靶向血小板源生长因子受体酪氨酸激酶抑制剂的临床研究进展

随着血小板源生长因子(platelet-derived growth factor,PDCF)及其受体(platelet-derived growth factor receptor,PDGFR)在抗肿瘤作用中研究的深入,通过阻断PDGF/PDGFR信号转导通路来抑制肿瘤的生长,为治疗肿瘤提供了新的方法和策略。本文对进入临床研究的PDGFR激酶抑制剂的研究进展作一综述。     

血小板衍生生长因子受体(PDGFR)抑制剂的研究进展

血小板衍生生长因子（platelet-derived growth factor, PDGF）是一种重要的促有丝分裂因子,与多种疾病的发生有关,PDGF发挥其生理作用是通过血小板衍生生长因子受体（platelet-derived growth factor receptor, PDGFR）介导的细胞信号传导实现的,PDGFR是一种酪氨酸蛋白激酶受体,已成为肿瘤等多种疾病的治疗靶点.目前已开发了喹喔啉、喹唑啉、吲哚酮等多种结构的PDGFR抑制剂,并有伊马替尼、苏尼替尼等多种抑制剂上市或进入临床实验研究阶段.本文旨在对PDGF的结构与功能以及PDGFR抑制剂的研究进展进行综述.     

肾脏疾病中血小板源性生长因子研究现状

血小板源性生长因子（platelet derived growth factor,PDGF）是一种重要细胞因子。它在。肾小球系膜细胞、间质纤维母细胞、血管内皮细胞均有异常表达,与肾脏发育、各种肾小球肾炎和肾间质疾病的发生、发展密切相关。其临床意义在于与PDGF的相关治疗可能会缓解。肾脏疾病。     

进行性肌营养不良患者肌肉组织血小板衍生生长因子受体的表达

血小板衍生生长因子(PDGF)是一个多功能因子~([1]), 是间充质结缔组织构成细胞的生长刺激和诱导剂~([2]),对骨骼肌的再生具有重要作用.目前有关肌营养不良肌肉组织PDGF受体(PDGFR)表达的研究报道较少,为此笔者对Duchenne型肌营养不良(DMD)、Becker 型肌营养不良(BMD)和先天性肌营养不良(CMD)肌活检进行了PDGFR α和PDGFR β的免疫定位检测,以阐明其在疾病进展中的作用.     

血小板源性生长因子受体-β在蛛网膜下腔出血后脑血管痉挛中的作用

目的观察兔蛛网膜下腔出血(SAH)后基底动脉的血小板源性生长因子受体-β(PDGFR-β)的表达变化规律,从侧面反映血小板源性生长因子(PDGF)-BB在SAH后脑血管痉挛(CVS)的作用。方法采用枕大池二次注血法建立稳定的兔CVS模型,应用HE染色、透射电镜、免疫组化技术等方法,观察兔基底动脉的超微结构变化及PDGFR-β的表达时间窗,并通过测量管径的变化来判断CVS的严重程度。结果电镜结果提示SAH组的基底动脉部分内皮细胞脱落,紧密联接打开,内皮间隙扩大;内弹力膜扭曲、断裂;平滑肌细胞胞浆空泡状,排列紊乱;外膜可见大量中性粒细胞、单核细胞浸润;管腔狭窄呈急性期收缩和迟发性痉挛双相改变;免疫组化结果提示对照组的PDGFR-β无阳性表达,SAH组的PDGFR-β表达升高,在第5、7天时最为明显(P<0.01),第10天后表达稍下降,但仍高于对照(P<0.05)。结论 PDGFR-β在SAH后CVS中基底动脉的表达呈现一定的时序性,提示PDGF-BB在迟发性脑血管痉挛的发生发展中起作用。     

血小板衍生生长因子受体α在女性非小细胞肺癌中的表达

PDGFR-α基因编码的蛋白质是血小板衍生生长因子受体α(PDGFR-α),属于Ⅲ型受体酪氨酸激酶家族[1],与其配体血小板衍生生长因子(PDGF)结合后活化,形成P-PDGFR-α,并且可以使其他酪氨酸蛋白磷酸化,促进肿瘤的发生、发展.     

