曲妥珠单抗获得性耐药机制及应对策略

摘 要：曲妥珠单抗是靶向人表皮生长因子2(HER2)的单克隆抗体药物,对HER2表达阳性乳腺癌及胃癌治疗效果确切。然而多数患者在用药1年内出现了获得性耐药,导致其疗效降低甚至无效。研究表明,信号通路异常激活;表皮生长因子受体(EGFR)及其配体异常表达及肿瘤诱发上皮—间质转化(EMT)均可成为曲妥珠单抗耐药的重要机制,联合使用PI3K/AKT/mTOR通路抑制剂及其相关生存信号通路抑制剂可逆转曲妥珠单抗耐药。本文就曲妥珠单抗耐药机制及逆转耐药策略进行综述。     

曲妥珠单抗的耐药机制及其逆转策略

曲妥珠单抗(trastuzumab;商品名为Herceptin,赫赛汀)是靶向人表皮生长因子受体2(human epidermal growth factor receptor2,HER2)的人源化单克隆抗体,与化疗药物联用可显著提高患者的无进展生存期.然而,曲妥珠单抗的原发性和获得性耐药严重制约了其临床疗效及应用.PI3 K/AKT/mTOR信号通路的异常活化、HER家族成员间的相互作用、药物压力下代偿性生存信号的激活、肿瘤干细胞表型形成等均可能成为曲妥珠单抗耐药的重要机制.随着曲妥珠单抗耐药机制研究的不断深入,克服耐药的治疗手段也越来越丰富.有研究表明,曲妥珠单抗与其他靶向HER2胞外域的单克隆抗体或靶向其他HER家族成员的抗体类药物联用可增强曲妥珠单抗的疗效.应用PI3 K/AKT/mTOR信号通路的小分子抑制剂或耐药相关促生存信号通路的特异性抑制剂可有效逆转耐药发生,延长患者的疾病无进展生存期.深入研究曲妥珠单抗耐药的机制,不断探索逆转耐药的治疗策略,可为乳腺癌个性化治疗方案的建立提供依据.本文将对曲妥珠单抗耐药机制及克服耐药的研究进展做一介绍.     

大肠癌的靶向治疗

癌症靶向治疗(targeted cancer therapy)是癌症治疗的新纪元,是建立在肿瘤分子生物学研究基础上,靶向治疗主要可以归纳为4个方面:①针对表皮生长因子受体(EGFR通道的靶向治疗;②针对血管内皮生长因子(VEGF)通道的靶向治疗;③基质金属蛋白酶(MMP)抑制剂;④选择性环氧化酶-2(COX-2)抑制剂,其中EGFR和VEGF是目前最为主要的靶点,有多种药物均是针对此靶点,且在临床试验或临床应用中取得很好疗效。1对表皮生长因子受体(EGFR)通道的靶向治疗人EGF受体(human epidermal growth factor receptor,HER)家族由4个成员组成,分别称为HER1(…     

表皮生长因子受体与肝癌发病机制及靶向治疗的研究进展

表皮生长因子受体(epidermal growth factor receptor,EGFR)是指跨膜酪氨酸激酶受体,包括Erb B1/HER1,Erb B2/HER2、Erb B3/HER3和Erb B4/HER4。通过结合细胞表面受体,表皮生长因子激活信号转导途径,包括PI3K/AKT、RAS/RK和JAK/STAT通路,从而抑制细胞死亡。EGFR的高表达在肝癌的发生、发展中起到重要的作用,并加剧了肝癌的侵袭性,靶向抑制EGFR可降低癌细胞的侵袭性,治疗肝癌。作者阐述了EGFR与肝癌的发生发展、靶向治疗相关的研究与进展。     

