关注原发性肝癌的靶向治疗研究

近年来,肿瘤的靶向治疗取得很大进展,成为肿瘤临床研究的热点,并对某些肿瘤取得明显疗效。针对原发性肝癌(下称肝癌)的靶向治疗亦引起进一步重视。肝切除术是目前肝癌治疗最有效的根治性手段。对于不能手术切除的肝癌可考虑从器官(组织)、细胞和分子三个水平实施靶向治疗。     

原发性肝癌的分子靶向治疗策略

原发性肝癌(简称肝癌)是严重危害我国人民健康的重大疾病,具有高发病率、高转移率、高复发率和高病死率的特点.探索新的更有效的肝癌治疗方法一直是研究的热点,也是对目前以外科手术切除和肝移植为主的肝癌综合治疗体系的有益补充和改进.     

肝癌的靶向治疗——对人肝细胞癌进行抗体介导的治疗

作的研究目的是开发肿瘤特异性靶抗原高亲和力和高稳定性的抗体及其片段，来尝试研制人肝细胞癌（HCC）新的治疗制剂。肿瘤相关抗原是药物和基因传送的很好靶位，具有细胞特异性的优点。作已经研究了使用抗人肝细胞癌细胞系的单克隆抗体（Mab）AF-20作为模型系统。     

IGF-1受体介导的信号通路与肝癌靶向治疗

胰岛素样生长因子家簇（IGFs）与肝癌（HCC）发生发展、转移和耐药相关。IGF-ⅠR和IGF-Ⅱ在HCC进展过程中过量表达,IGF-ⅠR与IGF-Ⅱ结合导致自身酪氨酸激酶磷酸化,激活下游信号通路,使肝细胞恶性转化潜力增加,已证实IGF-ⅠR是HCC分子治疗的理想靶点。本文概述了IGF-ⅠR在HCC发生发展过程中表达、作用及所介导的肝癌靶向治疗进展。     

抗体介导的肝癌靶向治疗现状及展望

针对肿瘤抗原的单克隆抗体可以特异地识别肿瘤细胞，并且能将效应分子如核素、化疗药物等选择性地携带至肿瘤局部杀伤肿瘤，从而使抗体介导的肝癌靶向治疗策略应运而生，并成为人们日益关注的焦点。     

肝细胞癌的靶向治疗

近年来,随着肝细胞癌(HCC)分子机制研究深入,靶向治疗也得到了迅猛发展,在延缓和改善患者疾病进展和预后方面作出了巨大贡献。由于HCC的发病机制错综复杂,单一的分子靶向治疗总体临床收益并不理想。因此,近年来靶向联合其他治疗方式的新方案不断出新,并取得了令人鼓舞的成果。就HCC分子靶向治疗药物、研究现状及临床联合应用治疗进展予以简要总结。     

肝细胞癌的分子靶向治疗进展

肝细胞癌是临床常见的恶性肿瘤,传统的手术及化疗难以使患者受益。近年来,分子靶向治疗对一些肿瘤已取得突破性进展,肝癌的分子靶向治疗也在临床试验中取得了令人鼓舞的结果。本文针对肝癌的分子靶向治疗的研究进展做一综述。     

肝细胞癌的分子靶向治疗

分子靶向治疗是近10年来肿瘤治疗领域的重大突破,在肺癌、恶性胃肠间质细胞瘤、恶性淋巴瘤、肠癌、乳腺癌等肿瘤的治疗中已获得很大的成功,尤其HCC的分子靶向治疗在小分子靶向治疗上取得了令人瞩目的新进展,特别是多靶点药物索拉非尼在HCC的靶向治疗中取得的成功,使HCC分子靶向全身治疗有了新的标准。     

肝癌的靶向治疗——肝细胞癌的免疫治疗策略

对肝细胞癌的治疗需要不断地寻找新的思路和方法。对癌症的免疫治疗是很吸引人的。因为免疫反应具有很好的特异性。HCC特异反应的激活可通过以肿瘤相关的自身抗原为靶向的策略来完成（例如，甲胎蛋白（AFP））。基因序列研究也已增加了能作为靶目标的HCC特异性基因产品。     

Effect of blocking IGF-Ⅰ receptor on growth of human hepatocellular carcinoma cells

