DC-CIK共培养细胞联合索拉菲尼对肝癌细胞体内外的杀伤效应

目的：观察DC、CIK共培养细胞（DC-CIK）联合索拉菲尼(sorafenib)对肝癌细胞BEL-7402的体内外杀伤效应。方法：取健康人外周血单个核细胞,加入不同细胞因子促进DC及CIK细胞成熟并混合共培养。CCK8试剂盒检测DC-CIK共培养细胞联合索拉菲尼对BEL-7402细胞的体外杀伤效应,Annexin V-FITC试剂盒检测两者联合对肝癌细胞凋亡率的影响。用肝癌细胞BEL-7402建立裸鼠皮下移植瘤模型,分为生理盐水对照组、索拉菲尼组、DC-CIK组、DC-CIK+索拉菲尼组,观察它们对裸鼠移植瘤生长的抑制作用。结果：联合组对肝癌细胞的杀伤率及诱导凋亡率均明显高于各单独治疗组,联合组杀伤率高达（75.24±1.91）%,是DC-CIK组的1.8倍,是索拉菲尼单药组的2.1倍（P<0.01）;联合组诱导肝癌细胞凋亡率达（78.32±2.54）%,与单独治疗组相比差异有统计学意义（P<0.05）。体内实验表明,DC-CIK+索拉菲尼组可明显抑制裸鼠BEL-7402移植瘤的生长,抑制率为（83.37±0.16）%,与单独治疗组相比差异有显著统计学意义（P<0.01）。结论：DC-CIK共培养细胞联合索拉菲尼在体内、外可显著抑制肝癌细胞的生长,分子靶向治疗联合细胞免疫治疗可能成为肝癌综合治疗的方法之一。     

索拉菲尼与TACE联合治疗原发性肝癌的临床效果及对bFGF、VEGF水平的影响

目的 分析索拉菲尼与肝动脉化疗栓塞术(TACE)联合治疗原发性肝癌的临床效果及对碱性成纤维细胞生长因子(bFGF)、血管内皮生长因子(VEGF)水平的影响.方法 收集原发性肝癌患者120例,分为治疗组(实施索拉菲尼与TACE联合治疗)与对照组(实施单一TACE治疗)2组,对2组治疗效果进行观察比较.结果 治疗组RR率为60.00％,DCR率为86.67％,均显著高于对照组的21.67％、56.67％ (P ＜0.05);治疗前2组bFGF、VEGF水平对比差异无统计学意义(P＞0.05);治疗后治疗组bFGF、VEGF水平均明显低于治疗前及对照组(P＜0.05);治疗组腹泻、皮疹、高血压以及手足综合征等不良反应发生率均明显高于对照组(P＜0.05),但在对症治疗后均得以快速好转.结论 针对原发性肝癌患者,实施索拉菲尼与TACE联合治疗,能够显著提升治疗的有效率以及疾病控制率,不良反应均为可耐受,具有疗效好,安全性高的优势.值得临床上推广及应用.     

晚期肝癌索拉菲尼治疗完全缓解1例报告简

晚期肝癌缺乏有效的治疗方法.近几年来,索拉菲尼用于晚期肝癌的临床治疗,两个大型临床试验证实对晚期肝癌患者具有明确的临床疗效[1,2],但有关索拉菲尼治疗晚期肝癌获得完全缓解（CR）的报道甚少.作者应用索拉菲尼治疗晚期肝癌,1例获得完全缓解,无瘤生存时间超过2年,现报道如下.     

肝癌血管生成的研究

肝癌是比较典型的多血管肿瘤,其生长和转移依赖肿瘤血管生成。栓塞已有的血管(肝动脉栓塞化疗),和阻断血管生成(索拉菲尼)的治疗已是临床标准的肝癌治疗方法。最近的证据显示侵袭性较强的肝癌可在癌周诱导特殊的环境     