表皮生长因子受体酪氨酸激酶抑制剂治疗肺癌停药标准研究

在肺癌组织中表达的表皮生长因子受体（EGFR）及其配体网络已经明确为治疗的关键靶点。EGFR酪氨酸激酶抑制剂（TKI）以高选择性和低毒性的优势在肿瘤临床治疗中取得令人瞩目的成绩[1]。酪氨酸激酶介导的信号转导与肿瘤的发生发展密切相关[2]抑制该受体活性可以有效抑制肿瘤。目前临床以简单的＂肿瘤进展停药＂为标准实施,但这种用药方式与决定TKI耐受和治疗疗效的肿瘤基因表达不相符。     

血小板源性生长因子与肾脏疾病的研究进展

血小板源性生长因子（platelet derived growth factor,PDGF）是目前已知多肽生长因子中最强的有丝分裂原。作为成纤维细胞、平滑肌细胞以及其他间充质来源细胞的强有丝分裂原和化学驱动剂,是一种具有多生物学效应、参与多组织器官生理活动与病理损伤过程的重要细胞因子,其过度表达可导致多种疾病的产生。     

表皮生长因子受体及其抑制剂的研究

表皮生长受体因子属于受体酪氨酸激酶家族成员,其过度表达和/或基因突变与多种肿瘤的形成具有密切的联系。近年来,小分子表皮生长因子受体酪氨酸激酶抑制剂的开发已成为肿瘤治疗领域中的研究热点。这里就表皮生长因子受体及其小分子抑制剂进行简要综述。     

表皮生长因子受体抑制剂新药研究进展

表皮生长因子受体（EGFR）抑制剂的耐药问题亟需新的治疗方法克服。新的EGFR酪氨酸激酶抑制剂（EGFR TKIs）重在加强对EGFR通路的抑制,并克服对不可逆抑制剂突变相关的耐药,强调增加EGFR TKI的抑制效力,双重抑制血管内皮细胞生长因子（VEGF）和EGFR途径,或抑制EGFR家族的多个成员等等,单克隆抗体也正在研究之中（见表1）。     

Tyrosine Kinase Inhibitors in Preclinical Development

Due to the limited efficacy of cytotoxic chemotherapy in the treatment of advanced malignancy and its excessive toxicity precluding its use in chemoprevention, new therapeutic and preventive strategies have been sought. One of the most interesting of these new approaches is the manipulation of signal transduction pathways. Among the approaches being considered to eventuate such a strategy is the inhibition of autophosphorylation, a critical first step in the signal transduction pathways of many cell surface receptor tyrosine kinases, as well as of non-receptor tyrosine kinases. This article is intended to review those tyrosine kinase inhibitors that are currently in preclinical development, for which there are data to support consideration for their use in chemoprevention or cancer treatment. We will focus upon those agents that have received attention in the past several years.     

来氟米特对糖尿病模型大鼠肾组织中血小板衍化生长因子的影响研究

目的:探讨来氟米特对糖尿病模型大鼠肾组织中血小板衍化生长因子(PDGF)的影响。方法:取大鼠单剂量注射链脲佐菌素60mg·kg-1建立糖尿病模型,建模成功后分为模型组(自来水)和治疗组(来氟米特,5mg·kg-1·d-1),每组16只,灌胃给予相应药物,于第4、8周末各组随机取样8只,检测血糖、胆固醇、甘油三酯、血肌酐、尿白蛋白、尿β2-微球蛋白(β2-MG)等生化指标及肾脏肥大指标的变化,并以免疫组化法检测肾组织中PDGF表达。另设正常对照组进行比较。结果:与模型组比较,治疗组大鼠第4周除血糖外、第8周除甘油三酯外,其他生化指标、肾脏肥大指标以及肾组织中PDGF表达均降低。结论:来氟米特可能通过下调糖尿病模型大鼠肾组织中PDGF表达来实现肾脏保护作用。     

Synthesis and Evaluation of Salicylanilide Derivatives as Potential Epidermal Growth Factor Receptor Inhibitors

Two series of novel salicylanilide were synthesized as potential epidermal growth factor receptor (EGFR) inhibitors. The enzyme inhibitory activity against EGFR of all compounds was carried out, and their antiproliferative activities against the A549 and A431 cell lines were also evaluated. Of the compounds studied, majority of them exhibited high antiproliferative activities compared with gefitinib; especially, 12a and 12b exhibited stronger inhibitory activity against EGFR with IC₅₀ values of 10.4 ± 2.25 and 15.4 ± 2.33 nm , respectively, which were comparable to the positive control of gefitinib (IC₅₀ = 12.1 ± 2.21 nm ). Compound 12b also showed outstanding inhibitory activity against A431 and A549 cell lines with the IC₅₀ values of 0.42 ± 0.43 μm and 0.57 ± 0.43 μm , which was better than the positive controls. In the molecular modeling study, compound 12b was bound into the active pocket of EGFR with two hydrogen bond and with minimum binding free energy ▵G_b = −25.1125 kcal/mol. The result also suggested that compound 12b could bind the EGFR kinase well.     