AIM: To study the expression level and localization of insulin-like growth factor -Ⅰ receptor (IGF-IR) in HepG2 cells and Chang liver cells, and to observe the effect of anti-IGF-IR monoclonal antibody (αIR3) on the growth of HepG2 cells.METHODS: The expression of IGF-IR in HepG2 cells and Chang liver cells was detected by immunohistochemistry.The influences of αIR3 on proliferation and apoptosis were examined by the 3- (4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and electron microscopy, respectively. Flow cytometry (FCM) was applied for the analysis of cell cycle and apoptosis was observed under electron microscope.RESULTS: IGF-IR was located in the membranes of both HepG2 and Chang liver cell lines, and the expression level of IGF-IR was higher in HepG2 cells than in Chang liver cells. Treated with 0.1 μg/mL αIR3 for 48 h in vitro, the cell growth index (GI) of HepG2 cells was significantly higher than that of control (103.41% vs 100%, P ＜ 0.01).However, the αIR3 for 24 h at final concentration of 4.0 μg/mL made the GI of HepG2 cells lower than that of control (93.37% vs 100%, P ＜ 0.01). Compared with control, treated with αIR3 for 48 h at final concentrations ranging from 1.0 μg/mL to 4.0 μg/mL markedly reduced the GIs of HepG2 cells (97.63%, 97.16%, 95.13%,92.53% vs 100%, P ＜ 0.05 or P ＜ 0.01), treated with αIR3 for 72 h at final concentrations ranging from 0.2 μg/mL to 4.0 μg/mL decreased the GIs of HepG2 cells obviously (95%, 91.63%, 90.77%, 89.84%, 88.51% vs 100%, P ＜ 0.01), and treated with αIR3 for 96 h at final concentrations ranging from 0.5 μg/mL to 4.0 μg/mL made GIs of HepG2 cells lower significantly (88.86%,83.97%, 79.81%, 77.24%, 70.51% vs 100%, P ＜ 0.05 or ,P ＜ 0.01). Moreover, treated with αIR3 from 24 h to 96 h at final concentrations ranging from 0.2 μg/mL to 4.0 μg/mL reduced the GI of HepG2 cells from 97.63% to 70.51% in a dose- and time-dependent manner. Also,αIR3 treatment for 72 h at final concentration from 0.5 μg/mL to 2.0 μg/mL increased the proportion of G0/G1 phase cells(61.73%, 67.1%, 83.7%,76.87% vs 44.47%,P ＜ 0.01) and significantly decreased that of S phase cells(28.63%, 25.13%, 15.63%, 23.13% vs 53.17%, P ＜ 0.01), in contrast to the proportion of G2/M phase cells.The apoptotic rates of HepG2 cells were increased more than that of control (7.83%, 16.13%, 21.1%, 37.73% vs 4.13%, P ＜ 0.01).CONCLUSION: The malignant cell phenotype of human hepatocarcinoma cell is related to overexpression of IGFIR. The blockage of IGF-IR with αIR3 may contribute to the inhibition of proliferation and induction of apoptosis in HepG2 cells.     

Effect of blocking IGF-Ⅰ receptor on growth of human hepatocellular carcinoma cells

AIM: To study the expression level and localization of insulin-like growth factor -I receptor (IGF-IR) in HepG2 cells and Chang liver cells, and to observe the effect of anti-IGF-IR monoclonal antibody (αIR3) on the growth of HepG2 cells. METHODS: The expression of IGF-IR in HepG2 cells and Chang liver cells was detected by immunohistochemistry. The influences of aIR3 on proliferation and apoptosis were examined by the 3- (4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and electron microscopy, respectively. Flow cytometry (FCM) was applied for the analysis of cell cycle and apoptosis was observed under electron microscope. RESULTS: IGF-IR was located in the membranes of both HepG2 and Chang liver cell lines, and the expression level of IGF-IR was higher in HepG2 cells than in Chang liver cells. Treated with 0.1μg/mLαIR3 for 48 h in vitro, the cell growth index (GI) of HepG2 cells was significantly higher than that of control (103.41% vs 100%, P<0.01). However, the aIR3 for 24 h at final concentration of 4.0μg/mL made the GI of HepG2 cells lower than that of control (93.37% vs 100%, P < 0.01). Compared with control, treated with aIR3 for 48 h at final concentrations ranging from 1.0μg/mL to 4.0μg/mL markedly reduced the GIs of HepG2 cells (97.63%, 97.16%, 95.13%, 92.53% vs 100%, P < 0.05 or P < 0.01), treated withαIR3 for 72 h at final concentrations ranging from 0.2μg/mL to 4.0μg/mL decreased the GIs of HepG2 cells obviously (95%, 91.63%, 90.77%, 89.84%, 88.51% vs 100%, P<0.01), and treated with aIR3 for 96 h at final concentrations ranging from 0.5μg/mL to 4.0μg/mL made GIs of HepG2 cells lower significantly (88.86%, 83.97%, 79.81%, 77.24%, 70.51% vs 100%, P<0.05 or P<0.01). Moreover, treated withαIR3 from 24 h to 96 h at final concentrations ranging from 0.2μg/mL to 4.0μg/mL reduced the GI of HepG2 cells from 97.63% to 70.51% in a dose- and time-dependent manner. Also,αIR3 treatment for 72 h at final concentration from 0.5μg/mL to 2.0μg/mL increased the proportion of G0/G1 phase cells(61.73%, 67.1%, 83.7%,76.87% vs 44.47%, P<0.01) and significantly decreased that of S phase cells(28.63%, 25.13%, 15.63%, 23.13% vs 53.17%, P<0.01), in contrast to the proportion of G2/M phase cells. The apoptotic rates of HepG2 cells were increased more than that of control (7.83%, 16.13%, 21.1%, 37.73% vs 4.13%, P< 0.01). CONCLUSION: The malignant cell phenotype of human hepatocarcinoma cell is related to overexpression of IGF-IR. The blockage of IGF-IR with aaaaaIR3 may contribute to the inhibition of proliferation and induction of apoptosis in HepG2 cells.     

