VEGF信号通路及结直肠癌抗VEGF/VEGFR靶向治疗

化疗联合靶向药物是晚期结直肠癌的主要治疗手段。VEGF信号通路在结直肠癌发生发展中地位特殊,且针对VEGF信号通路的靶向药物临床应用广泛、疗效好。本文就VEGF信号通路及结直肠癌抗VEGF/VEGFR靶向药物作一综述。     

靶向VEGF/VEGFR通路治疗胃癌的研究进展

胃癌是目前全球最常见的恶性肿瘤之一,早期诊断率低,预后差,手术及放化疗对进展期胃癌的疗效有限。自1971年Folkman首先提出实体肿瘤的发展和转移离不开新生血管后,抗血管新生方面的研究就一直是肿瘤学的热点。血管内皮生长因子（VEGF）是已知的被多种实体肿瘤分泌的、最强的血管调控生长因子和信号传递因子,VEGF高表达是胃癌的特征之一。VEGF及其受体VEGFR在胃癌的发生、发展中发挥了重要作用。因此,靶向VEGF/VEGFR信号通路的治疗有望在胃癌的综合治疗方面取得重大突破。本文就VEGF/VEGFR信号转导路径及胃癌抗血管治疗的最新研究进展作一简要综述。     

Hedgehog信号通路抑制剂抗肿瘤研究进展

0 引言 Hedgehog信号在哺乳动物形态及胚胎形成中扮演着重要角色,Hh信号通路的紊乱及其信号相关成分的突变可导致多种肿瘤的发生及发展,如基底细胞癌、小细胞肺癌、乳腺癌、前列腺癌等.     

乳腺癌干细胞相关信号通路及其抑制剂的研究进展

摘 要：乳腺癌干细胞是乳腺癌组织中少数具备自我更新能力与多向分化潜能的细胞,与乳腺癌的发生发展密切相关。目前,乳腺癌治疗后易转移、易复发与乳腺癌干细胞的存在相关。乳腺癌干细胞信号通路在激活乳腺癌细胞功能、乳腺癌调控细胞分化以及控制乳腺癌细胞分裂方面起着关键作用,打破其平衡状态将导致乳腺癌细胞失控性增长及肿瘤发生。针对相应通路进行阻断性靶向治疗可能成为乳腺癌治疗的新视角。全文主要就乳腺癌干细胞相关信号通路及其抑制剂的研究进展进行阐述,以期为乳腺癌患者获得更加有效的临床治疗提供参考。     

miR-409-3p通过抑制LHX2调控VEGF/VEGFR2信号通路促进前列腺癌细胞凋亡、抑制细胞增殖

目的:探讨微小RNA-409-3p（microRNA-409-3p,miR-409-3p）对前列腺癌细胞增殖、凋亡的影响及其分子机制。方法:qRT-PCR与Western blot平行检测前列腺癌细胞中miR-409-3p与LIM同源框基因2（LIM-homeobox gene 2,LHX2）的表达;CCK-8实验检测miR-409-3p过表达对前列腺癌细胞增殖能力的影响,以及LHX2过表达对前列腺癌细胞增殖能力的恢复作用;流式细胞术检测细胞凋亡率;双荧光素酶报告基因检测miR-409-3p与LHX2的靶向作用关系;Western blot检测细胞中LHX2、CyclinD1、CDK4、Cleaved-caspase-3及VEGF/VEGFR2信号通路相关蛋白表达。结果:miR-409-3p在前列腺癌细胞中的表达水平显著低于正常前列腺上皮细胞（P＜0.05）,LHX2的表达水平高于正常前列腺上皮细胞（P＜0.05）;miR-409-3p过表达可显著抑制前列腺癌细胞增殖,促进细胞凋亡（P＜0.05）,并可上调Cleaved-caspase-3的表达（P＜0.05）,下调CyclinD1、CDK4、VEGF、t-VEGFR2、p-VEGFR2的表达（P＜0.05）;双荧光素酶实验证明miR-409-3p与LHX2存在靶向关系,miR-409-3p可负性调控LHX2的表达;LHX2过表达可部分逆转miR-409-3p对前列腺癌细胞增殖、凋亡及VEGF/VEGFR2信号通路的影响。结论:miR-409-3p可通过下调LHX2的表达而促进前列腺癌细胞凋亡、抑制细胞增殖,其作用机制可能与抑制VEGF/VEGFR2信号通路激活有关。     