肝动脉化疗栓塞术后胸腺法新联合索拉菲尼治疗中晚期肝癌的疗效分析

目的:探讨中晚期肝细胞型肝癌患者肝动脉化疗栓塞术(transcatheter arterial chemoembolization,TACE)后索拉菲尼联合胸腺法新的疗效分析.方法:回顾性研究第四军医大学附属唐都医院54例中晚期原发性肝癌患者,所有患者均为乙型肝炎表面抗原阳性,并均接受了TACE手术治疗.在手术治疗后三天,开始口服索拉菲尼,以及皮下注射胸腺法新,观察患者的肝功能,计算治疗的有效率以及患者的生存时间.结果:观察组患者的总体有效率82.8%,显著高于对照组的56%,差异有统计学意义(P=0.032);观察组平均生存时间为13.8个月,对照组为10.2个月,可认为观察组生存时间长于对照组(P=0.021);治疗前两组AST、ALT以及白蛋白无明显差异(P>0.05);治疗3个月后与治疗前相比,两组的AST和ALT均得到改善(P<0.05),并且观察组白蛋白提高(P<0.001).结论:胸腺法新、索拉菲尼联合TACE的治疗方法可以有效的改善肝炎病毒所致的原发性肝癌的预后,提高患者的生存期,值得临床推广.     

索拉菲尼治疗中晚期肝癌的临床疗效及安全性

目的探讨索拉菲尼对中晚期肝癌患者的临床疗效。方法选取2014年1月至2015年7月间收治的84例中晚期肝癌患者,随机数表法分为观察组和对照组,每组42例。对照组42例患者采用经导管肝动脉化疗栓塞术(TACE)治疗,观察组42例患者在对照组治疗基础上口服索拉菲尼治疗,比较两组患者治疗的有效性和安全性。结果治疗后,观察组患者总有效率为83.3%,对照组患者为57.1%,差异有统计学意义(P<0.05)。观察组患者血清AFP和Child-Pugh评分均较对照组患者明显改善,差异有统计学意义(P<0.05)。两组患者不良反应症状均较轻,且均经对症处理好转。结论索拉菲尼治疗中晚期肝癌有利于提高患者的生活质量,不会明显增加治疗中不良反应,其疗效显著,且安全可靠,值得临床应用。     

索拉菲尼对原发性肝癌术后患者疗效的系统评价

目的:系统评价索拉菲尼对原发性肝癌切除术后患者的疗效。方法:在Medline、Embase、Cochrane Library、中国知网（CNKI）数据库、万方数据库、中国生物医学数据库（CBM）检索有关索拉菲尼对原发性肝癌患者术后辅助治疗效果,主要观察目标为总生存期,次要观察目标为肿瘤复发率和死亡率。结果:索拉非尼治疗组与对照组比较,总生存率无显着性差异（HR=1.39,95％CI:0.71~2.74,P=0.34）;复发率无显著性差异（RR=0.81,95％CI:0.65~1.01,P=0.06）。随即我们根据文献类型,将研究分为试验性研究和观察性研究两个亚组来分析患者死亡率,发现临床试验组中肝癌术后接受索拉菲尼治疗的患者死亡率虽然降低但无统计学意义（P=0.45）,而在观察研究组中是具有统计学意义的（RR=0.66,95％CI:0.51~0.87,P=0.003）。结论:对于肝癌术后患者索拉菲尼并不能提高患者总生存期,也不能降低肿瘤复发率,但亚组分析中可以降低患者的死亡率。因此索拉非尼是否是原发性肝癌切除后患者有效的辅助治疗手段,目前仍缺乏足够证据。     

索拉菲尼对COC1DDP细胞增殖凋亡及血管形成影响的研究

卵巢癌是女性生殖器管发病率仅次于子宫颈癌和子宫体癌的常见肿瘤之一,但是其死亡率却占女性各类生殖器官疾病之首。目前的综合治疗手段有化疗、手术、放疗、靶向治疗等。手术及化疗对进展期的卵巢癌治疗效果并不理想,而目前靶向治疗正逐渐成为抗肿瘤药物治疗的重点和热点。索拉菲尼是一种新型的多靶点的生物靶向药物,临床前研究和临床试验的结果都提示索拉菲尼具有抗肿瘤的作用。我们观察索拉菲尼对人体卵巢癌细胞株COC1／DDP的抑制作用,以期为使用索拉菲尼等靶向型药物治疗女性卵巢癌提供试验依据。     

