EGFR-TKI类药物治疗晚期非小细胞肺癌的研究进展

表皮生长因子受体酪氨酸激酶抑制剂（epithelial growth factor receptor tyrosine kinase inhibitors,EGFR-TKI）引领EGFR突变的晚期非小细胞肺癌精准治疗十多年,EGFR-TKI对EGFR常见突变的晚期非小细胞肺癌的疗效已得到明确的证实。然而对于EGFR罕见突变,EGFR-TKI的疗效在临床上存在众多争议。本文列举了目前已经进入临床阶段的EGFR-TKI类药物在EGFR突变阳性晚期非小细胞肺癌中的中位无进展及总生存期并进行比较,增加了EGFR罕见突变对EGFR-TKI疗效的相关研究,以期为临床EGFR-TKI的合理使用提供参考。     

非小细胞肺癌中EGFR突变与EGFR-TKI临床敏感性及耐药性的研究进展

目的阐述非小细胞肺癌(NSCLC)中表皮生长因子受体(EGFR)突变与表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)临床敏感性及耐药性之间的关系。方法分析总结已经发表的国内外相关文献,对非小细胞肺癌治疗中EGFR-TKI的敏感性和耐药性进行介绍。结果在NSCLC患者中用EGFR-TKI治疗有效性和EGFR活化性突变有着紧密的联系,二者都在亚洲人种,女性,不吸烟,腺癌患者中发生率较高;患者对EGFR-TKI耐药不仅与EGFR二次突变有关,还与KRAS突变,HER2过表达,蛋白酪氨酸磷酸酶基因(PTEN)缺失,胰岛素样生长因子受体1(IGFR-1)过表达等有联系。结论EGFR突变可作为临床衡量EGFR-TKI敏感性指标;耐药机制复杂多变,目前还没有完全研究清楚。     

表皮生长因子受体突变诱导吉非替尼获得性耐药机制分析

吉非替尼作为表皮生长因子受体络氨酸激酶抑制剂（EGFR-TKI）类靶向药物,广泛用于临床非小细胞肺癌（NSCLC）的治疗,但近几年的临床应用发现,肿瘤细胞对该类药物的敏感度逐渐下降,药物作用疗效呈现减低趋势,临床耐药问题逐渐凸显。近几年的深入研究表明,吉非替尼的耐药机制可能与表皮生长因子受体（EGFR）旁路效应、EGFR信号传导路径和EGFR靶基因的二次突变有关,基于此以吉非替尼作用机制为出发点对其获得性耐药机制进行归纳总结。     

EML4-ALK融合介导EGFR-TKI耐药晚期肺腺癌个案报告

表皮生长因子受体（EGFR）基因突变和间变性淋巴瘤激酶（ALK）基因融合的发现显著改变了非小细胞肺癌的治疗模式，并使患者生存显著获益。ALK融合突变是EGFR酪氨酸激酶抑制剂（TKI）耐药的机制之一。我们报告了1例64岁晚期肺腺癌女性患者，其存在EGFR突变，并在EGFR-TKI耐药后发生了ALK融合，通过先后使用EGFR-TKI或ALK-TKI获得了长期生存，为ALK融合介导的EGFR-TKI耐药患者的靶向治疗药物选择提供参考。     

EGFR-TKIs在NSCLC中的耐药机制及治疗策略研究进展

表皮生长因子受体（EGFR）抑制剂是目前临床治疗非小细胞肺癌（NSCLC）的一线小分子靶向药物,随着EGFR酪氨酸激酶抑制剂（EGFR-TKI）的广泛使用,其耐药现象也日趋明显,已成为其治疗NSCLC的巨大挑战。本文总结了EGFR-TKIs在NSCLC中的主要耐药机制,并对相关逆转策略的研究进展进行综述。     

