联合抗肿瘤策略：抑制表皮生长因子受体和血管生成

肿瘤的发生和发展与酪氨酸激酶（TK）受体的过表达有关，如表皮生长因子受体（EGFR，ErbB家族）在很多实体瘤中均高表达。体外实验表明，抗EGFR治疗能使肿瘤细胞增殖减弱，抑制细胞生长，但不能使其减少和凋亡；而在体内模型中，抗EGFR治疗导致肿瘤变小，暗示EGFR信号转导影响肿瘤细胞的生物学效应，以及肿瘤一宿主相互作用，如血管生成。     

表皮生长因子受体酪氨酸激酶抑制剂在肿瘤治疗中的应用

表皮生长因子受体 (EGFR)酪氨酸激酶 ,是细胞外信号传递到细胞内的重要枢纽 ,它在信号传导、细胞增殖、分化以及各种调节机制中发挥重要作用 ,在多种癌细胞中过度表达。许多研究表明 ,抑制EGFR酪氨酸激酶活性 ,可抑制肿瘤生长。目前 ,已有几种EGFR酪氨酸激酶抑制剂进入了临床试验。本文对几种EGFR酪氨酸激酶小分子抑制剂在肿瘤治疗中的研究进展做一综述。     

表皮生长因子受体酪氨酸激酶抑制剂BPI-2009的抗肿瘤作用及其机制的研究

目的:探讨一种口服的表皮生长因子受体(epidermalgrowthfactorreceptor ,EGFR)酪氨酸激酶抑制剂(BPI 2 0 0 9)的抗肿瘤作用及其机制。方法:Westernblot方法检测BPI 2 0 0 9对酪氨酸激酶和EGFR自动磷酸化的抑制作用,MTT法检测BPI 2 0 0 9对多种肿瘤细胞的生长抑制作用,使用A4 31肿瘤模型的荷瘤裸鼠进行体内的肿瘤抑制试验。结果:通过对EGFR激酶抑制剂化学文库的筛选,发现BPI 2 0 0 9是一个有效的EGFR激酶抑制剂。BPI 2 0 0 9对EGFR激酶的半数抑制浓度(IC50 )为5nmol·L- 1,当其浓度达到6 2 .5nmol·L- 1的时候可以完全抑制EGFR激酶的活性,但在10 0nmol·L- 1时对Abl、Abl相关基因(Abl relatedgenes ,Arg)以及c- Src酪氨酸激酶都没有明显的抑制作用。BPI 2 0 0 9可以阻断EGFR介导的细胞内蛋白酪氨酸的磷酸化,IC50 为4 5nmol·L- 1。在肿瘤细胞生长抑制试验中,BPI 2 0 0 9对于肿瘤细胞的生长抑制作用与EGFR在细胞中的表达密切相关。人类肿瘤细胞A4 31移植瘤抑制试验的研究表明BPI 2 0 0 9经口给药每天1次在10 0mg·kg- 1,肿瘤抑制率达6 4% ,有明显的剂量效应关系,并没有发现明显的病态和体重下降。结论:BPI 2 0 0 9是一种有效的高选择性的以EGFR酪氨酸激酶为靶点的抗肿瘤药物。     

EGFR酪氨酸激酶及其抑制剂的研究进展

表皮生长因子受体(EGFR)酪氨酸激酶是细胞外信号传递到细胞内的重要枢纽,它在信号传导、细胞增殖、分化以及各种调节机制中发挥重要作用,并在多种癌细胞中过度表达。许多研究表明,抑制EGFR酪氨酸激酶活性,可抑制肿瘤生长。本文对EGFR酪氨酸激酶及其几种小分子抑制剂在肿瘤治疗中的研究进展作一综述。     

