肝癌外科诊治的发展与现状：肝癌基因治疗研究近况

肝癌是全球恶性程度极高、预后极差的恶性肿瘤之一．在我国肝癌目前已处于恶性肿瘤死亡率的第2位。尽管目前肝癌的治疗方法有许多种，但治疗效果都十分有限，并未显著延长病人的生存期。肝癌的发生、发展涉及多方面多层次的问题．随着分子生物学和免疫学理论及技术的不断发展。对癌基因的认识不断深入。以及转基因技术的日趋完善，肝癌的基因冶疗领域已显示出一定的前景。本文就目前肝癌基因治疗的研究现状和发展趋势作一综述。     

原发性肝癌基因治疗新进展

基因治疗是一种具有巨大潜力的新的肝癌治疗策略 ,本文综述了近几年来国内外在该领域的研究现状 ,并提出了目前存在的问题及发展趋势     

原发性肝癌基因治疗新进展

基因治疗是一种具有巨大潜力的新的肝癌治疗策略,本文综述了近几年来国内外在该领域的研究现状,并提出了目前存在的问题及发展趋势。     

原发性肝癌基因治疗及护理

肿瘤基因治疗是目前医学研究领域中的前沿课题，是近几年发展起来用于根治癌症的最新方法。本文对其发展过程、方法及护理方面进行综述。     

原发性肝癌基因治疗及护理

肿瘤基因治疗是目前医学研究领域中的前沿课题，是近几年发展起来用于根治癌症的最新方法，本文对其发展过程，方法及护理方面进行综述。     

原发性肝癌免疫基因治疗研究进展

免疫反应是机体清除“异已” ,维持自身稳定的功能 ,但对于肿瘤而言 ,这种反应却往往无效。近年来研究认为肿瘤逃避免疫系统攻击的机制与以下因素有关 :肿瘤不表达特异性抗原 ,或低度表达抗原 ,但缺乏免疫原性 ,缺乏主要组织相容复合体 (ＭＨＣ)抗原 ,或缺乏其刺激分子的表达等。因此 ,免疫基因治疗的目的就是通过基因转染技术 ,增强肿瘤的免疫原性和刺激免疫效应细胞的间接机制 ,达到增强反应的目的。它是肿瘤基因治疗研究中最为活跃的领域。1　细胞因子基因治疗免疫效应细胞介导的细胞因子基因治疗 ,是目前常用的一种方式 ,它以过继免疫疗…     

介入医学与肝癌基因治疗

近年来 ,随着肿瘤分子生物学研究的快速发展 ,在一定程度上阐明了恶性肿瘤的发生、发展的癌变演进过程。目前研究表明肝癌的发生是一个多步骤的复杂过程 ,在这个过程中 ,有多种癌基因和抑癌基因的改变 ,肝癌的癌基因谱已逐渐明朗。肝癌的基因治疗是目前学术界研究的热点 ,已取得了很大的进展。本文综述肝癌基因治疗的研究进展并对介入医学在肝癌基因治疗中的地位和作用作一展望。1　癌基因治疗策略肝癌是多基因突变引起的 ,基因治疗的原则和目的基因的选择较复杂 ,常用的肝癌基因治疗策略可概括为以下几类 :1.1免疫性基因治疗　现代肿瘤免疫…     

基因治疗原发性肝癌的研究进展

目前研究表明,大多数恶性肿瘤的发生与某些特定基因的改变密切相关。因此,肿瘤又被认定是一种基因病。随着越来越多的肿瘤相关基因的确认,基因治疗为肿瘤的治疗提供了一条新的途径,且其将在人类攻克肿瘤这一顽症的过程中,占据重要地位并将成为一种常用手段。原发性肝癌是世界范围内死亡率最高的恶性肿瘤之一,且绝大部分原发性肝癌的预后极差,所以原发性肝癌一直是基因治疗研究的一个重要领域。本文就基因治疗原发性肝癌的研究进展作一简要综述,旨在为其进一步应用提供参考依据。     

肝癌基因治疗的基础研究与临床应用

肝癌基因治疗发展至今已有30余年,基因治疗的策略、载体和治疗基因随着科学的发展不断更新。近年来由于基础研究的重要突破,肝癌基因治疗逐步由基础研究走向临床治疗,并在临床实践过程中不断积累经验,不断成熟。本文将结合自身工作就肝癌基因治疗的基础研究与临床应用作一简短综述。     

