钙通道阻滞剂逆转造血系统恶性肿瘤多药耐药的研究进展

造血系统恶性肿瘤细胞较正常人组织细胞MDR-1基因和P-糖蛋白表达水平高,使化疗药溢出增加,是产生瘤细胞多药耐药性的主要机制.可选用HTCA,ECM,P-糖蛋白和MDR-1基因测定技术研究肿瘤细胞多药耐药性.钙通道阻滞剂能否逆转造血系统恶性肿瘤患者瘤细胞多药耐药性尚未定论.但逆转肿瘤细胞系多药耐药已较肯定.临床应用对心脏副作用小的r型维拉帕米,可能有助于克服造血系统恶性肿瘤多药耐药性.     

多药耐药相关蛋白1与肿瘤

多药耐药相关蛋白(MRP)家族与P-糖蛋白同属人ABC转运蛋白超家族,介导肿瘤细胞的多药耐药,目前已发现7个成员.MRP1是190kD的跨膜糖蛋白,MRP1与P-糖蛋白介导的多药耐药有诸多差异.现综述MRP1的结构、主要生理功能、转运底物、转运功能的调控和逆转及其在肿瘤研究中的意义等方面的研究进展.     

多药耐药相关蛋白1与肿瘤

多药耐药相关蛋白（MRP）家族与P-糖蛋白同属人ABC转运蛋白超家族,介导肿瘤细胞的多药耐药,目前已发现7个成员.MRP1是190kD的跨膜糖蛋白,MRP1与P-糖蛋白介导的多药耐药有诸多差异.现综述MRP1的结构、主要生理功能、转运底物、转运功能的调控和逆转及其在肿瘤研究中的意义等方面的研究进展.     

卵巢癌多药耐药逆转治疗研究进展

由多药耐药基因(mdrl)编码、P-糖蛋白(P-gp)介导的多药耐药性的产生是肿瘤化疗失败的重要原因.下调mdrl基因的表达,可逆转肿瘤细胞对化疗药物的敏感性,提高化疗疗效.现综述近年来以P-gp为靶点克服卵巢癌细胞多药耐药的研究进展.     

Mdr1反义寡核苷酸联合磁性载药微球逆转胰腺癌耐药实验研究

目的：探讨辐射促细胞转染的多药耐药（multidrug resistance,MDR）基因Mdr1反义寡核苷酸（ASON）逆转肿瘤细胞SW1990／Fu的耐药效果。方法应用RT-PCR方法和流式细胞仪,检测2种不同的转染方法对SW1990／Fu细胞的Mdr1-mRNA及其表达产物P-糖蛋白（ P-gp）的调控情况。结果反转录RT-PCR和流式细胞仪的结果显示,联合辐射的阳性脂质体介导ASON组的SW1990／Fu细胞Mdr1-mRNA的表达水平及细胞膜糖蛋白（ P-gp）的阳性率均明显低于反义寡核苷酸（ASON）组（P＜0．01）。结论辐射促转染的Mdr1ASON联合磁性载药微球对肿瘤细胞具有较好的耐药逆转作用。     

卵巢癌多药耐药逆转治疗研究进展

由多约耐药基因(mdrl)编码、P-糖蛋白(P-gp)介导的多药耐药性的产生是肿瘤化疗失败的重要原因。下凋mdrl基因的表达，可逆转肿瘤细胞对化疗药物的敏感性，提高化疗疗效。现综述近年来以P-gP为靶点克服卵巢癌细胞多药耐药的研究进展。     

膀胱肿瘤T24／ADM多药耐药细胞株的建立及耐药机制的研究

目的建立人类膀胱肿瘤多药耐药（MDR）细胞株并研究其耐药机制。方法以人类膀胱肿瘤细胞株T24为研究对象，用多柔比星（ADM）浓度梯度递增诱导法，建立人类膀胱肿瘤细胞多药耐药模型（简称T24／ADM）。用MTT法检测肿瘤细胞的MDR特性；RT—PCR检测膀胱肿瘤耐药细胞株MDR基因的表达情况。流式细胞术检测耐药细胞P-糖蛋白（P—gP）的表达。结果T24／ADM对多种化疗药物产生耐药，对ADM的耐药性提高了16-3倍。RT—PCR检测发现T24／ADM中MDR基因和P—gp的表达明显增强。结论T24／ADM细胞具有MDR特性，其耐药性与MDR基因和P—gP的过表达有关。     

