拓扑异构酶与肿瘤多药耐药及耐药逆转

多约耐药(MDR)的产生是肿瘤化疗失败的主要原因，拓扑异构酶Ⅱ(topoⅡ)介导的MDR为MDR的重要途径：耐药逆转剂的应用是克服肿瘤临床耐药．提高化疗效果的一种潜在的重要手段：现综述topoⅡ与肿瘤MDR及耐药逆转研究进展。     

肿瘤多药耐药的逆转措施

化疗是恶性肿瘤的主要治疗方法,而肿瘤多药耐药(MDR)是导致肿瘤化疗失败的重要原因之一.应用化学药物逆转剂、天然药物(中药)逆转剂、免疫治疗、基因治疗、纳米载体给药系统等逆转肿瘤MDR已取得初步进展.但研制出不良反应小、效果好、能够广泛应用于临床的逆转肿瘤MDR药物,仍需要更大努力.     

反义技术逆转多药耐药的现状与展望

多药耐药(multidrug resistance，MDR)是指肿瘤细胞对一种化疗药物产生耐药的同时，对其他结构和作用机制不同的化疗药物也产生交叉耐药的现象，是导致化疗失败的主要原因。因此，如何逆转，特别是在基因水平逆转MDR，已是肿瘤研究的热点。近年来，反义技术(antisense approach)逆转MDR     

肝癌多药耐药中药逆转剂的研究进展

多药耐药(MDR)是肿瘤化疗失败的主要原因,寻找高效、低毒的肝癌逆转剂已成为肝癌治疗领域的研究热点,现就中医药在逆转肝癌MDR方面的研究进展作一综述.     

多药耐药相关蛋白及其逆转剂的研究进展

多药耐药相关蛋白(MRP)是一种ATP依赖型跨膜蛋白,是谷胱甘肽(GSH)-S-共轭物运转泵,在GSH参与下,转运共轭的有机阴离子,起到药物外排泵的作用,是继P-170糖蛋白后发现的又一肿瘤多药耐药(MDR)机制.在一些肿瘤组织中,MRP的表达显著增高.它可能是肿瘤细胞发生耐药的重要机制.化学逆转剂可能具有逆转由MRP介导的MDR,从而增加肿瘤细胞对化疗药物的敏感性,克服耐药,提高化疗效果.     

肿瘤多药耐药治疗措施研究进展

多药耐药(MDR)是肿瘤化疗失败的主要原因，逆转MDR是目前研究的热点。从逆转剂的应用、MDR的基因治疗、特殊给药载体的介导、MDR的免疫学治疗及影响口服抗癌药物代谢途径等方面对目前国内外MDR治疗措施加以综述。     

肿瘤多药耐药的产生机制及逆转策略

肿瘤多药耐药（MDR）是导致临床化疗失败和患者死亡的主要原因。研究表明,MDR的发生与P-糖蛋白、多药耐药相关蛋白、乳腺癌耐药相关蛋白、肺耐药相关蛋白等多种因素相关。目前MDR的逆转策略主要包括化学药物逆转、基因逆转、免疫逆转、中药逆转和纳米载药系统逆转,并且均取得了一定进展,这将有助于提高肿瘤患者的化疗疗效。     

ABCG2介导的多药耐药机制及其逆转

多药耐药(MDR)是肿瘤化疗失败最常见的原因.ABCG2属于ABC转运蛋白超家族的一员,在多种肿瘤细胞中表达,能高效转运多种化疗药物.ABCG2的高表达既是侧群(sP)细胞的标志,又是肿瘤对化疗药物抵抗的重要原因.ABCG2的拮抗剂可在逆转肿瘤MDR中发挥一定作用.     

