Shanghai Key Laboratory for Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.
Biomedical Group, Campus Gasthuisberg, KU Leuven, Leuven 3000, Belgium.
World J Gastroenterol. 2018 Jul 7;24(25):2710-2721. doi: 10.3748/wjg.v24.i25.2710.
To compare therapeutic responses of a vascular-disrupting-agent, combretastatin-A4-phosphate (CA4P), among hepatocellular carcinomas (HCCs) and implanted rhabdomyosarcoma (R1) in the same rats by magnetic-resonance-imaging (MRI), microangiography and histopathology.
Thirty-six HCCs were created by diethylnitrosamine gavage in 14 rats that were also intrahepatically implanted with one R1 per rat as monitored by T2-/T1-weighted images (T2WI/T1WI) on a 3.0T clinical MRI-scanner. Vascular response and tumoral necrosis were detected by dynamic contrast-enhanced (DCE-) and CE-MRI before, 1 h after and 12 h after CA4P iv at 10 mg/kg (treatment group = 7) or phosphate-buffered saline at 1.0 mL/kg (control group = 7). Tumor blood supply was calculated by a semiquantitative DCE parameter of area under the time signal intensity curve (AUC30). MRI findings were verified by postmortem techniques.
On CE-T1WIs, unlike the negative response in all tumors of control animals, in treatment group CA4P caused rapid extensive vascular shutdown in all R1-tumors, but mildly or spottily in HCCs at 1 h. Consequently, tumor necrosis occurred massively in R1-tumors but patchily in HCCs at 12 h. AUC30 revealed vascular closure (66%) in R1-tumors at 1 h ( < 0.05), followed by further perfusion decrease at 12 h ( < 0.01), while less significant vascular clogging occurred in HCCs. Histomorphologically, CA4P induced more extensive necrosis in R1-tumors (92.6%) than in HCCs (50.2%) ( < 0.01); tumor vascularity heterogeneously scored +~+++ in HCCs but homogeneously scored ++ in R1-tumors.
This study suggests superior performance of CA4P in metastatic over primary liver cancers, which could guide future clinical applications of vascular-disrupting-agents..
通过磁共振成像（MRI）、微血管造影和组织病理学比较血管破坏剂 combretastatin-A4-磷酸（CA4P）在荷肝癌（HCC）和同种植入性横纹肌肉瘤（R1）大鼠中的治疗反应。
14 只大鼠经二乙基亚硝胺灌胃建立 36 个 HCC，同时每只大鼠肝内植入 1 个 R1，在 3.0T 临床 MRI 扫描仪上通过 T2-/T1-加权图像（T2WI/T1WI）监测。在 CA4Piv10mg/kg（治疗组=7 只）或磷酸盐缓冲盐水 1.0mL/kg（对照组=7 只）后 1h 和 12h，进行动态对比增强（DCE）和 CE-MRI，检测血管反应和肿瘤坏死。通过时间信号强度曲线下面积（AUC30）的半定量 DCE 参数计算肿瘤血供。MRI 结果通过死后技术验证。
CE-T1WI 上，与对照组所有肿瘤的阴性反应不同，治疗组 CA4P 在 1h 时迅速广泛地关闭了所有 R1 肿瘤的血管，但在 HCC 中仅轻度或散在关闭。因此，12h 时 R1 肿瘤大量发生坏死，而 HCC 中则呈斑片状坏死。AUC30 显示 1h 时 R1 肿瘤的血管闭塞（66%）（<0.05），随后 12h 时进一步灌注减少（<0.01），而 HCC 中的血管堵塞不太明显。组织形态学上，CA4P 在 R1 肿瘤中诱导的坏死（92.6%）明显多于 HCC（50.2%）（<0.01）；HCC 中肿瘤血管呈+~+++不均匀评分，而 R1 肿瘤中呈++均匀评分。
本研究表明 CA4P 在转移性肝癌中优于原发性肝癌，这可能为血管破坏剂的临床应用提供指导。
