EGFR家族受体的分子结构与药物作用机制

表皮生长因子受体(EGFR)及其同源蛋白HER2,HER3,HER4是调控细胞生长与分化的重要酪氨酸激酶受体.这些受体的突变或过表达将会引起激酶活性的失调,并导致包括肺癌与乳腺癌在内的各种癌症.因此,这些受体是治疗癌症的重要药物靶点.虽然目前对于EGFR激酶突变所引起的激酶活性失调及其致癌机制已有较深入的研究,但对于由EGFR或HER2过表达所引发的跨膜信号变化,相应的分子结构,以及由此导致的癌症发生与耐药性产生的分子机制则均不甚明了,在临床上也缺乏有效的靶向性药物或治疗窗口.本文将对EGFR家族受体的分子结构、跨膜信号传导机制,以及EGFR靶向药物的研究进行回顾和展望.     

肺癌EGFR突变与酪氨酸激酶抑制剂临床敏感性的关系

表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI)是近年来在临床中使用的一类新的小分子靶向药物,主要用于晚期非小细胞肺癌(NSCLC)的治疗,然而并非所有的NSCLC患者对TKI敏感。近期研究发现,在NSCLC治疗过程中,EGFR突变与TKI临床敏感性密切相关,通过检测肺癌EGFR突变状况可以预测TKI治疗的效果。     

EGFR靶向药物与化疗联合治疗恶性肿瘤进展

表皮生长因子受体(epidermal growth factor receptor EGFR)可以在多种恶性肿瘤细胞中表达,针对此靶点的靶向药物主要有单克隆抗体及酪氨酸激酶抑制剂(tyrosine kinase inhibitors TKIs)。本文通过广泛查阅国内外相关文献,对EGFR靶向药物机制及其与传统化疗药物联合应用从基础研究到临床研究进行综述,讨论二者联合应用的前景及研究方向。     

靶向EGFR家族的抗肿瘤药物研究进展

表皮生长因子受体（EGFR,ErbB）家族在肿瘤的发生、发展中具有重要的作用。很多实体肿瘤中存在EGFR家族受体过表达或异常激活。靶向EGFR家族的抗肿瘤药物研发已经成为一个热点领域,并且成功地应用于临床。靶向EGFR家族的抗肿瘤药物可以分为单克隆抗体和小分子酪氨酸激酶抑制剂两大类。单克隆抗体与受体胞外区结合阻止配体．受体的结合或者阻止配体结合引起的受体活化;而小分子酪氨酸激酶抑制剂则结合于胞内激酶区,抑制激酶自磷酸化和下游信号通路激活。     

EGFR耐药突变及其小分子抑制剂研究进展

表皮生长因子受体(epidermal growth factor receptor,EGFR)是一种具有酪氨酸激酶活性的重要跨膜受体,在多种恶性肿瘤中异常表达,与肿瘤细胞增殖、分化、转移等生命活动密切相关。EGFR已成为治疗肿瘤的靶点,针对该靶点设计的药物主要分为单克隆抗体和小分子抑制剂两大类,小分子抑制剂易导致EGFR出现突变而产生耐药现象,从而影响其临床应用。突变主要发生在酪氨酸激酶区域ATP结合位点附近,主要为19号外显子上的缺失突变,18号和21号外显子上的点突变。针对近几十年来国内外研究者对EGFR出现的耐药突变类型,及其与小分子抑制剂的相互作用方式进行综述,以期为后续EGFR靶点药物的研发提供参考。     

Cloning and Expression of EGFR Tyrosine Kinase and Construction of the Screening Model for the Enzymatic Inhibitors

表皮生长因子受体(Epidermal growth factor receptor,EGFR)属受体酪氨酸激酶(Tyrosine kinase,TK)家族,其胞内的酪氨酸激酶在细胞信号转导通路中具有十分重要的作用。许多肿瘤的发生、发展都与EGFR胞内酪氨酸激酶的异常表达密切相关。因此,EGFR胞内酪氨酸激酶的抑制剂有可能成为治疗肿瘤的有效药物。本研究从人脐静脉内皮细胞(HUVEC) 提取总RNA,采用RT-PCR获得EGFR酪氨酸激酶催化域的编码基因。将其克隆至载体pET-30a,在E.coli BL21(DE3)中进行了成功表达,采用Ni-NTA亲和层析对其进行了纯化。通过对酶的活性的测定,证明重组EGFR酪氨酸激酶蛋白具有利用ATP催化底物发生磷酸化反应的激酶活性。以该重组激酶为靶位构建了酶抑制剂筛选模型,拟对微生物代谢产物进行筛选。     

