Multimodality molecular imaging of glioblastoma growth inhibition with vasculature-targeting fusion toxin VEGF121/rGel.
Multimodality molecular imaging of glioblastoma growth inhibition with vasculature-targeting fusion toxin VEGF121/rGel.
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发表时间：
2007-03
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通讯作者：
A. Hsu;W. Cai;A. Veeravagu;K. Mohamedali;Kai Chen;Sehoon Kim;H. Vogel;Lewis C. Hou;V. Tse
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作者：
A. Hsu;W. Cai;A. Veeravagu;K. Mohamedali;Kai Chen;Sehoon Kim;H. Vogel;Lewis C. Hou;V. Tse
未标记的血管内皮生长因子A（VEGF-A）及其受体Flt-1/FLT-1（VEGFR-1）和Flk-1/KDR（VEGFR-2）是肿瘤血管生成和肿瘤生长的关键调节因子。本研究的目的是通过使用非侵入性体内生物发光成像（BLI）、MRI和PET，在原位胶质母细胞瘤小鼠模型中确定血管靶向融合毒素（VEGF（121）/rGel）的抗血管生成和抗肿瘤功效，该融合毒素由VEGF-A亚型VEGF（121）与重组植物毒素gelonin（rGel）通过G（4）S系链连接组成。方法荷瘤小鼠随机分为2组，根据BLI和MRI信号进行平衡。在VEGF（121）/rGel治疗之前，用（64）Cu-1，4，7，10-四氮杂环十二烷-N，N '，N“，N”"-四乙酸（DOTA）-VEGF（121）/rGel进行PET。（18）F-氟胸苷（（18）F-FLT）扫描在治疗前和治疗后获得以评估VEGF（121）/rGel治疗功效。体内结果证实了离体组织学和免疫组织化学分析。结果BLI峰值信号强度的对数变换与MRI肿瘤体积呈显著正相关（r = 0.89，n = 14）。治疗前用（64）Cu-DOTA-VEGF（121）/rGel进行的PET显示，在注射后18小时，肿瘤蓄积（平均值+/- SD）为11.8 +/-2.3%注射剂量/克，并且通过在过量VEGF存在下成功阻断摄取证实了肿瘤蓄积的受体特异性（121）。与对照小鼠相比，（18）F-FLT PET显示VEGF（121）/rGel治疗小鼠的肿瘤增殖显著降低。组织学分析显示，在用4个剂量的VEGF（121）/rGel治疗后，特异性肿瘤新生血管损伤;这种损伤伴随着峰值BLI肿瘤信号强度的显著降低。结论本研究结果表明，未来的临床多模态成像和VEGF（121）/rGel治疗可能提供一种有效的手段，以前瞻性地识别将从VEGF（121）/rGel治疗中获益的患者，然后分层，个性化和监测治疗，以获得最佳的生存结局。
UNLABELLED Vascular endothelial growth factor A (VEGF-A) and its receptors, Flt-1/FLT-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2), are key regulators of tumor angiogenesis and tumor growth. The purpose of this study was to determine the antiangiogenic and antitumor efficacies of a vasculature-targeting fusion toxin (VEGF(121)/rGel) composed of the VEGF-A isoform VEGF(121) linked with a G(4)S tether to recombinant plant toxin gelonin (rGel) in an orthotopic glioblastoma mouse model by use of noninvasive in vivo bioluminescence imaging (BLI), MRI, and PET. METHODS Tumor-bearing mice were randomized into 2 groups and balanced according to BLI and MRI signals. PET with (64)Cu-1,4,7,10-tetraazacyclododedane-N,N',N'',N'''-tetraacetic acid (DOTA)-VEGF(121)/rGel was performed before VEGF(121)/rGel treatment. (18)F-Fluorothymidine ((18)F-FLT) scans were obtained before and after treatment to evaluate VEGF(121)/rGel therapeutic efficacy. In vivo results were confirmed with ex vivo histologic and immunohistochemical analyses. RESULTS Logarithmic transformation of peak BLI tumor signal intensity revealed a strong correlation with MRI tumor volume (r = 0.89, n = 14). PET with (64)Cu-DOTA-VEGF(121)/rGel before treatment revealed a tumor accumulation (mean +/- SD) of 11.8 +/- 2.3 percentage injected dose per gram at 18 h after injection, and the receptor specificity of the tumor accumulation was confirmed by successful blocking of the uptake in the presence of an excess amount of VEGF(121). PET with (18)F-FLT revealed significant a decrease in tumor proliferation in VEGF(121)/rGel-treated mice compared with control mice. Histologic analysis revealed specific tumor neovasculature damage after treatment with 4 doses of VEGF(121)/rGel; this damage was accompanied by a significant decrease in peak BLI tumor signal intensity. CONCLUSION The results of this study suggest that future clinical multimodality imaging and therapy with VEGF(121)/rGel may provide an effective means to prospectively identify patients who will benefit from VEGF(121)/rGel therapy and then stratify, personalize, and monitor treatment to obtain optimal survival outcomes.