甲胎蛋白对索拉菲尼治疗进展期肝细胞癌的预后评价

近几年来以索拉菲尼为代表的分子靶向药物已成为进展期肝细胞癌综合治疗的热点之一,但目前对于索拉菲尼治疗进展期肝细胞癌的预后评价指标尚没有统一的标准。甲胎蛋白作为重要的肝癌肿瘤标志物,已经广泛地应用于肝细胞癌的筛查诊断,并被认为具有潜在的预测肝细胞癌患者的预后价值。本文总结了近几年来关于甲胎蛋白对索拉菲尼治疗进展期肝细胞癌预后评价的相关文献。从总体上看,甲胎蛋白对于索拉菲尼治疗进展期肝细胞癌预后评价作用是值得肯定的,并可以作为传统的基于影像学资料的肝细胞癌预后评价标准的补充,具有广泛的研究前景和应用价值。     

Selected combination therapy with sorafenib: a review of clinical data and perspectives in advanced solid tumors

The development of targeted therapies has provided new options for the management of patients with advanced solid tumors. There has been particular interest in agents that target the mitogen-activated protein kinase pathway, which controls tumor growth and survival and promotes angiogenesis. Sorafenib is an oral multikinase inhibitor that has been proven effective as a single-agent therapy in renal cell carcinoma, and there is a strong rationale for investigating its use in combination with other agents. In particular, targeting multiple Raf isoforms with sorafenib may help to overcome resistance to other agents, while the ability of sorafenib to induce apoptosis may increase the cytotoxicity of chemotherapeutic agents. Based on positive results in preclinical studies, further investigation in phase I and II studies has shown potential antitumor activity when sorafenib is combined with cytotoxic agents in different solid tumors, including hepatocellular carcinoma and melanoma. Promising results have been reported in phase I and II studies of sorafenib combined with paclitaxel and carboplatin, with oxaliplatin in gastric and colorectal cancer, with docetaxel in breast cancer, with gemcitabine in ovarian cancer, and with capecitabine in different solid tumors. Phase II and III studies are currently investigating the use of sorafenib in combination with different agents in a variety of solid tumors. The primary objective of this review is to summarize the early clinical studies of sorafenib with cytotoxic agents and discuss future perspectives of these combinations in different tumor types.     

肝细胞癌外照射放疗的研究进展

肝细胞癌（hepatocellular carcinoma,HCC）的根治性治疗方式主要为行手术切除、肝移植或消融术。然而,就诊时仅少数病例为可切除病变。随着放疗技术的发展,外照射放疗在HCC治疗中的应用越来越广泛。大量研究表明,放疗对肝功能良好的各期别肝癌均具有明显疗效。立体定向放射治疗（stereotactic body radiation therappy,SBRT）可替代射频消融治疗不可行手术切除的早期HCC,放疗联合其他局部或全身治疗, 如:经导管动脉化学栓塞（transcatheter arterial chemoembdization,TACE）、索拉非尼适用于局部晚期和远处转移晚期HCC的治疗。粒子束因Bragg峰而较X线具有更佳的剂量分布优势,临床应用前景广阔。本文重点阐述外照射放疗在各期别HCC治疗中的进展。      

Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells

Pemetrexed (ALIMTA, Lilly) is a folate antimetabolite that has been approved by the U.S. Food and Drug Administration for the treatment of non-small cell lung cancer and has been shown to stimulate autophagy. In the present study, we sought to further understand the role of autophagy in response to pemetrexed and to test if combination therapy could enhance the level of toxicity through altered autophagy in tumor cells. The multikinase inhibitor sorafenib (Nexavar, Bayer), used in the treatment of renal and hepatocellular carcinoma, suppresses tumor angiogenesis and promotes autophagy in tumor cells. We found that sorafenib interacted in a greater than additive fashion with pemetrexed to increase autophagy and to kill a diverse array of tumor cell types. Tumor cell types that displayed high levels of cell killing after combination treatment showed elevated levels of AKT, p70 S6K, and/or phosphorylated mTOR, in addition to class III receptor tyrosine kinases such as platelet-derived growth factor receptor beta and VEGF receptors, known in vivo targets of sorafenib. In xenograft and in syngeneic animal models of mammary carcinoma and glioblastoma, the combination of sorafenib and pemetrexed suppressed tumor growth without deleterious effects on normal tissues or animal body mass. Taken together, the data suggest that premexetred and sorafenib act synergistically to enhance tumor killing via the promotion of a toxic form of autophagy that leads to activation of the intrinsic apoptosis pathway, and predict that combination treatment represents a future therapeutic option in the treatment of solid tumors.     

