索拉非尼和沙利度胺对肝癌患者血清中VEGF-C、VEGF-D及微血管密度的影响

目的：探讨索拉非尼和沙利度胺这两种不同的化疗药物,对肝癌患者血清中VEGF-C、VEGF—D及微血管密度的影响。方法：将患者分成3组,每纽16例。对照组采用常规治疗并服用安慰剂;索拉非尼和沙利度胺这两个组患者中,前者服用索拉非尼400mg／次,2次／d,治疗6个月;后者服用沙利度胺每日服200mg,每周增加200mg／d,直至最大剂量每日600mg,至少服用4月。ELISA检测患者血清中VEGF-C、VEGF-D;免疫组织化学检测肝癌组织中微血管密度。结果：对照组患者血清中VEGF-C的水平为210ng／ml,索拉非尼组患者血清中VEGF—C的水平为132ng／ml,而沙利度胺组患者血清中VEGF—C的水平为186ng／ml。与对照组相比,索拉非尼组和沙利度胺组患者血清中VEGF—C的水平均降低。对照组患者血清中VEGF—D的水平为322ng／ml,索拉非尼组患者血清中VEGF—D的水平为217ng／ml,而沙利度胺组患者血清中VEGF—D的水平为256ng／ml。与对照组相比,索拉非尼组和沙利度胺组患者血清中VEGF—D的水平均降低。索拉非尼组患者血清中VEGF—D的水平明显低于沙利度胺高（P〈0．05）。对照组肝癌组织MVD为（44．32±5．16）个,索拉非尼组患者肝癌组织MVD为（21．75±1．49）个,而沙利度胺组患者肝癌组织MVD为（34．78±2．31）个。结论：多靶点化疗药物索拉非尼对肝癌患者血清中VEGF—C、VEGF—D及微血管密度的影响最大,深入探讨其作用机制．可为其肝癌患者提供新的化疗方案。     

索拉菲尼联合阿霉素对人肝癌细胞株HepG2的抑制作用

目的：探讨索拉非尼（Sorafenib）和阿霉素（adriamycin）联合用药对肝癌细胞株nepG2的作用及可能的机制。方法：以不同浓度索拉非尼和不同浓度阿霉素分别组成单药组和索拉非尼＋阿霉素联合用药组作用于HepG2细胞,MTT法检测增殖抑制率、流式细胞仪分析细胞周期和凋亡率。结果：索拉非尼、阿霉素单药与联用均能抑制HepG2细胞增殖,呈剂量依赖效应,两药联用有协同效应（P〈0.01）。索拉非尼、阿霉素单药与联用均能诱导HepG2细胞凋亡,并以联合组更为明显,与对照组比较有显著的统计学意义（P〈0.01）。索拉非尼及阿霉素单药作用均可使细胞周期阻滞于G0-G1期,联合用药组G0/Gl期细胞比率低于索拉非尼及阿霉素单药组,S期细胞比率高于单药组;阿霉素能抑制HepG2细胞Survivin mRNA表达诱导细胞的凋亡。结论：索拉非尼与阿霉素联合作用于人肝癌HepG2细胞具有协同作用,其机制可能是通过多途径共同抑制HepG2细胞增殖及诱导细胞凋亡。     

Involvement of androgen receptor and glucose-regulated protein 78 kDa in human hepatocarcinogenesis

Previous studies demonstrated that androgen receptor (AR) is expressed in human hepatocellular carcinoma (HCC), one of the male-dominant diseases. Glucose-regulated protein 78 kDa (GRP78/Bip), which has a role in cancer development, is one of the androgen response genes in prostate cell lines. The aim of this study was to investigate the impact of AR on endoplasmic reticulum (ER)-stress signaling in human hepatoma. AR and GRP78 expressions were examined in human liver tissue panels. Human hepatoma cells stably expressing short hairpin RNA targeting AR and cells over-expressing AR were generated. The expressions of ER-stress molecules and AR were measured by real-time RT-PCR and Western blotting. The effect of AR on ER-stress responsive gene expression was examined by reporter assay. Strong positive correlation between AR mRNA and GRP78 mRNA was observed in stage I/II-HCCs. AR enhanced ER-stress responsive element activities and GRP78 expression, and regulated ER-stress response in hepatocytes. Sorafenib strongly induced significant apoptosis in HepG2 cells by the inhibition of AR and inhibition of the downstream GRP78. AR seems a co-regulator of GRP78 especially in earlier-stage HCC. AR plays a critical role in controlling ER-stress, providing new therapeutic options against HCC.     

Hepatocellular cancer therapy in patients with HIV infection: Disparities in cancer care,trials enrolment,and cancer-related research

In the highly active antiretroviral therapy (HAART) era, hepatocellular carcinoma (HCC) is arising as a common late complication of human immunodeficiency virus (HIV) infection, with a great impact on morbidity and mortality. Though HIV infection alone may not be sufficient to promote hepatocarcinogenesis, the complex interaction of HIV with hepatitis is a main aspect influencing HCC morbidity and mortality.Data about sorafenib effectiveness and safety in HIV-infected patients are limited, particularly for patients who are on HAART. However, in properly selected subgroups, outcomes may be comparable to those of HIV-uninfected patients. Scarce data are available for those other systemic treatments, either tyrosine kinase inhibitors, as well as immune checkpoint inhibitors (ICIs), which have been added to our therapeutic armamentarium. This review examines the influence of HIV infection on HCC development and natural history, summarizes main data on systemic therapies, offers some insight into possible mechanisms of T cell exhaustion and reversal of HIV latency with ICIs and issues about clinical trials enrollment. Nowadays, routine exclusion of HIV-infected patients from clinical trial participation is totally inappropriate, since it leaves a number of patients deprived of life-prolonging therapies.     