抗肿瘤药Erlotinib

恶性肿瘤的特征是 ,细胞信号传导失调 ,导致细胞迅速增殖和 或凋亡抑制 ,进而引起癌细胞自发生长、入侵外围组织及转移。表皮生长因子受体 (EGFR)是一种 1型受体酪氨酸激酶 ,属信号蛋白 ,参与调节细胞分化 ,并在多种人类肿瘤(如肺癌、胰腺癌、卵巢癌、肾癌、胃癌、肝癌和乳腺癌     

以EGFR家族受体酪氨酸激酶为靶点的抗肿瘤治疗研究进展

表皮生长因子受体 (EGFR)家族的受体酪氨酸激酶与多种恶性肿瘤的发生、发展及预后等密切相关。近年来 ,许多以此为靶点的新的抗肿瘤药物和治疗方法陆续被开发 ,主要有单克隆抗体、双特异性抗体、小分子酪氨酸激酶抑制剂和基因治疗等。它们有的已进入临床试验 ,耐受性良好 ,并且在多种肿瘤治疗中取得了令人鼓舞的疗效     

血管生成抑制剂SU6668抗肿瘤作用的研究进展

血管生成是实体瘤生长和转移的必要条件，通过抑制血管生成来阻止肿瘤生长的抗血管生成疗法是目前肿瘤治疗的新策略。SU6668作用于广泛的酪氨酸受体，疗效优于选择性酪氨酸激酶受体抑制剂，Ⅰ期临床试验表明，SU6668是一种安全有效的抗癌药。     

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。     

厄洛替尼的严重不良反应及其防治措施

厄洛替尼（erlotinib）是一种人表皮生长因子受体-1（HER-1）和（或）表皮生长因子受体（EGFR）酪氨酸激酶（TK）抑制药,通过抑制表皮生长因子受体酪氨酸激酶（EGFR—TK）的自磷酸化反应,抑制信号传导,从而达到抑制癌细胞增殖作用,可显著延长晚期复发性非小细胞肺癌病人的生存期、延缓疾病进展和症状恶化。随着本品在临床使用时间的增加,关于其不良反应的报道也日益增多。本文就厄洛替尼的严重不良反应及其防治措施进行综述,供临床参考。     

表皮生长因子受体家族单克隆抗体耐药机制的研究进展

表皮生长因子受体（EGFR）家族广泛存在于体内各种细胞中,其异常活化与多种人类上皮组织肿瘤的发生、发展密切相关,因此已成为肿瘤治疗的重要靶点之一。目前靶向EGFR家族的药物包括小分子酪氨酸激酶抑制剂和单克隆抗体（简称单抗）类药物,特别是单抗类药物近年来在临床上获得了广泛的应用。但是,越来越多的临床资料表明,大量患者对这类药物表现出原发性耐药或获得性耐药。目前靶向EGFR家族单抗类药物产生耐药的原因主要包括：受体结构改变、血管生成、多种受体酪氨酸激酶的活化、EGFR的亚细胞定位、EGFR下游效应分子的持续激活和EGFR家族生长因子表达的上调等。本文就靶向EGFR家族单抗类药物耐药机制的研究进展进行综述。     

Oridonin inhibited the tyrosine kinase activity and induced apoptosis in human epidermoid carcinoma A431 cells

Oridonin, an active component isolated from the plant Rabdosia rubescens, has been reported to exhibit antitumor effects, but little is known about its molecular mechanism of action. In this study, we first investigated the mechanism involved in oridonin-induced cell death in human epidermoid carcinoma A431 cells, which overexpress epidermal growth factor receptor (EGFR). After treatment with various doses of oridonin for 24 h, the majority of A431 cells underwent apoptosis in a time- and dose-dependent manner as measured by an LDH activity-based assay. Treatment with oridonin at various concentrations for 24 h caused significant inhibition on the total tyrosine kinase activities and downregulation of EGFR expression or EGFR phosphorylation. Oridonin significantly affected the localization of EGFR and phosphorylated EGFR on the cell membrane. However, genistein (a well-known tyrosine kinase inhibitor) did not induce apoptotic A431 cell death. Importantly, oridonin exhibited much stronger inhibitory effect on the total tyrosine kinase activities or EGFR tyrosine phosphorylation as well as much stronger suppression on EGFR and phosphorylated EGFR localization than genistein in A431 cells. Taken together, oridonin exerted a potential inhibitory effect on the tyrosine kinase activity of A431 cells. The decrease in the tyrosine kinase activity and the blockage of EGFR tyrosine phosphorylation might be one of the causes of oridonin-induced A431 cell death.     