胃癌P-糖蛋白表达及其临床意义

采用免疫组织化学ABC法检测78例胃癌组织中多药材药基因产物P-糖蛋白。探讨胃癌组织中P-糖蛋白表达水平及其临床意义。结果表明,P-糖蛋白在胃癌组织中表达阳性率为42．3％（33／78）。P-糖蛋白表达在胄癌各临床分期、大体形态及组织学类型之间无显著性差异。胃癌组织中P-糖蛋白表达提示胃癌与多药耐药表型有关化疗药物的先天性耐药有关,可能是胃癌临床化疗疗效较低的重要原因。     

microRNAs与ABC转运蛋白介导的肿瘤多药耐药研究进展

目的回顾ABC转运蛋白与肿瘤耐药的研究现状,探讨miRNA在逆转肿瘤耐药过程中的作用机制。方法应用PubMed和CNKI期刊全文数据库检索系统,检索2010-01-01-2014-05-20的相关文献,以"ABC转运蛋白、miRNA和多药耐药"为关键词。纳入标准:1)ABC转运蛋白的表达水平与肿瘤耐药;2)miRNA对ABC转运蛋白表达水平的调控;3)miRNA对肿瘤细胞药物敏感性的影响,根据纳入标准符合分析的文献34篇。结果大多数癌症患者使用一种化疗药物治疗后,肿瘤细胞可能因为种种原因,不仅对该药产生耐药,而且对多种结构不同和作用机制完全不同的其他药物也产生交叉耐药。研究表明,在多药耐药导致肿瘤化疗失败的众多原因中,ABC转运蛋白过表达是导致肿瘤多药耐药的主要原因之一。在耐药肿瘤细胞当中高表达的ABC转运蛋白主要有乳腺癌耐药蛋白ABCG2,多药耐药相关蛋白ABCC1,P-糖蛋白ABCB1,这些蛋白采用ATP水解的能量将细胞内药物泵出细胞外,从而降低细胞内药物的浓度,使细胞产生耐药性。miRNA能与ABC转运蛋白mRNA的3′UTR结合,使mRNA降解或抑制其翻译,导致目标蛋白的表达受到抑制,从而增加肿瘤细胞的药物敏感性,逆转由ABC转运蛋白过表达引起的肿瘤多药耐药。结论 miRNA可以逆转由ABC转运蛋白家族高表达所引起的肿瘤耐药,这为肿瘤多药耐药的研究提供了新的思路。     

ATP结合盒转运蛋白介导的肿瘤多药耐药及其逆转剂

肿瘤多药耐药(MDR)是导致肿瘤化疗失败的主要原因之一,是多种复杂机制共同作用的结果。其中,肿瘤细胞膜上ATP结合盒(ABC)转运蛋白的表达或功能异常是肿瘤细胞产生MDR的重要机制之一。现以P-糖蛋白、多药耐药相关蛋白、乳腺癌耐药蛋白等为例,综述ABC转运蛋白的结构功能、与肿瘤的关系以及MDR逆转剂的研发进展。     

DARPP-32 mediates multidrug resistance of gastric cancer through regulation of P-gp and ZNRD1

Here, we firstly investigated the roles of DARPP-32 in multidrug resistance of gastric cancer cells. Inhibition of DARPP-32 by small interfering RNA led to decreased sensitivity of cells to chemotherapeutic drugs, accompanied by increased capacity of cells to efflux adriamycin. Inhibition of DARPP-32 expression could significantly up-regulate the expression of permeability glycoprotein (P-gp) and zinc ribbon domain-containing 1 (ZNRD1), but not alter the expression of multidrug resistance-associated protein or glutathione stransferase. The DARPP-32 siRNA-mediated MDR could be reversed by inhibitor of P-gp or siRNA of ZNRD1, indicating DARPP-32 might mediate MDR of gastric cancer through regulation of P-gp and ZNRD1.     