Synthesis,activity and docking studies of phenylpyrimidine–carboxamide Sorafenib derivatives

Two series of Sorafenib derivatives bearing phenylpyrimidine–carboxamide moiety (16a–g and 17a–p) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, MCF-7 and PC-3). Two selected compounds (17f and 17n) were further evaluated for the activity against VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line, with the IC₅₀ values of 6.35 ± 0.43 μM. Meanwhile, compound 17n revealed more active than Sorafenib against A549 cell line, with the IC₅₀ values of 3.39 ± 0.37 μM. Structure–activity relationships (SARs) and docking studies indicated that the second series (17a–p) showed more active than the first series (16a–g). What’s more, the introduction of fluoro atom to the phenoxy part played no significant impact on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity.     

Vascular endothelial growth factors and receptors: anti-angiogenic therapy in the treatment of cancer

Vascular endothelial growth factors (VEGFs) are critical regulators of vascular and lymphatic function during development, in health and in disease. There are five mammalian VEGF ligands and three VEGF receptor tyrosine kinases. In addition, several VEGF co-receptors that lack intrinsic catalytic activity, but that indirectly modulate the responsiveness to VEGF contribute to the final biological effect. This review describes the molecular features of VEGFs, VEGFRs and co-receptors with focus on their role in the treatment of cancer.     

IPGWAS: an integrated pipeline for rational quality control and association analysis of genome-wide genetic studies

Alveolar rhabdomyosarcoma (aRMS) is a very aggressive sarcoma of children and young adults. Our previous studies have shown that small molecule inhibition of Pdgfra is initially very effective in an aRMS mouse model. However, slowly evolving, acquired resistance to a narrow-spectrum kinase inhibitor (imatinib) was common. We identified Src family kinases (SFKs) to be potentiators of Pdgfra in murine aRMS primary cell cultures from mouse tumors with evolved resistance in vivo in comparison to untreated cultures. Treating the resistant primary cell cultures with a combination of Pdgfra and Src inhibitors had a strong additive effect on cell viability. In Pdgfra knockout tumors, however, the Src inhibitor had no effect on tumor cell viability. Sorafenib, whose targets include not only PDGFRA but also the Src downstream target Raf, was effective at inhibiting mouse and human tumor cell growth and halted progression of mouse aRMS tumors in vivo. These results suggest that an adaptive Src-Pdgfra-Raf-Mapk axis is relevant to PDGFRA inhibition in rhabdomyosarcoma.     

Targeting EZH2 as a novel therapeutic strategy for sorafenib‐resistant thyroid carcinoma

Thyroid carcinoma is the most common endocrine malignancy. Surgery, post‐operative selective iodine‐131 and thyroid hormone suppression were the most common methods for the therapy of thyroid carcinoma. Although most patients with differentiated thyroid carcinoma (DTC) showed positive response for these therapeutic methods, some patients still have to face the radioactive iodine (RAI)‐refractory problems. Sorafenib is an oral multikinase inhibitor for patients with advanced RAI refractory DTC. However, the side effects and drug resistance of sorafenib suggest us to develop novel drugs and strategies for the therapy of thyroid carcinoma. In this study, we firstly found that patients with sorafenib resistance showed no significant change in rapidly accelerated fibrosarcoma and VEGFR expression levels compared with sorafenib sensitive patients. Moreover, a further miRNAs screen by qRT‐PCR indicated that miR‐124‐3p and miR‐506‐3p (miR‐124/506) were remarkably reduced in sorafenib insensitive patients. With a bioinformatics prediction and functional assay validation, we revealed that enhancer of zeste homolog 2 (EZH2) was the direct target for miR‐124/506. Interestingly, we finally proved that the sorafenib resistant cells regained sensitivity for sorafenib by EZH2 intervention with miR‐124/506 overexpression or EZH2 inhibitor treatment in vitro and in vivo, which will lead to the decreased tri‐methylation at lysine 27 of histone H3 (H3K27me3) and increased acetylated lysine 27 of histone H3 (H3K27ac) levels. Therefore, we conclude that the suppression of EZH2 represents a potential target for thyroid carcinoma therapy.     

索拉非尼与舒尼替尼单药治疗晚期肝细胞癌的效果分析

目的:对比索拉非尼(Sorafenib)和舒尼替尼(Sunitinib)单药治疗晚期肝细胞癌的疗效及安全性。方法:对我院2004年1月-2010年10月收治的44例晚期肝细胞肝癌患者的临床资料进行回顾分析。根据不同给药方式,将患者分为两组。其中,索拉非尼组32例患者采取口服索拉非尼进行治疗,而舒尼替尼组12例患者给予口服舒尼替尼治疗。观察并比较两组患者的治疗效果及药物不良反应情况。结果:索拉非尼组总生存时间为6.3月,1年生存率为16%,肿瘤进展时间为3个月,疾病控制率为71%;舒尼替尼组总生存时间为4.7月,1年生存率为8%,肿瘤进展时间为3个月,疾病控制率为64%。两组临床效果差异无统计学意义(P=0.2415,0.5706,0.7132)。索拉非尼组患者手足皮肤反应、中性粒细胞减少及肝损伤等主要毒副反应的发生率均低于舒尼替尼组,差异具有统计学意义(P0.05)。结论:索拉非尼治疗晚期肝细胞肝癌的临床效果与舒尼替尼具有很好的一致性,药物不良反应相对较轻,患者依从性较好,值得临床推广应用。