分子靶向药物在肺癌治疗中的临床进展

人类表皮生长因子受体(human epidermal growth factor receptor,EGFR)家族由四个受体成员构成:HER1(亦称c-erbB1,EGFR)、HER2(亦称c-erbB2,neu)、HER3(c-erbB3)及HER4(c-erbB4).EGFR是一分子量为170 kD的跨膜糖蛋白,有配体依赖性的酪氨酸激酶活性,存在于大多数细胞中,在多种肿瘤中都有过表达,如非小细胞肺癌(NSCLC)中鳞癌EGFR表达率为85%,腺癌和大细胞癌为65%,而小细胞肺癌罕见EGFR表达.EGFR高表达的肿瘤细胞增长迅速,容易发生转移,复发率高,因此被认为是非小细胞肺癌靶向治疗的一个比较理想的分子靶点.阻断EGFR信号传导通路有两种方法:(1)酪氨酸激酶抑制剂与EGFR胞内部分的磷酸化酶位点结合,阻止磷酸化酶的活化.目前已有多种药物开发,以吉非替尼和Erlotinib为代表.(2)单克隆抗体与HER的胞外区结合从而阻断其活化.以HER2特异性的Herceptin及HER1/EGFR特异性单抗Cetuximab(C-225)为代表.     

乳腺癌的生物治疗进展

近些年,随着对乳腺癌分子分型、乳腺癌相关基因组学以及乳腺癌信号转导通路了解的不断加深,使乳腺癌的生物治疗——靶向治疗和免疫治疗成为了继手术、放疗、化疗之后的一种全新的治疗模式,并成为乳腺癌治疗的里程碑和研究热点. 1 与HER相关的靶向治疗 HER是一类具有酪氨酸激酶活性的受体家族,包括EGFR/HER-1、HER-2、HER-3和HER-4,其配体与细胞外的配体结构域结合(HER-2没有特定的配体,随时可以形成二聚体),形成二聚体.随后,HER的激酶结构域被磷酸化(HER-3没有激酶结构域),通过PI3K/Akt/mTOR和Ras/Raf/MEK/MAPK信号通路参与调节细胞的增殖、分化和凋亡等[1].     

表皮生长因子受体家族特点及与肿瘤关系的研究进展

人类表皮生长因子受体(human epidermal growth factor receptor,HER)家族属于酪氨酸激酶Ⅰ亚族的跨膜蛋白受体家族，包括4个成员，分别是HER1(EGFR/ErbB1)、HER2(ErbB2)、HER3(ErbB3)和HER4(ErbB4)，由erb基因编码，在细胞生长、增殖及凋亡等活动中起到重要的调节作用。同时，作为原癌基因家族，HER家族在许多人类肿瘤中异常激活及过度表达，是这些肿瘤发生和发展的关键因素，与多种肿瘤的临床病理特征及肿瘤患者的不良预后密切相关。HER家族一直是肿瘤领域基础实验研究和临床诊治研究的热点之一，以其为靶点的综合抗肿瘤治疗方案获得了良好的临床疗效。本文通过查阅对有关HER家族及其与肿瘤关系的相关文献，总结人表皮生长因子受体家族特点及其在肿瘤发生发展、生物靶向诊治方面的最新研究进展。相信随着HER家族临床研究成果的不断丰富及分子生物学技术的快速发展可为肿瘤临床诊治提供新的思路和帮助。     

HER2、EGFR信号通路与胃癌的靶向治疗

随着肿瘤分子生物学的发展,尤其是对肿瘤细胞增殖生长和转移过程中的信号转导通路作用机制研究的不断深入,继而为其特异性靶点而设计的分子靶向药物的开发,使肿瘤治疗已经进入了一个全新的时代。酪氨酸激酶受体HER家族中的HER2和EGFR在许多肿瘤中的过表达和（或）突变与许多肿瘤发生发展及预后密切相关,而以HER2和EGFR为靶向的胃癌治疗和针对其信号转导通路的信号转导干预治疗又备受关注。     