Molecular design and clinical development of VEGFR kinase inhibitors

Vascular angiogenesis has been shown to play a key role in many solid tumors. The vascular endothelial growth factor (VEGF) isoforms and their tyrosine kinase receptors (VEGFRs) have been under intense research for effective anticancer drug candidates. Epidermal growth factor (EGF) and its receptor (EGFR) provide another pathway critical in monitoring angiogenesis. VEGF exerts its effect through binding to tyrosine kinase receptors, mainly VEGFR-1 (Flt-1, the fms-like tyrosine kinase-1) and VEGFR-2 (Flk-1/KDR, fetal liver kinase-1). This paper reviews the progress, mechanism, and binding modes of recently approved kinase inhibitors, such as sunitinib (Sutent), sorafenib (Nexavar) and dasatinib (Sprycel), as well as other inhibitors that are still under clinical development. Recent clinical treatments suggest that most inhibitors of VEGFR (and/or EGFR) exert their therapeutic effect through not only targeting the VEGFR (and/or EGFR) pathway, but also inhibiting other pathways, such as RAF/MEK/ERK pathway. A new pharmacophore model for second generation of type II tyrosine kinase inhibitors and recent advances in the combination of VEGFR tyrosine kinase inhibitors and other chemotherapeutics are also covered.     

Second-generation epidermal growth factor tyrosine kinase inhibitors in non-small cell lung cancer

Inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) has an established role in the treatment of advanced non-small cell lung cancer. The first-generation EGFR inhibitors erlotinib and gefitinib have been approved for treatment in the second- and third-line setting. Second-generation EGFR tyrosine kinase inhibitors are now in development aiming to improve efficacy and overcome primary and secondary resistance to the first-generation drugs. The two most common strategies being used to achieve these aims are irreversible binding of drug to target and kinase multi-targeting. This is an overview of the early clinical development of selected second-generation tyrosine kinase inhibitors focusing on the treatment of non-small cell lung cancer.     

7-Substituted-[1,4]dioxano[2,3-g]quinazolines as inhibitors of epidermal growth factor receptor kinase

With the aim of developing inhibitors of EGFR tyrosine kinase, the 7-methoxymethyl-[1,4]dioxano[2,3-g]quinazolines (3a-b) and 7-mono- or di-alkylaminomethyl-[1,4]dioxano[2,3-g]quinazolines (4a-i) were prepared and evaluated for the inhibition of EGFR tyrosine kinase and the growth inhibition of human tumor cell lines. Among them, compounds 4d and 4h showed potencies against both EGFR tyrosine and the A431 cell line similar to that of PD153035 with greater aqueous solubilities of their HCl salts.     

EGFR基因突变与肿瘤靶向治疗

表皮生长因子受体(epidermal growth factor receptor,EGFR)属于受体酪氨酸激酶超家族,在多种恶性肿瘤中表达。配体与EGFR结合诱导形成二聚体和构象变化,活化酪氨酸激酶及信号转导途径,产生细胞增殖、侵润、转移及抗凋亡等效应。EGFR酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)类靶向药物,如吉非替尼和厄洛替尼等已应用于临床。临床研究显示仅10%~30%患者对TKIs敏感,部分位于EGFR激酶结构域的活化突变与药物敏感性相关。检测EGFR基因突变有助于预测对药物敏感性和提高疗效。随着治疗绝大多数敏感的患者获得继发耐药性,其中约半数有继发突变T790M,降低药物对靶分子的亲和力,其他许多位于EGFR下游信号途径或旁激活途径的分子也参与耐药形成。因此,未来个体化用药和准确预测敏感性,不仅仅要分析EGFR基因,而且要综合考虑下游和其他信号途径的基因,如PI3K,K-RAS,BRAF,MET和PTEN等。     

