新型耐药逆转剂PSC-833的研究与应用

耐药逆转剂是目前克服多药耐药(MDR)的主要方法.本文简介了耐药逆转剂valsponder(PSC-833)的耐药逆转作用、作用机制、毒副作用及其在临床各种肿瘤中的研究应用.     

新型耐药逆转剂PSC—833的研究与应用

耐药逆转剂是目前克服多药耐药（MDR）的主要方法。本文简介了耐药逆转剂valsponder（PSC－833）的耐药逆转作用、作用机制、毒副作用及其在临床各种肿瘤中的研究应用。     

胃癌多药耐药的研究进展

胃癌为我国最常见的恶性肿瘤之一,早期发现率低,多数为进展期胃癌,单纯手术常难以根治,化疗在综合治疗中发挥了重要作用,成为治疗胃癌的主要方法之一。但化疗的效果还远不够理想,原发性或获得性多药耐药（MDR）成为阻碍化疗效果提高的主要素之一。多药耐药（MDR）是指肿瘤细胞接触一种化疗药物并产生耐药性,同时对其他多种结构和作用机制不同的化疗药物也产生耐药。因此胃癌多药耐药的机制、临床意义及耐药逆转成为肿瘤研究中的热点之一。     

浙贝母碱逆转白血病细胞多药耐药的研究

浙贝母因其以化痰散结为主要药用功能,我们常常配合化疗药物治疗复发和难治性白血病（或）肿瘤,往往获得理想疗效。浙贝母中含有多种活性成分,其中浙贝母碱（贝母素甲,Ｐｅｉｍｉｎｅ）是其主要活性成分之一,属异甾类生物碱中的瑟文类（Ｃｅｖｉｎｅｇｒｏｕｐｓ）生物碱［１］。为了探讨浙贝母抗白血病的作用机制,我们研究了浙贝母碱逆转白血病细胞多药耐药作用。材料和方法１　细胞株　Ｋ５６２／Ａ０２：多药耐药细胞株,以Ｐ糖蛋白（Ｐｇｐ）蛋白升高为主要耐药机制。由中国医学科学院血液学研究所药物室提供。对阿霉素耐药４０…     

MET和HER2在胃癌中的表达及临床意义

目的分析胃癌人群中癌基因MET、人表皮生长因子受体2(HER-2)的蛋白表达及其与临床病理学特征的关系,为探索其对胃癌根治术患者复发及生存的预测价值。方法收集2007年2月20日至2013年2月20日来接受手术切除的胃或胃食管交界处腺癌患者标本共180例。采用En Vi Sion免疫组化法和FISH法对每个标本中的MET和HER2进行其相关的基因阳性表达水平进行检测,并对二者与患者的相关个人信息、病变部位、肿瘤的分化程度、有无转移等相关信息之间的线性相关关系进行研究。观察免疫组化评分与荧光原位杂交检测HER2的高表达与基因扩增之间的重叠率。统计患者两年内病死率。结果通过对180例胃癌患者进行免疫组化以及FISH方法检测HER2发现,HER2和MET的阳性表达率是40.0%和31.1%,基因扩增率是36.7%和34.4%,HER2和MET的高表达与基因扩增之间的重叠率是73.6%和78.6%,各个免疫组化间的重叠率比较差异有显著性(P0.01)。MET表达与患者的个人信息、病变大小、病变部位以及是否出现淋巴道转移无关(P0.05),而与分化程度、临床分期以及是否出现门脉侵犯有关(P0.05);HER2表达与患者的个人信息、是否出现门脉侵犯、病变部位、是否出现淋巴道转移以及临床分期无关(P0.05),而与分化程度与病变大小有关(P0.05)。经过为期2年的随访工作发现,死亡率为33.3%(60/180),其中54例患者在检测过程中呈MET和HER2的双向高度表达。结论 MET和HER2的共同高度表达与胃癌患者病死率之间有相关性,HER2与肿瘤的分化程度和病变大小有关,MET与肿瘤分化程度和门脉侵犯有关,为今后临床上对胃癌患者癌基因的检测结果分析提供了重要的生物学资料。     

