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。     

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。     

VEGF受体酪氨酸激酶抑制剂的研究进展

肿瘤的生长和侵袭、转移依赖于新生血管的形成.抑制肿瘤介导的血管生成,阻断癌细胞的营养途径,就可有效抑制癌细胞增殖.血管内皮生长因子(VEGF)是肿瘤新生血管形成中的关键性促血管生长因子,它与特异性高表达在新生血管内皮细胞表面的受体酪氨酸激酶结合,激活酪氨酸激酶从而发挥生物学功能.因而以VEGF受体酪氨酸激酶为靶点的肿瘤血管靶向性治疗已成为近几年肿瘤治疗的新途径[1-3].     

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(EGFR)酪氨酸激酶抑制剂的研究进展

表皮生长因子受体（EGFR）酪氨酸激酶介导的信号转导与肿瘤发生发展密切相关，抑制该受体活性可以有效地抑制肿瘤。近年来，许多以此为靶点的新抗肿瘤药物陆续被开发，在多种肿瘤治疗中取得了令人鼓舞的疗效。综述了EGFR的结构和作用以及近年来EGFR酪氨酸激酶抑制剂的研究进展。     

表皮生长因子受体酪氨酸激酶抑制剂吉非替尼

吉非替尼(ZD1839,Iressa)是一种表皮生长因子受体酪氨酸激酶抑制剂,通过阻断酪氨酸激酶信号传导通路抑制肿瘤生长.2个大型的Ⅱ期临床试验(IDEAL)证实了其对于晚期非小细胞肺癌具有应用前景,可以改善症状,延长患者的生存期.此外,在对多种恶性实体瘤的Ⅰ期和Ⅱ期临床研究中也初步证实了该药具有抗肿瘤活性.     

VEGFR酪氨酸激酶抑制剂的临床应用与研究进展

血管内皮生长因子（ VEGF ）可诱导肿瘤的血管新生,在肿瘤生长中起到了关键作用。抑制血管内皮生长因子受体（ VEGFR）酪氨酸激酶能在一定程度上抑制肿瘤的生长, VEGFR酪氨酸激酶抑制剂已成为现在研究的热点之一。该文对VEGF和VEGFR进行了简要介绍,并简述了VEGFR酪氨酸激酶抑制剂的临床应用和主要化学结构类型。     

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。     

《中国新药杂志》2005年第7单元继续教育试题

1bortezomib属于哪一种抑制剂?A免疫抑制剂B蛋白酶体抑制剂C内皮生长因子抑制剂D表皮生长因子抑制剂E血管紧张素转换酶抑制剂2FDA批准bortezomib的临床适应证为下列哪一种?A皮肤癌B性淋巴瘤C复发性和难治性多发性骨髓瘤D转移性结肠直肠癌E前列腺癌3表皮生长因子酪氨酸激酶抑制剂主要用于。A抗肿瘤B降血压C调血脂D免疫调节E抗炎4关于表皮生长因子酪氨酸激酶抑制剂的作用机制叙述不正确的是。A通过与ATP竞争性结合胞外的配体结合位点,阻断分子内酪氨酸的自身磷酸化,阻断酪氨酸激酶活化,抑制EGFR激活B抑制细胞周期进程C加速细胞凋…     

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。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.