重视肿瘤多细胞耐药的研究

恶性肿瘤细胞对化疗药物产生耐受性是影响化疗疗效和患者预后的重要因素。为了逆转肿瘤的耐药性,人们对肿瘤的耐药机制进行了大量的研究。20世纪80年代以来对于肿瘤耐药机制的研究主要集中于多药耐药(multidrug resistance,MDR)方面,通过研究,阐明了产生MDR的相关机制,同时提出     

TopoⅡ与胶质瘤替莫唑胺化疗耐药性的关系

背景与目的:TopoⅡ与替莫唑胺(temozolomide,TMZ)治疗胶质瘤后产生化疗耐药的关系依然未清楚,本文探讨拓扑异构酶Ⅱ(topoⅡ)与胶质瘤细胞替莫唑胺化疗耐药性的关系。方法:替莫唑胺诱导构建耐药细胞株U251/TR,CCK-8法检测该细胞株的耐药性,RT-PCR法检测topoⅡ在U251和U251/TR中的表达变化。采用siRNA技术沉默耐药细胞株中topoⅡ的表达后,检测其对化疗药物敏感性变化。结果:成功构建TMZ耐药细胞株U251/TR,该细胞系对替莫唑胺有耐药性,其topoⅡ的表达明显升高,沉默topoⅡ的表达后,耐药性成功逆转。结论:TopoⅡ与替莫唑胺化疗耐药性有关。     

肿瘤多药耐药性及其治疗进展

肿瘤细胞多药耐药的产生是导致肿瘤化疗失败的主要原因.肿瘤细胞的多药耐药性成为目前肿瘤化疗的难点,多药耐药的产生机制目前并未阐明,随着对肿瘤细胞的MDR认识的深入,不断有新的逆转药物发现,而且不断有新的基因技术应用于肿瘤细胞的MDR逆转.本文简要介绍肿瘤细胞的耐药性发生机制及其逆转策略,并对近年来肿瘤耐药基因研究进展及其在肿瘤临床治疗中的意义、存在的问题及展望做简要综述.     

Verapamil suppresses the emergence of P-glycoprotein-mediated multi-drug resistance

Selection protocols were designed to determine whether non-cytotoxic chemomodifiers can influence the evolution of the drug-resistant phenotype. To this end, the human multiple myeloma cell line RPMI 8226 (8226/S) was selected with either doxorubicin, verapamil or doxorubicin plus verapamil. Using this approach low-level multi-drug-resistant (MDR) cell lines were obtained when 8226/S was selected with doxorubicin only or doxorubicin plus verapamil but not with verapamil only. The MDR phenotypes obtained were mechanistically distinct. In doxorubicin only-selected cells (8226/dox4), drug resistance was mediated by over-expression of the MDR1 gene and its cognate protein P-glycoprotein. In contrast, the drug resistance seen in the doxorubicin plus verapamil-selected cells was mediated through decreases in topoisomerase II protein levels and catalytic activity and not by P-glycoprotein over-expression. Cells selected with verapamil alone did not become resistant to any of the drugs tested. None of the 3 selected cell lines showed any changes in MRP gene expression when compared with 8226/S. Our results indicate that the inclusion of verapamil during drug selection with doxorubicin influences the drug-resistant phenotype by preventing the selection of MDR1/P-glycoprotein-positive cells. © 1996 Wiley-Liss, Inc.     

肿瘤多药耐药机制的研究进展

多药耐药 (Multi drugresistance ,MDR)是肿瘤化疗失败的主要原因之一。从药物转运、药物代谢、药物靶、细胞凋亡及凋亡相关基因 4个方面 ,全面复习近年来有关MDR的机制 ,为肿瘤临床化疗及临床MDR研究提供重要的理论依据     