趋化因子受体CXCR3在乳腺癌分子亚型HER2过表达型中的表达及意义

目的探讨趋化因子CXCR3在乳腺癌分子亚型HER2过表达型的表达及临床意义。方法用免疫组织化学法检测趋化因子CXCR3在60例乳腺癌分子亚型HER2过表达型中的表达,采用卡方检验进行统计学处理。结果CXCR3的表达在乳腺癌分子亚型HER2过表达型中阳性率高,CXCR3阳性表达率与淋巴结转移呈正相关性,二者均有显著性差异(P<0.05)。结论趋化因子CXCR3A检测可以作为判断乳腺癌预后的因子,为诊断乳腺癌分子亚型患者、判断预后以及指导治疗提供一定的参考。     

在HER2过表达乳腺癌细胞中曲妥珠单抗抵抗的分子机制

目的已有研究显示HER2基因过表达乳腺癌细胞对曲妥珠单抗(TZB)产生抵抗性与LC3的过表达相关,本研究通过RNAi沉默耐TZB的SKBR3(SKBR3-TR)细胞LC3的表达,探讨HER2阳性乳腺癌对TZB抵抗的机制.方法以SKBR3乳腺癌细胞及SKBR3-TR细胞为研究对象,检测两组细胞中LC3表达情况.以SKBR3-TR细胞为研究对象,通过慢病毒载体沉默SKBR3-TR细胞LC3的表达,实时定量PCR(RealtimePCR)、蛋白免疫印迹检测LC3mRNA、蛋白的表达及水平,通过CCK-8法检测基因沉默前后细胞存活率.结果 SKBR3-TR细胞导入RNAi LC3载体后,LC3mRNA及蛋白表达水平呈现明显降低,CCK8法检测显示沉默组细胞存活率明显降低.结论 LC3在HER2阳性乳腺癌对曲妥珠单抗抵抗过程中发挥重要作用,而LC3是自噬的重要标志,说明自噬在引起曲妥珠单抗抵抗HER2阳性乳腺癌中可能发挥某种重要的调控机制.     

中药与骨肉瘤耐药逆转研究探讨

肿瘤多药耐药（multidrug resistance,MDR）是制约肿瘤成功化疗的重要因素之一,逆转MDR治疗恶性肿瘤是肿瘤治疗的有效策略,但由于肿瘤MDR机制复杂,耐药逆转药物作用靶点及机制单一,其治疗效果并不理想。中药抗肿瘤及耐药逆转具有高效低毒、多靶点、多阶段性等作用特点及其他优点,可针对肿瘤多药耐药的多种机制进行有效逆转。MDR亦是骨肉瘤化疗的主要障碍,骨肉瘤及其耐药有其特殊性,根据骨肉瘤耐药机理及中药耐药逆转机理,中药有潜力开发成为低毒高效的骨肉瘤耐药逆转剂,可能成为骨肉瘤治疗的理想药物。     

NVP-BEZ235逆转伯基特淋巴瘤RAJI细胞阿霉素耐药的研究

目的:研究NVP-BEZ23对耐阿霉素细胞株RAJI/DOX的逆转耐药作用。方法:利用浓度梯度法诱导耐阿霉素细胞株RAJI/DOX;Western blot测定各组细胞Pgp、p-AKT、p-mTOR蛋白水平;MTT法检测细胞抑制率,SPSS软件测定IC₅₀。结果:成功诱导出耐阿霉素细胞株RAJI/DOX。耐阿霉素细胞株RAJI/DOX中Pgp、p-AKT、p-mTOR蛋白水平高于亲本细胞RAJI。NVP-BEZ235可引起耐阿霉素细胞株RAJI/DOX中p-AKT、p-mTOR蛋白水平下降。NVP-BEZ235能够抑制耐阿霉素细胞株RAJI/DOX增殖,与阿霉素具有协同作用。结论:PI3K/AKT/mTOR通道在耐阿霉素伯基特淋巴瘤细胞中进一步活化;NVP-BEZ235通过抑制PI3K/AKT/mTOR信号通道活化,能够与阿霉素协同抑制伯基特淋巴瘤耐药细胞,逆转伯基特淋巴瘤耐药细胞对阿霉素的耐药性。     