原发性肝癌基因治疗的实验研究进展

针对原发性肝癌的传统治疗方法疗效欠佳,预后较差,基因治疗成为新的研究方向,基因治疗的实验研究发展迅速。动物模型不断改进,新的治疗基因不断涌现,载体系统不断更新,导入方法不断优化,本文对上述进行了总结,发现经导管途径的脂质体联合配体受体系统介导的多基因联合治疗将成为广泛运用的基因治疗方法。     

Current approaches in the transcriptional-guided gene therapy of human hepatocellular carcinoma

Hepatocellular carcinoma (HCC), the predominant histological subtype of primary human liver cancer, is one of the most prevalent cancer types worldwide, accounting for an estimated 500,000 deaths annually. The clinical management of HCC is challenging on many counts. HCC is a phenotypically and genetically heterogeneous polyclonal disease and is resistant to most conventional chemotherapy. Early manifestation of HCC is characteristically silent and slow growing with few symptoms, and HCC is therefore often diagnosed at an advanced stage, when potentially curative surgical or local ablative therapy is not feasible. Therefore, clinically validated biomarkers that could confer pathological and functional changes associated with the formation and progression of HCC are urgently needed to provide important molecular basis for the development of novel treatments. Recently, comprehensive molecular gene profiling of primary liver cancer tissues has been employed to identify specific genes that are linked to hepatocarcinogenesis. Current attempts to translate molecular knowledge to design strategies for the experimental gene therapy of HCC are reviewed.     

Alpha-fetoprotein promoter-targeted sodium iodide symporter gene therapy of hepatocellular carcinoma

Due to limited treatment options the prognosis of patients with advanced hepatocellular cancer (HCC) has remained poor. To investigate an alternative therapeutic approach, we examined the feasibility of radioiodine therapy of HCC following human sodium iodide symporter (NIS) gene transfer using a mouse alpha-fetoprotein (AFP) promoter construct to target NIS expression to HCC cells. For this purpose, the murine Hepa 1-6 and the human HepG2 hepatoma cell lines were stably transfected with NIS cDNA under the control of the tumor-specific AFP promoter. The stably transfected Hepa 1-6 cell line showed a 10-fold increase in iodide accumulation, while HepG2 cells accumulated (125)I approximately 60-fold. Tumor-specific NIS expression was confirmed on mRNA level by northern blot analysis, and on protein level by immunostaining, that revealed primarily membrane-associated NIS-specific immunoreactivity. In an in vitro clonogenic assay up to 78% of NIS-transfected Hepa 1-6 and 93% of HepG2 cells were killed by (131)I exposure, while up to 96% of control cells survived. In vivo NIS-transfected HepG2 xenografts accumulated 15% of the total (123)I administered per gram tumor with a biological half-life of 8.38 h, resulting in a tumor absorbed dose of 171 mGy MBq(-1) (131)I. After administration of a therapeutic (131)I dose (55.5 MBq) tumor growth of NIS expressing HepG2 xenografts was significantly inhibited. In conclusion, tumor-specific iodide accumulation was induced in HCC cells by AFP promoter-directed NIS expression in vitro and in vivo, which was sufficiently high to allow a therapeutic effect of (131)I. This study demonstrates the potential of tumor-specific NIS gene therapy as an innovative treatment strategy for HCC.     

无法手术的肝细胞性肝癌的分子靶向治疗

肝细胞性肝癌严重威胁着人类健康。迄今为止,索拉非尼仍是唯一一个被批准用于无法手术的肝细胞性肝癌的药物。近年来,分子靶向治疗药物层出不穷,但其在肝细胞性肝癌的治疗方面却停滞不前,多个III期临床研究都以失败告终。本文详细的回顾了过去2年内公开报道的分子靶向药物在肝癌中的II期和III期临床研究结果,就其研究失败的结果进行了总结,为接下来在肝癌中开展临床研究的药物的研发给出了一点意见和建议。     

A novel tumor-specific replication-restricted adenoviral vector for gene therapy of hepatocellular carcinoma.

Transducing and distributing a vector throughout a tumor mass are presently insufficient for effective cancer gene therapy. To overcome these difficulties an adenoviral vector was designed that would replicate specifically in tumor cells. This tumor-specific replication-restricted adenoviral (TSRRA) vector was constructed by requiring that the essential E1A gene be expressed from a tumor-specific promoter, namely, the alpha-fetoprotein (AFP) gene promoter. This promoter was chosen since the AFP gene is highly expressed in 70-80% of patients with hepatocellular carcinoma (HCC) but not in normal adults. HCC is one of the major worldwide causes of cancer death. A vector was constructed (AvE1a04i) and demonstrated to replicate in human AFP-producing HCC cell lines. However, little replication was observed in seven other, non-AFP-producing human cell lines, as well as primary cultures of normal human lung epithelial and endothelial cells. In addition, AvE1a04i was shown to prevent tumor growth of an ex vivo-transduced AFP-expressing HCC cell line but not a non-AFP-expressing cell line. Finally, in situ administration of AvE1a04i into preestablished tumors resulted in a greater than 50% long-term survival rate. This novel TSRRA vector for HCC demonstrated both specificity and efficacy in vitro and in vivo.     