肺癌表皮生长因子受体酪氨酸激酶抑制剂获得性耐药的逆转

以表皮生长因子受体（EGFR）为靶点治疗非小细胞肺癌是治疗肺癌的前沿手段,其产生的获得性耐药限制了靶向药物的发展。目前已有大量的有关EGFR突变耐药的数据,利用这些数据,人们正在探讨克服EGFR靶向治疗耐药的3个基本方法：强化EGFR的抑制、EGFR抑制剂与其他靶向治疗相结合以及通过替代途径改变抗癌治疗方法。     

吉非替尼和厄洛替尼耐药机制

吉非替尼和厄洛替尼是首批用于晚期非小细胞肺癌(NSCLC)的分子靶向药物,尽管治疗效果显著,但最终多数患者均会发生耐药.近年来研究表明,其耐药机制与表皮生长因子受体(EGFR)二次突变、其他酪氨酸激酶家族受体异常活化及信号通路成分或调节因子基因表达的改变等有关.另有研究表明,可能与EGFR受体内化及肿瘤微环境改变也有相关性.进一步研究其耐药机制,并寻找克服或逆转耐药的方法、开发新的靶向药物已成为肺癌治疗领域的前沿课题.     

Dermatomycosis in Goats in India

Summary: In an extensive survey involving 2176 goats 1.56% of goats manifested clinical lesions of ringworm infection. Animals below the age of 6 months were affected most (4.20%). The incidence of infection was higher during the winter months. T. verrucosum, T. mentagrophytes and M. gypseum were isolated from the skin scrapings of 12, 4, and 2 goats respectively. It is suggested that the infected animals could be a source of disease to human population in which the zoophilic dermatophyte invasion is characterized by severe inflammatory lesions of the skin. The zoonotic importance of different dermatophytes is stressed.
Zusammenfassung: In einer ausgedehnten Untersuchung an 2176 Ziegen wurden bei 1,56% klinische Zeichen einer Hautmykose festgestellt. Tiere, die jühger als 6 Monate alt waren, zeigten mit 4,20% am häfigsten Krankheitssymptome. In den Wintermonaten war die Erkrankungshäufigkeit am gröBten. T. vermcosum, T. mentagrophytes and M. gypseum wurden jeweils von 12,4 bzw. 2 Ziegen isoliert. Die inflzierten Tiere köinnen eine Infektionsquelle für die menschliche Bevölkerung darstellen und dort Mykosen mit stark entzündlichen Veränderungen auslösen. Die Bedeutung verschiedener Dermatophyten als Erreger von Zoonosen wird hervorgehoben.     

Trends in zygomycosis in children

Zygomycosis, or mucormycosis, is associated with significant morbidity and mortality in both children and adults. Studies in adults have shown an increase in the incidence of zygomycosis, particularly among haemtopoietic stem cell transplant (HSCT) recipients and patients with haematologic malignancies. There is a paucity of data on the epidemiology of zygomycosis in children. We performed a retrospective analysis to describe trends in zygomycosis between 1 January 2003 and 31 December 2010. We used the Pediatric Health Information System (PHIS) database to identify paediatric patients who were diagnosed with zygomycosis during the study period. Administrative data on diagnoses, demographics, underlying conditions and clinical experiences were collected. Summary statistics were calculated and tests for trend were conducted. We identified 156 unique patients with zygomycosis. The prevalence of zygomycosis did not significantly increase over time (P=0.284). The most common underlying condition was malignancy (58%) and over half received intensive care. Voriconazole utilisation among all hospitalised children significantly increased during the period (P=0.010). Our study demonstrates that the incidence of zygomycosis is not significantly increasing. During the time period there was a significant increase in the use of voriconazole among children.     