非小细胞肺癌EGFR-TKIs治疗及PET分子成像的研究进展

表皮生长因子受体(epithelial growth factor receptor,EGFR)信号转导通路在非小细胞肺癌(Non-Small Cell Lung Cancer,NSCLC)中发挥重要作用,尤其胞内酪氨酸激酶结构域的突变状态决定了目前NSCLC的靶向治疗。针对EGFR突变的分子靶向药物表皮生长因子受体酪氨酸激酶抑制剂(epithelial growth factor receptor tyrosine kinase inhibitors,EGFR-TKIs)已开发并应用于NSCLC的治疗。在治疗过程中,EGFR的突变状态随时间发生动态变化,因此精准掌握EGFR的突变状态是靶向治疗方案制定、优化的关键。PET分子成像可在细胞和分子水平,对在体生物活动的发生、发展过程进行实时成像,使实时、在体揭示EGFR的突变状态成为可能。因此,多种以TKIs为前体标记放射性核素作为靶向肿瘤突变EGFR胞内段分子成像探针的研究逐渐增多。本文就EGFR-TKIs在NSCLC治疗及相关PET分子成像方面的研究进展进行综述。     

靶向表皮生长因子受体的全新小分子配体筛选

肿瘤靶向分子的筛选一直是肿瘤治疗和早期诊断的研究热点 . 表皮生长因子受体 (EGFR) 在很多肿瘤细胞表面过量表达,是一个理想的药物输送靶点 . 选择了 EGFR 表面不同于表皮生长因子 (EGF) 结合位点的一个凹陷部位作为计算机模拟筛选的结合位点,然后使用 DOCK 软件包对 DTP-Plated 有机小分子数据库进行了两遍筛选,最后选择了 7 个有机小分子作为可能的靶向分子 . BIAcore 体外结合实验对所选择的小分子样品进行了进一步的验证,结果表明,小分子 NSC51186 能特异地与 EGFR 结合 . 小分子 NSC51186 和 EGFR 之间的动力学常数也得到进一步的测定 . 新的靶向分子和药物、纳米粒子或者基因载体相连,将有可能用于靶向于 EGFR 的肿瘤治疗和诊断 .     

恶性转化的成纤维细胞表皮生长因子受体的研究

本文用受体的放射性配基结合分析方法观察了C_3H小鼠胚胎成纤维细胞C_3H_(10)T1/2 CL8(简称NC_3H_(10))和~3H-TdR恶性转化的C_3H_(10)T1/2CL8(简称TC_3H_(10))的表皮生长因子受体(EGFR)。结果表明细胞恶性转化前后的EGFR都存在高亲和力和低亲和力两种结合位点,细胞恶性转化后能结合表皮生长因子的EGFR结合位点减少,Western blotting和受体的亲和交联分析表明EGFR的分子量为170kD,是单链多肽。     

ER、EGFR在分化型甲状腺癌中的表达及其临床意义

目的:探讨雌激素受体(ER)和表皮生长因子受体(EGFR)在分化型甲状腺癌(DTC)中的表达及其意义.方法:用免疫组化SP法检测45例(DTC)组织中ER和EGFR的表达.结果:ER在DTC组中的阳性率为37.3％,明显高于良性腺瘤和正常组(P＜0.05);EGFR在DTC组中的阳性率为57.7％,明显高于两对照组(P＜0.05).ER在DTC中的表达与性别和年龄有关;EGFR的表达与DTC中的淋巴结转移有关.结论:ER和EGFR的表达可以作为鉴别甲状腺肿瘤良恶性的指标EGFR可作为甲状腺癌患者预后的指标.     

Bases sémantiques et pharmacologiques d’une nouvelle classification des antipsychotiques

The main stages involved in the development of drugs effective against psychotic manifestations are presented, as well as their mechanisms of action. Justification is given for the terms antipsychotic drugs, neuroleptic antipsychotic drugs, non-neuroleptic antipsychotic drugs, and non neuroleptic antipsychotic drugs, effective against negative expressions of schizophrenia. These constitute the basis of the new classification of antipsychotic drugs suggested. Finally, the term “atypical neuroleptic drugs”, frequently used in France, is described as badly constructed and unfortunate and should therefore be abandoned.     

当前我国畜牧业抗菌药应用与耐药性应对趋势

抗菌药在现代农业和医学中发挥了举足轻重的作用,然而,随着民众对食品安全和生态环保意识的逐渐增强,抗菌药物的使用愈发受关注。如何科学合理使用抗菌药,确保动物安全健康,防止药物残留超标,进而实现畜牧业绿色发展是当前研究的重要课题。本文结合当前畜牧业抗菌药使用现状,从四个方面分析了滥用抗菌药的危害,并归纳总结了耐药机制研究进展,最后提出抗菌药替代策略,旨在为畜牧业抗菌药安全使用和抗菌药替代技术研发提供参考。     

Current status and perspectives of biopharmaceutical drugs

Since the first approval of recombinant human insulin three decades ago, more than 150 biopharmaceutical drugs have been marketed, and some of them became blockbuster drugs in market size. The patent expiration of the oldest biopharmaceutical drugs resulted in the development of biosimilar drugs. However the short serum half-life of biopharmaceutical drugs incurs a frequent injection to maintain a target clinical outcome in patients. The other major critical concern of biopharmaceutical drugs is immunogenicity producing anti-drug antibodies. These antibodies may reduce clinical efficacy by neutralizing biological activity, and may not only cause a severe allergic reaction but also other serious adverse reactions by blocking endogenous proteins. In order to improve pharmaceutical properties and reduce immunogenicity, the next generation biobetter drugs were achieved by glycoengineering technology, pegylation technology and protein engineering technology. Other biobetter drugs having optimized binding sites were also generated by in vitro display technology. Many of those biobetter drugs have been developed and/or are under development, and come into the clinical field in the near future.     