Nutlin‐3 enhances sorafenib efficacy in renal cell carcinoma

The renal cell carcinoma (RCC) is one of the top 10 cancers in USA. The renal tumors are highly angiogenic and are resistant to conventional interventions, particularly radiotherapy. The advent of multi‐specific tyrosine kinase inhibitor sorafenib has improved the progression‐free survival in RCC, but overall survival in recurrent and metastatic RCC is still a concern that has lead to characterization of combinatorial regimens. Hence, we studied the effect of combination of nutlin‐3, an MDM2 inhibitor, which increases p53 levels, and sorafenib in RCC. Sorafenib along with nutlin‐3 synergistically inhibited the cell survival and enhanced caspase‐3 cleavage leading to apoptosis in RCC. Nutlin‐3 and sorafenib were more effective in reducing the migration of RCC, in combination than as single agents. Sorafenib and nutlin‐3 decreased the phosphorylation of vascular endothelial growth factor receptor‐2 (VEGFR‐2) and ERK along with inducing p53 activity. The sorafenib and nutlin‐3 co‐treatment lead to enhanced levels of p53, p‐p53, and increase in the levels of p53 pro‐apoptotic effector PUMA, Bax, and decrease in the anti‐apoptotic Bcl‐2 levels. Importantly, our studies revealed that sorafenib alone can activate p53 in a concentration dependent manner. Thus, co‐treatment of nutlin‐3 with sorafenib leads to increased half‐life of p53, which in turn can be activated by sorafenib, to induce downstream pro‐apoptotic and anti‐proliferative effects. This is the first report showing the synergistic effect of sorafenib and nutlin‐3 while providing a strong clinical‐translational rationale for further testing of sorafenib and nutlin‐3 combinatorial regimen in human RCC. © 2011 Wiley Periodicals, Inc.     

Elevated hepatocyte growth factor expression as an autocrine c‐Met activation mechanism in acquired resistance to sorafenib in hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer‐related deaths worldwide. Limitations in HCC treatment result due to poor prognosis and resistance against traditional radiotherapy and chemotherapies. The multikinase inhibitor sorafenib is the only FDA approved drug available for advanced HCC patients, and development of second‐line treatment options for patients who cannot tolerate or develop resistance to sorafenib is an urgent medical need. In this study, we established sorafenib‐resistant cells from Huh7 and Mahlavu cell lines by long‐term sorafenib exposure. Sorafenib‐resistant HCC cells acquired spindle‐shape morphology, upregulated mesenchymal markers, and showed significant increase in both migration and invasion abilities compared to their parental counterparts. Moreover, after long‐term sorafenib treatment, HCC cells showed induction of hepatocyte growth factor (HGF) synthesis and secretion along with increased levels of c‐Met kinase and its active phosphorylated form, indicating autocrine activation of HGF/c‐Met signaling. Importantly, the combined treatment of the resistant cells with c‐Met kinase inhibitor SU11274 and HGF neutralizing antibody significantly reversed the increased invasion ability of the cells. The combined treatment also significantly augmented sorafenib‐induced apoptosis, suggesting restoration of sorafenib sensitivity. These results describe, for the first time, compensatory upregulation of HGF synthesis leading to autocrine activation of HGF/c‐Met signaling as a novel cellular strategy in the acquisition of sorafenib resistance. Therefore, we suggest that combinatorial therapeutic strategies with HGF and c‐Met inhibitors comprise promising candidates for overcoming sorafenib resistance.     

A sorafenib derivative and novel SHP-1 agonist,SC-59, acts synergistically with radiotherapy in hepatocellular carcinoma cells through inhibition of STAT3