原发性肝癌基因治疗的研究进展

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和热点。新的基因治疗策略不断涌现，载体系统不断更新，导人方法不断优化，动物模型不断改进，本文就以上方面进行综述。     

Radioimmunotherapy for unresectable hepatocellular carcinoma using131I-Hepama-1 mAb: preliminary results

Twenty-three patients with surgically verified unresectable hepatocellular carcinoma (HCC) have been treated by intrahepatic arterial administration of¹³¹I-labeled anti-HCC monoclonal antibody (Hepama-1) combined with hepatic artery ligation. Radioimmunoimaging demonstrated that the median tumor/liver ratio was 2.1 (1.1–3.6) at day 5. A decline in -fetoprotein level and shrinkage of tumor were observed in 75% (12/16) and 78% (18/23) of patients respectively. Sequential resection was done in 11 patients (48%) after treatment. The surgical specimens revealed massive necrosis of tumor, but residual cancer cells were found at the edge of the specimens. Anti-antibody was determined in 43% (10/23) of patients 2–4 weeks after the administration of¹³¹I-Hepama-1 mAb. No marked toxic effects were noted. It is suggested that¹³¹I-Hepama-1 mAb might be of value as one of the multimodality treatments for unresectable HCC.     

Role of the tissue microenvironment as a therapeutic target in hepatocellular carcinoma

Hepatocellular carcinoma is difficult to treat,primarilybecause the underlying molecular mechanisms drivingclinical outcome are still poorly understood.Growingevidence suggests that the tissue microenvironmenthas a role in the biological behavior of the tumor.Themain clinical issue is to identify the best target fortherapeutic approaches.Here,we discuss the hypothesis that the entire tissue microenvironment might beconsidered as a biological target.However,the tissuemicroenvironment consists of several cellular and biochemical components,each of which displays a distinctbiological activity.We discuss the major components ofthis environment and consider how they may interactto promote tumor/host crosstalk.     

Progress in systemic therapy of advanced hepatocellular carcinoma

Primary liver cancer, mainly consisting of hepatocellular carcinoma (HCC), is one of common malignancies worldwide, and prevalent among the Chinese population. A diagnosis of early stage HCC has proven to be very difficult because of its insidious feature in onset and development. At the time of diagnosis, most HCC cases are locally advanced and/or distant metastatic, which results in difficulty to be treated and poor prognosis. For advanced HCC, systemic therapy is frequently adopted as an important palliative method. In recent years, clinical studies and observations have often reported about systemic anti-cancer therapy of advanced HCC, including molecular target therapy, systemic chemotherapy and immunotherapy. In this article, we review these treatment modalities to provide a reference for clinicians.     

原发性肝癌伴门脉癌栓综合诊治的研究进展

原发性肝细胞癌（HCC）是较常见的消化道恶性肿瘤之一，其死亡率居我国恶性肿瘤的第二位，而伴有门脉癌栓（PVTT）的肝癌因易发生肝内及远处转移，被认为是预后差的主要指标之一，生存期为2．4～2．7个月。虽然HCC合并门脉癌栓是预后不良的标志，但在肝功能及一般情况允许的情况下，仍可尝试多种治疗方法以提高此类患者的生存率，综合治疗在该病的治疗中起着重要的作用。     