核质转运通路及其抑制剂在肿瘤靶向治疗中的研究进展

0 引言 恶性肿瘤是世界范围内死亡率较高的疾病,并有逐年上升的趋势.尽管近年来不断涌现出新的抗肿瘤药物,但肿瘤的高复发性和耐药性仍不可避免.肿瘤细胞的恶性增殖与一系列信号转导通路的异常激活或抑制密切相关.其中转录因子及转录辅助因子,通过核孔复合体(nuclear pore complexes,NPC)和出入核转运受体进出细胞核,诱导或阻滞下游基因的表达,可促使信号转导通路异常激活或抑制[1].已有许多报道证实通过出入核抑制剂阻断这些重要转录因子的作用可抑制肿瘤细胞的增殖,诱导细胞凋亡和逆转肿瘤的耐药性.本文对目前核质转运通路及其抑制剂在恶性肿瘤靶向治疗中的进展加以阐述.     

靶向抗VEGFR治疗恶性肿瘤的研究进展

血管内皮生长因子受体通过与相应的血管内皮生长因子结合刺激血管内皮细胞增殖和迁移,促进新生血管的生成,与机体多种常见肿瘤的发生和转移有着密切的关系。因此以它为靶点,通过现代分子生物学和遗传学等技术方法在基因及细胞分子水平对其表达、活性及其效应等多个环节进行有效抑制而达到治疗肿瘤的目的,是近年来抗肿瘤治疗新的方法和手段之一。本文就抗血管内皮生长因子受体靶向治疗方面的研究做一综述。     

以VEGF及其受体为靶点的抗肿瘤血管生成研究进展

肿瘤的抗血管治疗是目前的研究热点之一。现综述以VEGF及VEGFR为靶点的抗肿瘤血管生成治疗策略。     

以VEGF/VEGFR为靶点的抗肿瘤药物的研究进展

肿瘤的生长和迁移依赖于大量新生血管的生成，其中VEGF/VEGFR途径在肿瘤新生血管生成中起关键作用。近年来，以VEGF/VEGFR作为靶标的抗肿瘤药物的研发取得了很大的进展，已有数种药物进入临床试验或已上市。针对VEGF/VEGFR信号传导途径研发的抗肿瘤药物主要包括中和VEGF/VEGFR     

Antitumour efficacy of VEGFR2 tyrosine kinase inhibitor correlates with expression of VEGF and its receptor VEGFR2 in tumour models

During the development of indazolylpyrimidines as novel and potent inhibitors of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2) tyrosine kinase, we observed that some human tumour xenografts are more sensitive to VEGFR2 kinase inhibitors than others. A better understanding of the basis for this differential response may help to identify a predictive marker that would greatly aid in the identification of a suitable patient population for treatment. One representative compound from the indazolylpyrimidine series is GW654652 that inhibited all three VEGFRs with similar potency. The inhibition of VEGFR2 kinase by GW654652 was about 150 to >8800 more potent than the inhibition of eight other kinases tested. GW654652 inhibited VEGF- and bFGF-induced proliferation in endothelial cells with an IC(50) of 110 and 1980 nM, respectively, and has good pharmacokinetic profile in mouse and dog. We investigated the association between VEGF and VEGFR2 expression and the antitumour efficacy of GW654652, in various xenograft models. Statistically significant associations were observed between the antitumour efficacy of GW654652 in xenografts and VEGF protein (P=0.005) and VEGFR2 expression (P=0.041). The oral dose of GW654652 producing 50% inhibition of tumour growth (ED(50)) decreased with increasing levels of VEGF (r=-0.94); and, in contrast, the ED(50) increased with the increased expression of VEGFR2 (r=0.82). These results are consistent with the observed inverse correlation between VEGF and VEGFR2 expression in tumours. These findings support the hypothesis that VEGF and VEGFR2 expression by tumours may predict the therapeutic outcome of VEGFR kinase inhibitors.     

