Long Term Survival of Mice With Hepatocellular Carcinoma after Pulse Power Ablation with Nanosecond Pulsed Electric Fields
Long Term Survival of Mice With Hepatocellular Carcinoma after Pulse Power Ablation with Nanosecond Pulsed Electric Fields
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DOI：
10.7785/tcrt.2012.500237
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发表时间：
2012-02-01
影响因子：
2.8
通讯作者：
Beebe, S. J.
中科院分区：
文献类型：
--
作者：
Chen, X.;Zhuang, J.;Beebe, S. J.
需要新的治疗方法来治疗肝细胞癌（HCC），而不会在一次手术中复发。在这项工作中，我们评估了脉冲功率消融（PPA）与纳秒脉冲电场（nsPEFs），一个非热，非药物，局部，区域的方法，在体内肝细胞癌肿瘤消融的抗肿瘤作用，并研究其分子机制。用C57 BL/6小鼠建立了Hepa 1 -6肝癌细胞异位肿瘤模型。通过具有不同电场强度（33、50和68 kV/cm）的针电极或环形电极输送持续时间为30或100 ns且上升时间较快的脉冲，并且在三个治疗疗程（每个疗程300个脉冲）中输送900个脉冲或单次900个脉冲治疗。通过超声监测治疗和对照肿瘤体积，并通过免疫组织化学评价细胞凋亡和血管生成标记物。75%的原发性肝细胞癌肿瘤在单次治疗或三次治疗中以68 kV/cm的100 ns脉冲900次脉冲根除，9个月内无复发。使用定量分析，治疗动物中的肿瘤显示出nsPEF介导的核浓缩（脉冲后3小时）、细胞收缩（1小时）、活性执行者半胱天冬酶（半胱天冬酶-3> -7 > -6）和末端脱氧核苷酸转移酶dUTP缺口末端标记（1小时）的增加以及血管内皮生长因子表达（7天）和微血管密度（14天）的降低。NsPEF消融通过靶向两个治疗部位（细胞凋亡诱导和血管生成抑制，这两个都是重要的癌症标志）消除肝细胞癌肿瘤。这些数据表明，PPA与nsPEF不仅限于治疗皮肤癌，并提供了一个理由，继续研究脉冲功率消融肝细胞癌使用其他模型在临床前应用，并最终在临床试验。基于目前对特定HCC阶段的治疗，预计nsPEF可以替代使用热、冷或化学品的消融治疗或与消融治疗联合使用。
Novel therapies are needed for treating hepatocellular carcinoma (HCC) without recurrence in a single procedure. In this work we evaluated anti-neoplastic effects of a pulse power ablation (PPA) with nanosecond pulsed electric fields (nsPEFs), a non-thermal, non-drug, local, regional method and investigated its molecular mechanisms for hepatocellular carcinoma tumor ablation in vivo. An ectopic tumor model was established using C57BL/6 mice with Hepa1-6 hepatocellular carcinoma cells. Pulses with durations of 30 or 100 ns and fast rise times were delivered by a needle or ring electrode with different electric field strengths (33, 50 and 68 kV/cm), and 900 pulses in three treatment sessions (300 pulses each session) or a single 900 pulse treatment. Treated and control tumor volumes were monitored by ultrasound and apoptosis and angiogenesis markers were evaluated by immunohistochemistry. Seventy five percent of primary hepatocellular carcinoma tumors were eradicated with 900 hundred pulses at 100 ns pulses at 68 kV/cm in a single treatment or in three treatment sessions without recurrence within 9 months. Using quantitative analysis, tumors in treated animals showed nsPEF-mediated nuclear condensation (3h post-pulse), cell shrinkage (1 h), increases in active executioner caspases (caspase-3 > -7 > -6) and terminal deoxynucleotidyl transferase dUTP nick-end-labeling (1h) with decreases in vascular endothelial growth factor expression (7d) and micro-vessel density (14d). NsPEF ablation eliminated hepatocellular carcinoma tumors by targeting two therapeutic sites, apoptosis induction and inhibition of angiogenesis, both important cancer hallmarks. These data indicate that PPA with nsPEFs is not limited to treating skin cancers and provide a rationale for continuing to investigate pulse power ablation for hepatocellular carcinoma using other models in pre-clinical applications and ultimately in clinical trials. Based on present treatments for specific HCC stages, it is anticipated that nsPEFs could be substituted for or used in combination with ablation therapies using heat, cold or chemicals.