The role of HER3 in gastric cancer

Gastric cancer is the second leading cause of cancer mortality in the world. HER family tyrosine kinases play a critical role in the development of gastric cancer. The HER family of receptor tyrosine kinases includes EGF receptor (EGFR), HER2, HER3, and HER4. Targeted drugs antineoplastic therapies such as EGFR tyrosine kinase inhibitors have application with confrontation of gastric cancer. However, less attention has been paid to the oncogenic functions of HER3 essepecially in the gastric cancer due to its lack of intrinsic kinase activity. Recent work, however, has placed the role of HER3 in gastric cancer in the spotlight as a key signaling hub in several contexts. First, HER3 overexpression may be associated with poor prognosis and unfavorable survival mediated by PI3K/AKT signaling pathway. Second, a large amount of direct evidence has emerged the benefit of anti-HER3 agents in combination with EGFR tyrosine kinase inhibitors as well as anti-HER2 agents in gastric cancer. Furthermore, we can further elucidate the relationship between HER3 and MET inhibitors in gastric cancer that the development of resistance to MET inhibitors may result from the overexpression of HER3. This review focuses on the current achievements of the relationship between HER3 and gastric cancer in vivo and in vitro, the development of HER3 molecule-targeted therapy, additionally, the challenge which we will meet in the future.     

MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells

HER2 amplification is found in more than 15% of gastric cancers and is associated with poor clinical outcome. Lapatinib, a dual HER2 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown promising in vitro results in treating HER2(+) cancer cells. However, several studies have shown that activation of alternative receptor tyrosine kinases can mediate resistance to HER-targeted therapy. Here, we investigated whether activated MET can confer resistance to lapatinib inhibition of gastric cancer cells. A panel of gastric cancer cell lines was treated with lapatinib, and we observed that cell proliferation was reduced by 70% and that the degree of HER2 amplification corresponds to sensitivity to lapatinib. Immunoblotting analysis indicated that phosphorylation of HER2, EGFR, MET, AKT, and extracellular signal-regulated kinase was inhibited by lapatinib and presumably led to cell-cycle arrest as observed with flow cytometry. Hepatocyte growth factor (HGF) activation of MET receptors rescued cells from lapatinib-induced growth inhibition by restimulating the downstream pathways and restoring normal cell-cycle progression. This rescue effect could be abrogated by inhibiting MET with PHA-665752 (a highly specific MET inhibitor) or downregulating MET expression with short interfering RNA. No synergy in growth inhibition was observed when cells were treated with a combination of lapatinib and PHA-665752. Repeat studies using insulin-like growth factor 1 and fibroblast growth factor 3 could not uniformly rescue the lapatinib-treated gastric cancer cells. In conclusion, HGF/MET-mediated resistance to lapatinib is a novel mechanism of resistance to HER2-targeted agents in gastric cancer cells. Development of inhibitors targeting multiple receptors or common downstream signaling proteins merits further investigation.     

双色银染原位杂交技术检测胃癌HER2基因扩增及临床意义

目的 探讨双色银染原位杂交技术（dual-color silver-enhanced in-situ hybridization,DSISH）检测胃癌人类表皮生长因子受体2（human epidermalgrowth factor receptor-2,HER2）基因扩增的可行性及其与临床病理学特征的关系.方法 应用DSISH技术检测230例患者胃癌切除组织中HER2基因扩增状态,并进行相关统计学分析.结果 DSISH检测230份胃癌标本中43例存在HER2基因扩增,HER2基因扩增率为18.7％.HER2基因扩增与胃癌的分化程度、淋巴结转移有关（P均＜0.05）,与患者年龄、性别、肿瘤发生部位、浸润深度、神经以及脉管侵犯无关（P均＞ 0.05）.结论 DSISH技术检测胃癌HER2基因扩增状态具有可行性;HER2基因扩增可以反应胃癌生物学行为.     