非小细胞肺癌EGFR-TKI耐药后转化为小细胞肺癌2例

摘 要 表皮生长因子受体-酪氨酸激酶抑制药 (EGFR-TKI) 治疗晚期非小细胞肺癌 （NSCLC）的耐药机制逐渐明了,其中小细胞肺癌（SCLC）转化引发了学者极大关注。本文详细报道2例女性EGFR基因19外显子缺失突变肺腺癌患者,在EGFR-TKI靶向治疗耐药后伴随血清神经元特异性烯醇化酶（NSE）水平的显著升高;同时,二次活检发现小细胞肺癌（SCLC）的转化,予以标准SCLC化疗方案治疗有效。提示医生应考虑NSCLC EGFR-TKI 治疗失败后 SCLC 转化的可能,并重视NSE动态监测及二次活检病理分析的重要性。     

表皮生长因子受体非突变型非小细胞肺癌分子靶治疗有效1病例报道及相关文献复习

目的：了解表皮生长因子受体（ epidermal growth factor receptor ,EGFR）酪氨酸激酶抑制剂（ EGFR tyrosine kinase inhibitor , EGFR-TKI）对于非EGFR突变的非小细胞肺癌（ non-small cell lung cancer ,NSCLC）的疗效。方法1例化疗后进展的非EGFR突变的非小细胞肺癌肺癌接受EGFR-TKI治疗,靶向治疗后定期复查评价疗效。结果患者接受吉非替尼治疗（250 mg qd）3 w后症状部分缓解（ PR）,4月后KPS提高到90分,化疗后2月及4月复查胸部CT与老片比较达PR。患者目前随访中,病情稳定。结论对于非EGFR基因突变的NSCLC, EGFR-TKI治疗仍然是一种有效治疗手段。     

阿美替尼治疗非小细胞肺癌的研究进展

肺癌是全球癌症相关死亡的最常见原因,其中85%为非小细胞肺癌(non-small-cell lung cancer,NSCLC),表皮生长因子受体(epidermal growth factor receptor,EGFR)是治疗晚期NSCLC最重要的靶点之一。第一、二代EGFR酪氨酸激酶抑制剂(EGFR-tyrosine kinase inhibitor,EGFR-TKI)一直是晚期EGFR突变NSCLC患者的标准治疗方法,但获得性耐药几乎不可避免,主要耐药原因为T790M突变。阿美替尼是中国首个自主研发的第三代EGFR-TKI,对包括L858R和19号外显子缺失在内的EGFR敏感突变,以及T790M耐药突变均具有活性,同时保留野生型EGFR,克服了第一、二代EGFR-TKI的耐药性和选择性问题,其临床前和临床研究均显示出良好的有效性与安全性,为我国NSCLC患者提供了新的用药选择。本综述对阿美替尼的结构、作用机制、临床前研究、药动学,在NSCLC治疗中的临床疗效、安全性,以及与其他第三代EGFR-TKI的比较进行了总结,为该药的临床使用及未来的探索研究提供参考。     

第三代EGFR-TKI奥希替尼临床研究进展

奥希替尼是第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）,被批准用于治疗EGFR T790M突变阳性的局部晚期或转移性非小细胞肺癌（NSCLC）的抗肿瘤药物。其疗效显著,耐受性较好,副作用较第一、二代EGFR-TKI更易被接受。对已接受其他EGFR-TKI治疗且出现耐药的患者,奥希替尼可为该类患者带来新的选择。2017年3月22日国家食品药品监督管理总局（CFDA）加速批准了阿斯利康公司的甲磺酸奥希替尼片的进口申请。现就奥希替尼的作用机制、上市情况、临床实验、药动学、耐受性和安全性进行综述,为临床应用提供参考。     

伏美替尼治疗EGFR基因突变非小细胞肺癌的研究进展

肺癌以非小细胞肺癌（NSCLC）为主,而NSCLC常伴有表皮生长因子受体（EGFR）基因突变。目前,表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）是一线治疗EGFR基因突变NSCLC的优选方案。伏美替尼是国内第2个上市的由我国自主研发的第三代EGFR-TKI。本文综述结果显示,伏美替尼具有双重活性、强抑瘤性、高选择性和高安全性等特点,对EGFR敏感突变、EGFR 20号外显子T790M耐药突变、EGFR 20号外显子插入突变以及中枢神经系统转移NSCLC患者疗效确切,且其相关临床试验均仅入组我国患者,对我国NSCLC患者的治疗更具指导意义。     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

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.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

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.