Overcoming multi-drug resistance using an intracellular anti-MDR1 sFv

We made an intracellular single-chain variable fragment (sFv) from the C219 monoclonal antibody that recognized the intracellular domain of the multidrug resistance (MDR) gene product, P-glycoprotein (P-gp). Immuno-cytochemistry using the FITC conjugated anti-C-myc tag antibody showed that the sFv protein was expressed in the cytoplasm of the cells. Although transfection of the sFv did not result in the down-regulation of P-gp expression in P-gp positive MDR cells as determined by flow cytometry analysis, Adriamycin (ADM) uptake and Rhodamine123 (Rh123) retention were increased by the C219 intra-cellular sFv transfection. The transfected cells exhibited a higher sensitivity to ADM using a 10-day colony formation assay. The conventional 3-day MTT assay showed the drug resistant tendency in C219 sFv transfected cell we tested. The growth rate of C219 sFv transfected cells was delayed in all non-MDR and MDR cells that might be the reason why C219 transfected cells exhibited the drug resistant tendency in the MTT assay. Despite this unexpected effect of C219 sFv on growth rate, our data suggest that the intra-cellular sFv technique could knockout MDR functionally and may offer a means of increasing the effectiveness of tumor chemotherapy.     

阿霉素耐药性研究与流式细胞分析

目的 探讨流式细胞术在阿霉素多药耐药研究中的特殊意义。方法 对两组不同耐药倍数的阿霉素耐药细胞系（S－180R和BGC－823／DOX）进行动态、对比性流式细胞分析。结果 流式细胞术在高倍数耐药细胞系S－180R中表现出与亲代细胞耐药性的直观的整体差异，在低倍数耐药细胞系BGC－823／DOX中则可以定量地分辨与亲代细胞耐药性的细微差异。在动态分析中，检测到耐药细胞群中个体细胞耐药性的变化，即个体细胞内荧光含量的接近，细胞荧光峰的集中。结论 流式细胞术在阿霉素耐药性研究中具有灵敏、准确、定量的作用。     

Association of multi-drug resistance gene polymorphisms with pancreatic cancer outcome

BACKGROUND:

The purpose of this study was to identify single nucleotide polymorphisms (SNPs) of multidrug resistance genes that are associated with clinical outcome in patients with potentially resectable pancreatic adenocarcinoma who were treated with preoperative gemcitabine‐based chemoradiotherapy at M. D. Anderson Cancer Center.

METHODS:

We selected 8 SNPs of 7 drug resistance genes, including MDR1 (ABCB1), MRP1‐5 (ABCC1‐5), and BCRP (ABCG2), reported to be important in mediating drug resistance. Genotype was determined by the Taqman method. The associations of genotype with tumor response to therapy and overall survival (OS) were evaluated using log‐rank test, Cox regression, and logistic regression models.

RESULTS:

MRP5 A‐2G AA genotype showed significant association with OS (log‐rank P = .010). The hazard ratio (95% confidence interval) was 1.65 (1.11‐2.45) after adjusting for clinical predictors. The MRP2 G40A GG genotype had a weak association with reduced OS (log‐rank P = .097). A combined effect of the two genotypes on OS was observed. Patients with none of the adverse genotypes had a median survival time (MST) of 34.0 months, and those with 1‐2 deleterious alleles had a significantly lower MST of 20.7 months (log‐rank P = .006). MRP2 G40A GG genotype was also significantly associated with poor histological response to chemoradiotherapy (P = .028).

CONCLUSIONS:

These observations suggest a potential role of polymorphic variants of drug resistance genes in predicting therapeutic efficacy and survival of patients with potentially resectable pancreatic cancer. Cancer 2011. © 2010 American Cancer Society.     