HER3 mRNA as a predictive biomarker in anticancer therapy

Importance of the field: Heterodimerization of human EGF receptor (HER) 2 and HER3, a co-receptor of HER2, plays an important and dominant role in the functionality and transformation of HER-mediated pathways. Understanding the role of HER3 in oncogenesis as well as its place as a target for anticancer therapy is an ongoing area of research. Determination of biomarkers for clinical benefit from agents targeting HER3 is an essential component of translating basic science into real-world effective anticancer therapies, with the aim of ensuring the patients most likely to benefit from such treatments can be identified.

Areas covered in this review: This review focuses on the targeting of HER2 and HER3 by monoclonal antibodies and the potential for HER3 mRNA levels to predict treatment outcome in ovarian cancer.

What the reader will gain: An understanding of the value of biomarkers for clinical benefit to anticancer therapy and the current status of HER3 mRNA as a biomarker for clinical benefit of the HER2–HER3 dimerization inhibitor pertuzumab.

Take home message: HER3 mRNA levels may be a biomarker for active ligand-induced HER2–HER3 signaling, with low HER3 mRNA levels correlated with clinical benefit from the HER2–HER3 dimerization inhibitor pertuzumab.     

Recent advances in the HER2 targeted therapy of gastric cancer

Recent advances in molecular targeted therapies, including targeting human epidermal growth factor receptor 2(HER2), had a major forward step in the therapy for gastric cancer patients. Application of HER2-targeted therapies, in particular trastuzumab in combination with chemotherapy in metastatic HER2-positive gastric cancers, resulted in improvements in response rates, time to progression and overall survival. Nevertheless, as with breast cancer, many patients with gastric cancer develop resistance to trastuzumab. Several promising therapies are currently being developed in combination with chemotherapy to increase the efficacy and overcome the cancerresistance. Here we review the current overview of clinical application of agents targeting HER2 in gastric cancer. We also discuss the ongoing trials supporting the use of HER2-targeted agents combined with cytotoxic agents or other monoclonal antibodies.     

Pertuzumab and breast cancer: another piece in the anti-HER2 puzzle

Introduction: The mechanism of action of pertuzumab, a recombinant anti-HER2 humanized monoclonal antibody, is complementary to trastuzumab’s. On 8 June 2012, the Food and Drug Administration approved the combination of pertuzumab with trastuzumab and docetaxel as first-line treatment of HER2-positive metastatic breast cancer. Furthermore, pertuzumab is the first drug to be approved in the neoadjuvant setting using a pathological complete response as an endpoint.

Areas covered: The review provides insights into the main mechanisms of action of pertuzumab. In addition, it gives complete coverage of the landmark clinical and translational trials for this agent.

Expert opinion: The new therapeutic algorithm in the treatment of HER2-positive advanced disease and the awaited results of the Aphinity trial are expected to impact the sequence of anti-HER2 treatment. Accordingly, the value of pertuzumab beyond progression needs to be properly studied. Furthermore, to improve the toxicity profile and efficacy of future treatment, new pertuzumab-based regimens are being investigated.     

溶血磷脂酸在卵巢癌细胞内HER2/neu的激活作用

目的探索溶血磷脂酸(LPA)在卵巢癌细胞内HER2/neu的激活作用。方法通过免疫沉淀反应和蛋白印迹法检测卵巢癌细胞中HER2的变化。结果 LPA能诱导卵巢癌细胞中HER2的快速和瞬态的磷酸化。结论 LPA在卵巢癌细胞中作为HER2的上游分子,对卵巢癌细胞有强有力的刺激,可诱导卵巢癌细胞中HER2磷酸化。