Use of a pharmacophore model for the design of EGFR tyrosine kinase inhibitors: isoflavones and 3-phenyl-4(1H)-quinolones

Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase together with published X-ray crystal data of quercetin (2) in complex with the Hck tyrosine kinase and of deschloroflavopiridol (3b) in complex with CDK2, a putative binding mode of the isoflavone genistein (1) was proposed. Then, based on literature data suggesting that a salicylic acid function, which is represented by the 5-hydroxy-4-keto motif in 1, could serve as a pharmacophore replacement of a pyrimidine ring, superposition of 1 onto the potent EGFR tyrosine kinase inhibitor 4-(3'-chlorophenylamino)-6, 7-dimethoxyquinazoline (4) led to 3'-chloro-5,7-dihydroxyisoflavone (6) as a target structure which in fact was 10 times more potent than 1. The putative binding mode of 6 suggests a sulfur-aromatic interaction of the m-chlorophenyl moiety with Cys 773 in the "sugar pocket" of the EGFR kinase model. Replacement of the oxygen in the chromenone ring of 6 by a nitrogen atom further improved the inhibitory activity against the EGFR kinase. With IC50 values of 38 and 8 nM, respectively, the quinolones 11 and 12 were the most potent compounds of the series. N-Alkylation of 11 did not further improve enzyme inhibitory activity but led to derivatives with cellular activity in the lower micromolar range.     

Icotinib,an effective treatment option for patients with lung adenocarcinoma harboring compound EGFR L858R and A871G mutation

Investigational New Drugs - Compound epidermal growth factor receptor (EGFR) mutations are defined as double or multiple independent mutations of the EGFR tyrosine kinase domain (TKD), in which an...     

Pharmacogenetics of EGFR in lung cancer: perspectives and clinical applications

Lung cancer is a lethal disease, and most cases have already disseminated at the time of diagnosis. Driver mutations in the EGFR tyrosine kinase domain (mainly deletions in exon 19 and L858R mutation in exon 21) have been identified in lung adenocarcinomas, mostly in never smokers, at frequencies of 20-60%. The EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib attain a response rate of 70% and progression-free survival of 9-13 months, although there are subgroups of patients with long-lasting remissions. No significant correlation between EGFR overexpression and response to treatment has been found, while controversial results have been reported regarding EGFR gene amplification. The pretreatment presence of the T790M mutation, initially identified as an acquired resistance mutation to treatment with EGFR TKIs, has also been reported and may indicate a genetically distinct disease. Finally, other genetic factors, such as mRNA expression of BRCA1 and components of the NF-κB pathway, can modulate response to EGFR TKIs in EGFR-mutated patients.     

Lack of somatic mutations in EGFR tyrosine kinase domain in hepatocellular and nasopharyngeal carcinoma

Activating EGFR somatic mutations have been shown to predict treatment response to small molecules targeting the EGFR intracellular tyrosine kinase domain. Recent work on cell-lines and animal models had demonstrated an inhibitory effect of EGFR tyrosine kinase inhibitors in hepatocellular and nasopharyngeal carcinoma, and clinical trials in these tumour types are ongoing. There are few data on the presence or prevalence of EGFR mutations in hepatocellular and nasopharyngeal carcinomas. We studied exons 18-21 of the EGFR gene from 100 hepatocellular and 102 nasopharyngeal carcinomas, and found no exonic mutations of potential significance. Alternative mechanisms may be important for the observed activity of small molecule EGFR tyrosine kinase inhibitors in hepatocellular and nasopharyngeal carcinomas.