Eradication of hepatocellular carcinoma xenografts by radiolabelled, lipiodol-inducible gene therapy

The promoter region of the early-growth response-1(Egr-1) gene has been shown to be activated by external radiation, thus making a selective tumoricidal effect possible. A previous experiment showed that the Egr-1 promoter can be activated by internal radiation using radioisotopes as well as external radiation. Internal radiation using I-131 lipiodol (I-131-Lip) has been established as one of the most useful therapeutic strategies against hepatoma. We herein linked the Egr-1 promoter to the herpes simplex virus-thymidine kinase (HSV-TK) gene, and investigated its efficacy in hepatoma gene therapy in combination with I-131-Lip. A luciferase assay showed the Egr-1-promoter activity to be markedly increased in hepatoma tissue specimens in an I-131-dose-dependent manner, whereas a less than two-fold increase in this activity was observed in other organs. In addition, the radioactivity derived from I-131 was selectively accumulated in the tumor tissue specimens. To examine the efficacy of EgrTK/ganciclovir (GCV) gene therapy in vivo, subcutaneous hepatoma xenografts in nude mice were transfected using a hemagglutinating virus of Japan (HVJ)-liposome vector. Complete tumor regression was observed in all the EgrTK-transfected tumors following combination treatment with I-131-Lip and GCV 42 days after treatment without any side effects (n=8). In contrast, the tumors continued to grow in all control mice (n=10). Furthermore, the serum alpha-fetoprotein levels decreased in the combination therapy group, while they increased in the controls. In conclusion, these data indicate that Egr-1 promoter-based gene therapy combined with internal radiation has a selective effect on hepatoma tumors while also showing an improved in vivo efficacy. This combination therapy might, therefore, be an effective human hepatoma gene therapy, even in advanced multiple cases.     

Laparoscopic microwave coagulation therapy for hepatocellular carcinoma

BACKGROUND AND STUDY AIMS: Several different effective forms of treatment are available, singly or in combination, for patients with hepatocellular carcinoma (HCC). These include surgical resection, transcatheter arterial embolization, percutaneous ethanol injection, and percutaneous microwave coagulation therapy. In this study, we carried out laparoscopic microwave coagulation therapy (LMCT), using laparoscopic microwave electrodes to treat HCC. PATIENTS AND METHODS: Under local anesthesia, 24 patients with HCCs located on or near the liver surface underwent LMCT under direct laparoscopic vision, with ultrasound guidance. LMCT was performed using microwave electrodes with tips ranging from 15-45 mm in length, and the effectiveness of the treatment was confirmed using contrast-enhanced computed tomography (CT) within two weeks of the LMCT procedure. RESULTS: The mean longest axis of the 26 HCC nodules in 24 patients was 20 mm, and that of the coagulated areas including the nodules was 40 mm, with additional therapy being required in two patients. Complete efficacy of the treatment was observed in 21 patients (87.5%), but local recurrences were seen in three of them one year after LMCT. The three-year survival rate was 92%, but the number of patients included in the study was small. Hemostasis was complete, but mild pneumothorax occurred in three patients. CONCLUSIONS: LMCT under local anesthesia is a minimally invasive and effective therapy when carried out on a single occasion to treat HCCs located near the liver surface, and it can be safely performed under direct visual guidance.     

肝细胞肝癌分子靶向治疗的影像学评价进展

肝细胞肝癌(简称肝癌)是最常见的恶性肿瘤之一,发病率和死亡率均较高,临床治疗面临着严峻的挑战。近年来分子靶向治疗肿瘤成为国际研究热点,在肝癌治疗上也取得突破性进展,尤其是在不适宜手术切除的晚期肝癌中。及时、准确地评价分子靶向治疗的疗效对于延长晚期肝癌患者的生存期,准确评估预后具有十分重要的意义。笔者主要就目前各种影像学成像技术(超声、CT及MRI)对肝癌分子靶向治疗疗效评价研究进展进行综述。