作用于VEGF信号通路的血管生成抑制剂

分类介绍作用于血管内皮细胞生长因子信号通路的血管生成抑制剂研究近况以及该类药物存在的缺陷。血管生长促进因子和血管抑制因子的活性及其表达水平对肿瘤的发生和发展具有关键性的作用,所以,针对于血管生成,尤其是靶向于血管内皮细胞生长因子的药物已成为近年来抗肿瘤药物研究的热点之一。     

表皮生长因子受体在人体肺癌表达的研究

应用免疫组织化学方法对人体肺癌表皮生长因子受体的表达进行了研究。实验结果表明：表皮生长因子受体表达定位于细胞浆和细胞膜。表皮生长因子受体表达与人体肺癌的组织学类型及病理分级有关。小细胞肺癌阳性表达率明显低于其他各型肺癌（非小细胞癌）的阳性表达率。     

Arsenite suppresses angiogenesis of vascular endothelial cells mediated by Platelet Derived Growth Factor Receptor-beta

The present study aimed to investigate the effects of sodium arsenite (NaAsO₂) on the angiogenesis of human umbilical vein endothelial cells (HUVECs) and the mechanism involved. Firstly, a Matrigel-based in vitro angiogenesis assay demonstrated that arsenite suppressed the angiogenesis of HUVECs in a dose-dependent manner. Then by using a global inhibitor for multiple growth factor receptors (E7080) and a specific inhibitor of PDGFR-beta (CP-673451), we found that E7080 completely prevented and CP-673451 significantly decreased the angiogenesis of HUVECs. This suggested that angiogenesis of HUVECs depends on the signal pathway mediated by tyrosine kinase receptors and that among them, PDGFR-beta has an important regulatory function. Finally by using porcine aortic endothelial cells which stably express human PDGFR-beta, we found that arsenite suppressed the angiogenesis mediated by PDGFR-beta. Based on these results, we conclude that arsenite suppressed the angiogenesis of the vascular endothelial cells, that this effect is mediated by PDGFR-beta, and postulate that it might contribute to the injuries of blood vessel in arsenism.     

Discovery of Novel Vascular Endothelial Growth Factor Receptor 2 Inhibitors: A Virtual Screening Approach

A virtual screening approach was performed to develop novel and potent vascular endothelial growth factor receptor 2 inhibitors. The Specs database was filtered by ‘rule of five’, a pharmacophore model, and docking filter. Sixteen molecules were selected for tube formation assay, a naphthalenol group containing molecule, 12 , showed good performance in the study. In the following aortic ring assay and 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay, 12 was discovered to efficiently inhibit angiogenesis and tumor cell growth. It is the first time to discover naphthalenol scaffold as potent vascular endothelial growth factor receptor 2 inhibitors. Thus, a molecular dynamic simulation process was applied to discover key features of 12 in binding to vascular endothelial growth factor receptor 2. Hydrophobic interactions were discovered to play significant role in the ligand–receptor binding.     

表皮生长因子受体和可溶性白细胞介素2受体在食管癌中的表达及其临床意义

目的研究表皮生长因子受体(EGFR)和可溶性白细胞介素2受体(sIL-2R)在食管癌中的表达及其临床意义。方法应用免疫组织化学技术和双抗体夹心法,对食管癌及其良性对照组织标本中EGFR的含量和血清中sIL-2R水平进行检测,探讨其与临床病理参数的关系。结果①在良性对照组中,EGFR的表达率及sIL-2R水平显著低于食管癌组(P<0.01)。②EGFR表达及sIL-2R水平与患者的性别、病变部位无关(P>0.05),与临床分期、分化程度、浸润深度及淋巴结转移情况相关(P<0.05)。结论 EGFR和sIL-2R水平的检测可作为判断肿瘤的恶性程度、预测淋巴结转移的趋势和预后评估的有益指标。