Radiotherapy shows limited benefit as treatment for hepatocellular carcinoma (HCC). In this study, we aimed to overcome the radioresistance of HCC by using a novel sorafenib derivative, SC-59 that targets SHP-1-related signaling. HCC cell lines (SK-Hep1, Hep3B, and Huh7) were treated with sorafenib, SC-59, radiation, sorafenib plus radiation, or SC-59 plus radiation, and then apoptosis, colony formation, signal transduction and the phosphatase activity were analyzed. The synergistic effect of radiotherapy and SC-59 was analyzed using a combination index (CI) approach. In vivo efficacy was determined in a Huh7-bearing subcutaneous model. Mice were treated with radiation (5 Gy, one fraction per day) for 4 days, SC-59 (10 mg/kg/day) for 24 days, or a combination. Tumor samples were further analyzed for p-STAT3 and SHP-1 activity. SC-59 displayed a better synergistic effect when used in combination with radiotherapy than sorafenib in HCC cell lines. SC-59 downregulated p-STAT3 and its downstream targets and increased SHP-1 phosphatase activity. Both ectopic STAT3 and inhibition of SHP-1 abolished SC-59-induced radiosensitization. Moreover, SC-59 significantly synergized radiotherapy in a Huh7 xenograft model by targeting SHP-1/STAT3 signaling. The novel sorafenib derivative, SC-59, acting as a SHP-1 agonist, displays a better synergistic effect when used in combination with radiotherapy than sorafenib for the treatment of HCC. Further clinical investigation is warranted.     

Pituitary metastasis from a renal cell carcinoma progressed after sorafenib treatment

Pituitary metastasis from renal cell carcinoma is rare and has never been reported for renal cell carcinoma primarily treated with sorafenib. Herein, we present a case of an advanced clear-cell renal cell carcinoma in which pituitary metastasis progressed but extracerebral metastases showed partial response to sorafenib treatment.     

Transarterial chemoembolization and sorafenib in hepatocellular carcinoma

Transarterial chemoembolization (TACE) is considered as the standard therapy for patients with intermediate-stage hepatocellular carcinoma. However, given the high heterogeneity of this population, no common strategy or protocol standardization has been defined yet. In the last few years TACE treatment has been combined with sorafenib systemic therapy, reporting overall positive results both in terms of safety and efficacy. This systematic review presents and critically discusses the evidence available on the use of TACE in combination (concomitant or sequential) with sorafenib, focusing also on clinical trials currently ongoing to better define an optimal therapeutic strategy for this group of patients.     

Sorafenib: recent update on activity as a single agent and in combination with interferon-alpha2 in patients with advanced-stage renal cell carcinoma

Metastatic renal cell carcinoma does not respond favorably to conventional treatment strategies and is not very responsive to cytokine therapy. Therefore, novel targeted treatment approaches have been explored for patients with renal cancer who have chemotherapy-refractory disease. Sorafenib (BAY 43-9006) is a smallmolecule inhibitor that has been shown to target members of multiple classes of tyrosine kinases that are known to be involved in tumor cell proliferation and tumor angiogenesis. These kinases include vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor, Flt-3, c-kit, and Raf kinases. Based on the significant improvement in progressionfree survival, sorafenib received Food and Drug Administration approval in December 2005 for the treatment of renal cell carcinoma. In combination studies, sorafenib with other antitumor agents has demonstrated significant clinical activity in patients with renal cell carcinoma. As discussed in this mini-review, the clinical potency of sorafenib as a single agent or in combination with other antitumor agents is being evaluated in several ongoing clinical trials in patients with renal carcinoma.     

Sorafenib: Recent Update on Activity as a Single Agent and in Combination with Interferon-α2 in Patients with Advanced-Stage Renal Cell Carcinoma

Metastatic renal cell carcinoma does not respond favorably to conventional treatment strategies and is not very responsive to cytokine therapy. Therefore, novel targeted treatment approaches have been explored for patients with renal cancer who have chemotherapy-refractory disease. Sorafenib (BAY 43-9006) is a smallmolecule inhibitor that has been shown to target members of multiple classes of tyrosine kinases that are known to be involved in tumor cell proliferation and tumor angiogenesis. These kinases include vascular endothelial growth factor receptor (VEGFR)–1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor, Flt-3, c-kit, and Raf kinases. Based on the significant improvement in progressionfree survival, sorafenib received Food and Drug Administration approval in December 2005 for the treatment of renal cell carcinoma. In combination studies, sorafenib with other antitumor agents has demonstrated significant clinical activity in patients with renal cell carcinoma. As discussed in this mini-review, the clinical potency of sorafenib as a single agent or in combination with other antitumor agents is being evaluated in several ongoing clinical trials in patients with renal carcinoma.