Radiation therapy for portal venous invasion by hepatocellular carcinoma

AIM: To clarify the efficacy and safety of three-dimensional conformal radiotherapy (3-D CRT) for this disease and to specify patient subgroups suitable for this treatment. METHODS: Fifty-two patients with HCC received PVI-targeted radiation therapy from January 1995 through December 2003. Portal venous invasion (PVI) was found in the second or lower order branches of the portal vein in 6 patients, in the first branch in 24 patients and in the main trunk in 22 patients. Child classifications of liver function before radiation therapy were A, B, and C for 19, 24 and 2 patients, respectively. All patients received three-dimensional conformal radiotherapy with a total dose ranging from 39 to 60 Gy (57.0 Gy in average). RESULTS: Overall survival rates at 1, 2, 3, 4, and 5 years were 45.1%, 25.3%, 15.2%, 10.1%, and 5.1%, respectively. Univariate analysis revealed that Child status, the number of tumor foci, tumor type, transcatheter arterial embolization (TAE) after radiation therapy were statistically significant prognostic factors. Multivariate analysis showed that the number of tumor foci and TAE after radiation therapy were statistically significant. CONCLUSION: The results of this study strongly suggest the efficacy of 3-D CRT as treatment for PVI in HCC. 3-D CRT is recommended in combination with post-radiation TAE for PVI of HCC with 5 tumor foci or less in the liver and with Child A liver function.     

Improved long-term survival for unresectable hepatocellular carcinoma (HCC) with a combination of surgery and intrahepatic arterial infusion of 131I-anti-HCC mAb. Phase I/II clinical trials

Resectional therapy has been accepted as the only curative therapy for hepatocellular carcinoma (HCC). Unfortunately, it is estimated that only 10% of HCC are resectable at the time of diagnosis. Cytoreduction and sequential resection offer a new hope for patients with unresectable HCC. Radioimmunotherapy (RIT) is an attractive approach for cytoreduction. We have previously shown that intrahepatic arterial ¹³¹I-labelled anti-HCC monoclonal antibody (¹³¹I-Hepama-1 mAb) could be used safely in combination with hepatic artery ligation for treatment of unresectable HCC, and encouraging results have been achieved. In this paper, the long-term survival and the prognostic factors in HCC patients treated with radioimmunotherapy will be analysed. Sixty-five patients with surgically verified unresectable HCC were treated with hepatic artery ligation plus hepatic artery cannulation and infusion from 1990 to 1992. Thirty-two patients were enrolled in a phase I–II clinical trial with infusion of ¹³¹I-radiolabelled anti-HCC monoclonal antibody (Hepama-1 mAb) via the hepatic artery (the RIT group). Another 33 patients formed the group treated with intrahepatic-arterial chemotherapy (the non-RIT group). T cell subsets were measured in 24 patients and human anti-(murine Ig) antibody (HAMA) were monitored in the RIT group. The 5-year survival rate was significantly higher in the RIT group than in the chemotherapy group, being 28.1% compared to 9.1% (P < 0.05); this was mainly a result of better cytoreduction and a higher sequential resection rate (53.1% compared to 9.1%). Significant prognostic factors in the RIT group included tumour capsule status and the number of tumour nodules. HAMA incidence and CD₄ ⁺ T lymphocytes influenced short-term, but not long-term survival. It is suggested that intrahepatic-arterial RIT, using ¹³¹I-Hepama-1 mAb, combined with hepatic artery ligation might be an effective approach to improve long-term survival in some patients with unresectable HCC, which may successfully be made resectable by intra-arterial infusion of ¹³¹I-Hepama-1 mAb. Received: 21 April 1997 / Accepted: 14 January 1998     

肝细胞癌的分子靶向治疗

肝细胞癌(hepatocellular carcinoma,HCC)是人类第5大恶性肿瘤,死亡率极高.在我国,HCC的治疗已取得显著进展,但总体发病率和死亡率尚无明显改观,对于不适宜手术切除的晚期HCC,现有的药物治疗并不能改善患者预后,进一步提高疗效仍面临严峻挑战.所以,发现新的靶向治疗药物或新的靶点对HCC的早期诊断、化学预防以及治疗显得尤为重要.目前从对HCC发生、发展的分子机制的研究中,人类已发现了多个潜在分子靶点.这些靶点大部分为酪氨酸激酶受体激活的信号传导通路,包括:Raf/MEK/ERK,PI-3K/Akt/mTOR和Jak/Stat等.以索拉菲尼、舒尼替尼等为药物代表的多靶点、多激酶抑制剂治疗HCC更是受到高度关注.本文主要介绍HCC潜在的分子靶点以及常用靶向药物的临床进展.