Chk1表达与急性髓系白血病细胞多药耐药的关系及临床意义

目的通过检测急性髓系白血病（acute myeloid leukemia,AML）患者的骨髓中单个核细胞上细胞周期检测点激酶1（checkpoint kinase 1,Chk1）的表达,探讨Chk1表达水平与急性髓系白血病临床疗效及预后的关系。方法分析48例急性髓系白血病患者,按临床疗效将其分为完全缓解组和难治耐药组,应用RT-PCR和Western-blot分别检测Chk1 mRNA、蛋白质及磷酸化水平的表达,比较两组间及各组治疗前后Chk1表达水平的差异及其与AML缓解率、复发、无瘤生存期和总生存期的关系。结果 Chk1mRNA及蛋白表达水平在完全缓解组和难治耐药组组间及治疗前后差异无统计学意义（P〉0.05）;Chk1磷酸化（P-Chk1）水平在难治耐药组治疗前后分别为1.17±1.32、2.27±0.98,完全缓解组为0.81±0.62、1.07±0.96,治疗前两组间P-Chk1水平的表达差异无统计学意义（P〉0.05）,治疗后,难治耐药组明显高于完全缓解组,差异有统计学意义（P〈0.05）,且难治耐药组治疗后P-Chk1水平明显高于治疗前,差异有统计学意义（P〈0.05）,完全缓解组治疗前后差异无统计学意义（P〉0.05）;本研究以治疗后P-Chk1/β-actin的比值≥1.0定为P-Chk1阳性表达,根据此标准,难治耐药组P-Chk1阳性表达率为70.6%,显著高于完全缓解组19.4%（P〈0.05）。P-Chk1阳性患者的完全缓解率为37.5%,与P-Chk1阴性患者（78.12%）相比,差异有统计学意义（P〈0.05）;P-Chk1阳性患者复发率高、无瘤生存期和总生存期均短于阴性患者,差异有统计学意义（P〈0.05）。结论 DNA损伤后P-Chk1水平的升高影响了AML细胞对药物的敏感性,P-Chk1阳性表达与AML低解率、高复发率、短的无瘤生存期及总体生存期密切相关,提示Chk1的活化状态参与调控白血病细胞耐药的形成,故推测P-Chk1水平可作为判断急性髓系白血病临床疗效及预后的指标之一。     

肿瘤专科医院多重耐药菌医院感染的动态分析研究

目的:动态观察我院从2009年到2012年,4年间多重耐药菌的检出率和耐药性。方法:采用美国临床实验室标准化委员会(NCCLS/CLSI)推荐的纸片扩散确证法检测ESBLs与MRSA。MIC法做药敏试验,利用WHONET5.4分析软件对药敏试验进行统计分析。结果:4年来ESBLs阳性率大肠埃希菌由59.3%升至72.1%;肺炎克雷伯菌由21.2%升至46.7%;奇异变形杆菌阳性率偏低。ESBLs阳性株对碳青霉烯类、阿米卡星和β-内酰胺类/β-内酰胺酶抑剂类的耐药率较低;MRSA阳性率由53.3%降至29.8%;MRCNS阳性率由54.7%升至56.6%,无明显变化。但MRSA呈多重耐药性,对MRSA菌株的治疗首选糖肽类抗菌药物;多重耐药非发酵菌的检出率呈上升趋势。结论:4年来,大肠埃希菌和肺炎克雷伯菌中ESBLs阳性率逐年上升;MRSA阳性率呈现下降趋势,而MRCNS阳性率则变化不大;多重耐药非发酵菌的检出率呈上升趋势。     

PSC833逆转人骨肉瘤细胞株多药耐药性的研究

目的 探讨PSC 833对骨肉瘤耐药细胞株U2OS/DOX的逆转作用及其机制。方法 用MTT法进行PSC 833逆转MDR活性测定;用流式细胞仪技术，观察PSC833对细胞内Rh123积聚和外排的影响；用免疫荧光技术定量检测逆转剂对P-gp表达水平的影响。结果 PSC833能显著增加DOX对U2OS/DOX的细胞毒性作用，逆转效果明显强于VPL和 CSA，且存在剂量依赖关系,对敏感株U2OS无明显作用；PSC 833能使耐药株细胞内Rh123外排减少、积聚增加，而对P-gp的表达水平没有明显影响。结论 PSC833能增强DOX对U2OS/DOX的细胞毒性作用，逆转MDR效果明显优于VPL和CSA，其机理在于抑制耐药株细胞膜上P-gp的功能，而对P-gp的表达水平没有影响。