Dual VEGF/VEGFR inhibition in advanced solid malignancies: Clinical effects and pharmacodynamic biomarkers

Our prior phase I study of the combination of vascular endothelial growth factor (VEGF) antibody, bevacizumab, and VEGF receptor (VEGFR) inhibitor, sunitinib, in advanced solid tumors identified an encouraging response evaluation. An expansion phase of this study was thus undertaken to obtain further safety data, response assessment and characterization of pharmacodynamic biomarkers in melanoma, renal, and adrenal carcinoma patients. Patients with metastatic solid tumors received sunitinib (37.5 mg/d, 4 wk on/2 wk off) and bevacizumab (5 mg/kg intravenously every 2 wk). Responses were assessed every 2 cycles. Serum levels of angiogenic molecules were measured using ELISA assays. Twenty-two patients were enrolled, including 11 melanoma, 5 renal cell carcinoma (RCC), 5 adrenal cancer, and 1 angiosarcoma. Grade 3 or higher adverse events were observed in 15 patients, including hypertension (41%), thrombocytopenia (23%), and fatigue (14%). Three RCC patients, and 1 melanoma patient developed thrombotic microangiopathy (TMA). Partial response (PR) occurred in 21% patients, including melanoma (2), adrenal (1), and renal (1) carcinomas. Overall, 6 patients demonstrated some reduction in their tumor burden. Serum VEGF and several other proangiogenic proteins declined over the first 4 wk of treatment whereas the putative VEGF-resistant protein, prokineticin-2, increased over 10-fold. Occurrence of TMA related to dual VEGF/VEGFR inhibition can result from systemic or nephron specific injury even in non-renal malignancies. While the combination of sunitinib and bevacizumab was clinically efficacious in renal cell carcinoma and melanoma, the observance of microangiopathy, even in non-RCC patients, is a significant toxicity that precludes further clinical development.     

血管内皮生长因子及其受体在结直肠癌中的表达及其意义

目的：探讨血管内皮生长因子（ＶＥＧＦ）及其受体（ＦＬＴ、ＦＬＫ－１）在结直肠癌组织中的表达及其对肿瘤新生血管生成及转移的影响。方法应用免疫组化技术,检测５０例人结直肠癌组织ＶＥＧＦ、ＦＬＴ、ＦＬＫ－１的表达和微血管密度（ｍｉｃｒｏｖｅｓｓｅｌｓ ｄｅｎｓｉｔｙ,ＭＶＤ）,并分析其与病理分型、分级、浸润深度、淋巴结、淋巴管和血管转移的相关。结果ＶＥＧＦ、ＦＬＴ、ＦＬＫ－１主要表达于癌浸润边缘和坏死组     

VEGF—C、VEGFR-3在肿瘤淋巴管生成中作用的研究进展

血管内皮生长因子C是调节淋巴管生成的主要因子,在许多肿瘤组织中高表达,与其受体血管内皮生长因子受体3结合后,可特异性作用于淋巴管内皮,刺激淋巴上皮增殖,诱导瘤内或瘤周围淋巴管生成和／或扩张,促进肿瘤微淋巴管生成。肿瘤淋巴管生成是肿瘤转移过程中的重要条件,肿瘤细胞可通过表达淋巴管生成的调控因子VEGF—C和VEGFR-3促使淋巴管生成,促进肿瘤细胞的淋巴转移。肿瘤淋巴管生成及其对抗研究是当前肿瘤研究的热点,并有可能成为治疗肿瘤淋巴转移的靶点。二者间关系密切,且相互作用,相互影响。     

PI3K/AKT/mTOR信号通路抑制剂在淋巴瘤中的研究进展*

磷脂酰肌醇-3 激酶（phosphatidylinositol 3-kinase,PI 3K）- 蛋白激酶B（protein kinaseB ,PKB ,又称AKT ）- 雷帕霉素靶蛋白（mammalian target of  rapamycin,mTOR）信号通路与细胞的生长、增殖、分化、凋亡、代谢等密切相关,在多种实体肿瘤中已发现该信号通路的异常。近年来,以抑制该通路特定位点的靶向治疗已成为抗肿瘤的研究热点。许多该位点新型抑制剂也已进入淋巴瘤的临床试验中,本文就该通路在淋巴瘤中的活化状态及各个分子靶点抑制剂的研究进展做一综述。