Molecular dynamics simulation as a tool for assessment of drug binding property of human serum albumin

Human serum albumin (HSA) is a major plasma protein and binding of drugs with this plasma protein has a great importance. It possess esterase activity which can cleave the drugs containing ester bond and thus, can regulate the effect of drugs. Till date no systematic study has been done to analyse binding of such drugs and to compare the results with the drugs which do not have ester bond. Therefore, in the present study two different categories—ester and non-ester drugs have been considered to analyse their interaction with HSA at two principle drug binding sites using molecular modelling tools. It is observed that the drugs irrespective of ester or non-ester nature prefer either Sudlow site I or II by hydrogen bond and hydrophobic interactions. The information obtained from the study can assist to study pharmacokinetics of the drugs and that in turn will help in noval drug discoveries.     

多肽药物的发展现状

随着生物技术与多肽合成技术的日臻成熟,越来越多的多肽药物被开发并应用于临床。因适应证广、安全性高且疗效显著,多肽药物目前已广泛应用于肿瘤、肝炎、糖尿病、艾滋病等疾病的预防、诊断和治疗,具有广阔的开发前景。简介多肽药物的来源与特点及制备方法,重点综述国内外多肽药物的研发概况、国外近年获准上市的主要多肽药物和我国自主研发并进入临床研究的主要多肽药物,旨在为该类新药的研发提供参考。     

Blood pressure and heart rate and withdrawal of antihypertensive drugs.

The immediate effects on heart rate and blood pressure of withdrawing antihypertensive drugs were studied over three-day periods in 26 patients. Four groups of drugs were studied. After withdrawal all patients taking clonidine showed a considerable increase in heart rate and blood pressure with intense ectopic activity. Patients taking postganglionic neurone-blocking drugs showed a similar but less pronounced reaction with increased ventricular ectopic activity. No alarming reactions were seen after withdrawal of methyldopa or beta-blocking drugs. Methyldopa and, especially, beta-blocking drugs are less likely to produce withdrawal reactions than clonidine or the postganglionic neurone-blocking drugs, and patients taking these drugs are therefore less likely to suffer violent reactions if they forget to take their tablets.     

N-acetylcysteine and captopril protect DNA and cells against radiolysis by fast neutrons

N-Acetylcysteine and captopril, respectively mucolytic and antihypertensive drugs, contain free sulfhydryl groups. Since in general thiols have well-established radioprotective abilities, we sought putative radioprotective effects of these drugs against therapeutic fast neutrons. We show that pBR322 plasmid DNA is indeed protected against radiolytic strand breakage by both drugs. The oxygen independent protection is consistent with a hydroxyl radical scavenging mechanism. A clonogenicity assay reveals an increase of the survival of SCL-1 cultured keratinocytes irradiated in the presence of the drugs compared with cells irradiated without drugs. Our results suggest possible interferences between treatment with drugs bearing-SH groups and radiotherapy.     

Dopaminergic and serotonergic drug use: a nationwide register-based study of over 1,300,000 older people

Objective

To investigate the use of dopaminergic and serotonergic drugs in elderly people.

Methods

We analyzed data on age, sex and dispensed drugs for individuals aged ≥65 years registered in the Swedish Prescribed Drug Register from July to September 2008 (n = 1 347 564; 81% of the total population aged ≥65 years in Sweden). Main outcome measures were dopaminergic (enhancing and/or lowering) and serotonergic (enhancing and/or lowering) drugs and combinations of these.

Results

Dopaminergic and serotonergic drugs were used by 5.6% and 13.2% the participants, respectively. Female gender was related to use of both dopaminergic and, particularly, serotonergic drugs. Higher age was associated with use of dopamine lowering drugs and serotonergic drugs, whereas the association with use of dopamine enhancing drugs declined in the oldest old. The occurrence of combinations of dopaminergic and serotonergic drugs was generally low, with dopamine lowering + serotonin lowering drug the most common combination (1.6%). Female gender was associated with all of the combinations of dopaminergic and serotonergic drugs, whereas age showed a mixed pattern.

Conclusion

Approximately one out of ten older patients uses serotonergic drugs and one out of twenty dopaminergic drugs. The frequent use of dopaminergic and serotonergic drugs in the elderly patients is a potential problem due to the fact that aging is associated with a down-regulation of both these monoaminergic systems. Future studies are needed for evaluation of the impact of these drugs on different cognitive and emotional functions in old age.