：2、4、8和12 h（每个时间点n = ≥5）。在两个治疗组中，在联合治疗后的早期时间点（1和8 h）观察到血管参数的显著变化。第一组（暴露前1小时处理）血管参数的时间变化类似于先前报道的仅与辐射暴露相关的模式。相反，在第二组（照射前8小时治疗）中，所有血管参数在照射后2-4小时显示出初始反应，随后在随后的时间点明显缺乏反应。定义西仑吉肽和辐射的“协同作用”的特征时间点是辐射后4小时。例如，在使用1小时间隔的组合治疗后4小时（遵循亚治愈方案），肿瘤血流量显著降低，比基线低近50%（P = 0.007），而在使用8小时间隔的组合治疗后4小时（遵循治愈方案），肿瘤血流量仅比基线低10%。第一组和第二组之间的比较进一步显示，大多数其他血管参数在联合治疗后4小时差异最大。总之，数据与西仑吉肽血管正常化时间窗内的放射治疗可改善放射治疗结局的论断一致。根据相似条件下的已知肿瘤反应，在不同递送时间的组合治疗后的不同血管反应将表明时机对治疗结果和长期存活具有关键影响。跟踪单一疗法或联合疗法后肿瘤生理学的急性变化似乎有助于确定给药的有利时机，并且可能具有预测价值。因此，合理的治疗时机可能会导致最佳的治疗反应。
In this study we used magnetic resonance imaging (MRI) biomarkers to monitor the acute temporal changes in tumor vascular physiology with the aim of identifying the vascular signatures that predict response to combined anti-angiogenic and radiation treatments. Forty-three athymic rats implanted with orthotopic U-251 glioma cells were studied for approximately 21 days after implantation. Two MRI studies were performed on each animal, pre- and post-treatment, to measure tumor vascular parameters. Two animal groups received treatment comprised of Cilengitide, an anti-angiogenic agent and radiation. The first group received a subcurative regimen of Cilengitide 1 h before irradiation, while the second group received a curative regimen of Cilengitide 8 h before irradiation. Cilengitide was given as a single dose (4 mg/kg; intraperitoneal) after the pretreatment MRI study and before receiving a 20 Gy radiation dose. After irradiation, the post-treatment MRI study was performed at selected time points: 2, 4, 8 and 12 h (n = ≥5 per time point). Significant changes in vascular parameters were observed at early time points after combined treatments in both treatment groups (1 and 8 h). The temporal changes in vascular parameters in the first group (treated 1 h before exposure) resembled a previously reported pattern associated with radiation exposure alone. Conversely, in the second group (treated 8 h before exposure), all vascular parameters showed an initial response at 2–4 h postirradiation, followed by an apparent lack of response at later time points. The signature time point to define the “synergy” of Cilengitide and radiation was 4 h postirradiation. For example, 4 h after combined treatments using a 1 h separation (which followed the subcurative regimen), tumor blood flow was significantly decreased, nearly 50% below baseline (P = 0.007), whereas 4 h after combined treatments using an 8 h separation (which followed the curative regimen), tumor blood flow was only 10% less than baseline. Comparison between the first and second groups further revealed that most other vascular parameters were maximally different 4 h after combined treatments. In conclusion, the data are consistent with the assertion that the delivery of radiation at the vascular normalization time window of Cilengitide improves radiation treatment outcome. The different vascular responses after the different delivery times of combined treatments in light of the known tumor responses under similar conditions would indicate that timing has a crucial influence on treatment outcome and long-term survival. Tracking acute changes in tumor physiology after monotherapy or combined treatments appears to aid in identifying the beneficial timing for administration, and perhaps has predictive value. Therefore, judicial timing of treatments may result in optimal treatment response.