Increased apoptosis in cancer cells in vitro and in vivo by ceramides in transferrin-modified liposomes

Lysosomes are a promising therapeutic target for induction apoptosis in cancer cells due to lysosomal membrane permeabilization (LMP) leading to leakage of hydrolytic enzymes, especially the cathepsins, into the cytoplasm. We hypothesized that with the modification of the ceramide-loaded liposomes with transferrin (Tf), we would achieve both tumor targeting and increased delivery of lysosome-destabilizing agents, such as ceramides to lysosomes, to initiate LMP-induced apoptosis. We prepared Tf-modified (TL) and plain (PL) liposomes and loaded with short (C6)- or long (C16) N-acyl chain ceramides. Uptake, intracellular localization of liposomes, stability of the lysosomal membrane and release of cathepsin D were investigated on Hela cells by fluorescence microscopy and flow cytometry. Apoptosis was evaluated by binding of fluorescently-labeled Annexin V. Antitumor and pro-apoptotic effects of C6Cer-loaded Tf-liposomes were demonstrated in vivo in an A2780-ovarian carcinoma xenograft mouse model. TL were internalized specifically via the TfR-dependent endocytic pathway and localized within the endosome-lysosomal compartment. Ceramide-loaded Tf-liposomes significantly increased apoptosis compared with ceramide-free and ceramide-loaded non-modified liposomes. The treatment of cancer cells with TL led to increased LMP and cytoplasmic relocation of the intralysosomal cathepsin D. A strong antitumor and pro-apoptotic effect of C6Cer-loaded TL was also demonstrated in vivo in an A2780-ovarian carcinoma xenograft mouse model. The lysosomal accumulation of ceramides delivered by Tf-liposomes initiates the permeabilization of the lysosomal membranes required for the release of lysosomal cathepsins into the cytoplasm and initiation of the cancer cell apoptosis both in vitro and in vivo.     

Ringworm in animals in a farm in Assiut

Bericht über das Auftreten von Hautmykosen bei Tieren auf der Farm der Landwirtschaftlichen Fakultät der Universität Assiut. Von 70 Kälbern waren 42 pilzkrank, davon 22 durch T. mentagrophytes, 20 durch T. verrucosum. Von 180 Kühen waren 8 pilzbefalien, sämtlich durch T. mentagrophytes. Von 2 kranken Bullen wurde T. verrucosum isoliert. Auch die 3 Pferde und 2 Maultiere der Farm waren pilzinfiziert; Erreger war in diesen Fällen T. equinum. Auch ein Kalb war von T. equinum befallen. Die gleiche Pilzart wurde ferner von 3 Tierpflegern isoliert, die Pilzherde am Hals und an den Armen aufwiesen.     

Socioeconomic factors in cancer in Sweden

It is well known that certain cancers have shown clustering in socioeconomic groups, but limited data are available on recent results and time trends in such clustering. We determined standardized incidence ratios (SIR) for cancer, adjusted for age, period, region, parity and age at first childbirth among men and women in 6 socioeconomic groups based on the Swedish Family-Cancer Database. Persons had to be identified with the same socioeconomic status in the census of years 1960 and 1970, or of years 1960, 1970 and 1980; the comparison group was all people according to the same censuses. Cancers were followed from years 1970 to 1998 or from 1980 to 1998. Both increased and decreased SIRs were found, and a consistent pattern emerged, although the overall SIRs for cancer did not differ much, the lowest being for farmers (0.85) and the highest for professional men (1.07) and women (1.11). At individual sites, manual workers were at risk of tobacco-, alcohol- and occupation- and human papilloma virus-related cancers and at a decreased risk at most other cancers. Manual workers and farmers showed an excess of stomach cancer; professionals had an excess of melanoma and squamous cell skin cancer. Male and female SIRs correlated highly for manual and blue-collar workers and for professionals. The overall population-attributable fraction for selected sites was 16.7% for men and 10.9% for women and it was highest, over 50%, for lung cancer in both genders.     

Survey of changes in dietary preferences in cancer patients in China

Objective The aim of this study was to investigate the changes in dietary preferences in cancer patients in China and to determine the need for encouraging the adherence to a sensible diet among such patients.Methods A total of 468 cancer patients were interviewed using a self-designed questionnaire focusing on changes in the intake of specific foods. Data were analyzed using SPSS 16.0. Results Most patients completely avoided roosters and carp(73.1%), condiments(51.9%), and meat of aquatic species(40.4%). All other types of the specific foods were completely avoided by different subpopulations of the patients.Conclusion In addition to focusing on disease treatment, medical professionals need to help cancer patients overcome barriers associated with the customs of avoiding specific foods encompassed by the term ”fawu” and provide them with dietary guidance in order to prevent negative nutritional effects.     

