Prevention of liver tumor formation in woodchucks with established hepatocellular carcinoma by treatment with cationic liposome-DNA complexes.
Prevention of liver tumor formation in woodchucks with established hepatocellular carcinoma by treatment with cationic liposome-DNA complexes.
复制标题
DOI：
10.1186/s12885-017-3163-2
复制
发表时间：
2017-03-06
期刊：
影响因子：
3.8
通讯作者：
Menne S
中科院分区：
文献类型：
--
作者：
Fairman J;Liu KH;Menne S
全世界约有2.5亿人慢性感染B型肝炎病毒（HBV），超过一半的肝细胞癌（HCC）病例归因于这种感染。由于HCC具有高死亡率，并且目前的治疗选择非常有限，因此有必要开发新的治疗性治疗策略。在这项研究中，土拨鼠感染土拨鼠肝炎病毒（WHV），并与预先存在的肝肿瘤，被用来作为一个模型，以调查复合物的阳离子脂质体和非编码DNA（JVRS-100）是有效的治疗肝癌。观察到在典型的慢性WHV感染中存在的高血清病毒载量（即，比人病毒载量高约100倍）导致免疫抑制和对JVRS-100治疗的抗性。基于对JVRS-100治疗的响应性，具有与通常在人HBV感染中观察到的病毒载量更紧密匹配的较低血清病毒载量的土拨鼠的治疗似乎是免疫系统发展的更好模型。在后一种情况下，WHV DNA和WHV表面抗原在12周的治疗期间显著下降，并且WHV标志物在12周随访期间的大多数时间点保持抑制。甚至更值得注意的是，与在媒介物处理的对照动物中发展的几种新肿瘤相比，在用良好耐受剂量的JVRS-100处理的土拨鼠中没有观察到新肝肿瘤的形成。虽然在治疗时存在的肝肿瘤的体积几乎没有减少，但人们普遍认为，预防几乎总是致命的癌症如HCC的扩散和转移，从而将其减少为慢性和可治疗的疾病也可以是一种成功的治疗方法。土拨鼠的结果证明了JVRS-100作为预防慢性HBV感染和HCC发展高风险患者肝癌的干预措施的研究。
Approximately 250 million people worldwide are chronically infected with hepatitis B virus (HBV) and more than half of the hepatocellular carcinoma (HCC) cases are attributed to this infection. As HCC has a high mortality rate, and current treatment options are remarkably limited, the development of new therapeutic treatment strategies is warranted. In this study, woodchucks infected with woodchuck hepatitis virus (WHV), and with pre-existing liver tumors, were used as a model to investigate if complexes of cationic liposomes and non-coding DNA (JVRS-100) were effective in treatment of HCC. It was observed that the high serum viral load that is present in a typical chronic WHV infection (i.e., approximately 100-fold higher than human viral loads) results in immune suppression and resistance to treatment with JVRS-100. Treatment of woodchucks with lower serum viral load that more closely matched with the viral load usually seen in human HBV infection appears a better model for immunotherapeutic development based on the responsiveness to JVRS-100 treatment. In the latter case, marked declines in WHV DNA and WHV surface antigen were determined over the 12-week treatment period and WHV markers stayed suppressed during most time points of the 12-week follow-up period. Even more remarkably, the formation of new liver tumors was not observed in woodchucks treated with a well-tolerated dose of JVRS-100, as compared to several new tumors that developed in vehicle-treated control animals. Although there was little decrease in the volumes of the liver tumors existing at the time of treatment, it is generally accepted that preventing the spread and metastasis of almost always fatal cancers such as HCC and thus, reducing it to a chronic and treatable disease can also be a successful therapeutic approach. The results in woodchucks warrant the investigation of JVRS-100 as an intervention to prevent liver cancer in patients chronically infected with HBV and at high risk for HCC development.