Advances in cancer epidemiology in Japan

Epidemiologists in Japan have been performing calculations to estimate nationwide cancer incidence rates as well as 5‐year survival rates using population‐based cancer registry data. There have been remarkable changes in cancer incidence and/or mortality in cancers of the lung, liver and stomach, which were thought to be attributed to the changing impact of exposure to cigarette smoking, chronic hepatitis C virus infection and Helicobacter pylori infection, respectively. In systematic reviews providing evidence in risk/protective factors for cancer sites using case–control and cohort studies of the Japanese population, there were associations between cancer sites (esophagus, stomach, colo‐rectum, liver, pancreas, lung and breast) and various lifestyle factors. In the past 10 years, a hospital‐based case–control study at Aichi Cancer Center provided valuable evidence of gene‐environment interaction on the development of cancer [i.e., the effects of aldehyde dehydrogenase‐2 (ALDH2) polymorphism and heavy alcohol drinking on esophageal cancer, ALDH2 polymorphism and smoking on lung cancer, methylenetetrahydrofolate reductase polymorphism and heavy alcohol drinking on pancreatic cancer]. The database with stored DNA was also used and identified seven loci containing significant but low‐penetrance polymorphisms associated with the development of breast cancer. These findings together with established risk factors are likely to be useful to predict personalized breast cancer risk in East Asian women. In 2005, the Japan Multi‐Institution Collaborative Cohort (J‐MICC) study was launched to elucidate gene‐environment interactions as well as to confirm preclinical diagnostic biomarkers of cancer. J‐MICC, which has recruited 92,000 healthy individuals by the end of 2012, will follow the individuals until 2025.     

Foreign bodies in ENT in a teaching hospital in Eastern India

Objective

To evaluate the nature, common sites, modes of presentation of various foreign bodies (FB) in Ear, Nose and Throat (ENT).

Materials and methods

Observational retrospective study carried out at Vivekananda Institute of Medical Sciences, Ramakrishna Mission Seva Pratishthan. The study period was between Jan 2006 to Jan 2007. The information obtained from the hospital record books.

Results

Four hundred and eighty-two patients presented in the Department of Otorhinolaryngology of Vivekananda Institute of Medical Sciences, in the study period with FB in their ENT. Out of 482 pts, the commonest location of FB was to be in throat with 302 pts (62%) followed by ear with 119 pts (25%) and nose 61 pts (13%). Amongst the FB in throat the commonest was fish bone and the commonest site being tonsils. Artificial denture accounted for a significant number of 13 (4.3%). External auditory canal was the commonest site of FB lodgment in ear found in 118 patients (99.16%). Nasal FB were found in 61 patients; more common in pediatric age group (98.36%).

Conclusion

From this study we have found that FB lodgement is a very common complaint with which patients come to otolaryngologist. The commonest site of FB lodgement is in the throat. Most of the FB could be removed in emergency room (ER) with or without Local Anesthesia.     

整合素在急性白血病中的研究进展

急性白血病是一种早期造血干/祖细咆的恶性克隆性疾病.微小残留病和耐药被认为是其复发和难治的根源.近来,越来越多的证据显示白血病细胞通过与骨髓微环境中的基质细胞或细胞外基质相互作用促进其存活,并增强其对常规化疗药物的耐药.整合素是介导细胞与细胞外基质（细胞与非细胞成分）粘连的最主要黏附分子,在细胞增殖、存活等生物学过程中发挥关键作用,但作用机制尚不完全清楚.现就目前揭示的整合素及肿瘤微环境在急性白血病发生、发展中的作用进行综述.