Overexpression and significance of prion protein in gastric cancer and multidrug-resistant gastric carcinoma cell line SGC7901/ADR

In our previous work, cellular prion protein (PrPc) was identified as an upregulated gene in adriamycin-resistant gastric carcinoma cell line SGC7901/ADR compared to its parental cell line SGC7901. Here we investigate the expression of PrPc in gastric cancer and whether it was involved in multidrug resistance (MDR) of gastric cancer. We demonstrated that PrPc was ubiquitously expressed in gastric cancer cell lines and tissues. PrPc conferred resistance of both P-glycoprotein (P-gp)-related and P-gp-nonrelated drugs on SGC7901, which was accompanied by decreased accumulation and increased releasing amount of adriamycin in PrPc-overexpressing cell line. Inhibition of PrPc expression by antisense or RNAi technology could partially reverse multidrug-resistant phenotype of SGC7901/ADR. PrPc significantly upregulated the expression of the classical MDR-related molecule P-gp but not multidrug resistance associated protein and glutathione S-transferase pi. The PrPc-induced MDR could be partially reversed by P-gp inhibitor verapamil. PrPc could also suppress adriamycin-induced apoptosis and alter the expression of Bcl-2 and Bax, which might be another pathway contributing to PrPc-related MDR. The further study of the biological functions of PrPc may be helpful for understanding the mechanisms of occurrence and development of clinical gastric carcinoma and PrPc-related MDR and developing possible strategies to treat gastric cancer.     

Expression of P-gp, MRP, LRP, GST-π and TopoIIα and intrinsic resistance in human lung cancer cell lines

This study aimed to determine the relationship between the endogenous levels of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), glutathione-s-transferase-π (GST?π) and topoisomerase IIα (TopoIIα) and intrinsic drug resistance in four human lung cancer cell lines, SK-MES-1, SPCA-1, NCI-H-460 and NCI-H-446, of different histological types. The expression of P-gp, MRP, LRP, GST-π and TopoIIα was measured by immunofluorescence, Western blotting and RT-PCR. Drug resistance to cisplatin, doxorubicin and VP-16 was determined using MTT assays. The correlation between expression of the resistance-related proteins and their roles in the resistance to drugs in these cancer cell lines was analyzed. We found that the endogenous levels of P-gp, MRP, LRP, GST-π and TopoIIα in the four cell lines varied. The level of GST-π in the SK-MES-1 cells was the highest, whereas the level of P-gp in the SPCA-1 cells was the lowest. The chemoresistance to cisplatin, doxorubicin and VP-16 in the four cell lines was different. The SPCA-1 cell line was most resistance to cisplatin; SK-MES-1 was most resistance to VP-16; whereas SK-MES-1 was most sensitive to doxorubicin. There was a positive correlation between GST-π expression and resistance to cisplatin, between TopoIIα expression and resistance to VP-16; and a negative correlation was noted between TopoIIα expression and resistance to doxorubicin. In summary, the endogenous expression of P-gp, MRP, LRP, GST-π and TopoIIα was different in the four human lung cancer cell lines of different histological types, and this variance may be associated with the variation in chemosensitivity to cisplatin, doxorubicin and VP-16. Among the related proteins, GST-π may be useful for the prediction of the intrinsic resistance to cisplatin, whereas TopoIIα may be useful to predict resistance to doxorubicin and VP-16 in human lung cancer cell lines.     

耐药相关蛋白P-gp、MRP、LRP在非小细胞肺癌组织中的表达及意义

Objective： To explore the expression and significance of the multidrug resistance-related proteins P-glycoprotein （P-gp）, multidrug resistance-related protein （MRP）, lung resistance protein （LRP）in human non-small cell lung cancer （NSCLC） tissues and paratumor tissues. Methods： Immunohistochemistry （IHC） was used to examine the expression level of proteins P-gp, MRP and LRP in 43 samples of NSCLC and 15 samples of paratumor tissues. Results： The expression rates of P-gp, MRP and LRP in 43 tumor tissues were 74.42% （32/43）, 67.44% （29/43） and 88.37% （38/43）, respectively, while in 15 paratumor tissues were 13.33% （2/15）, 20.00% （3/15） and 6.67% （1/15）, respectively. There was significant difference in the expression of proteins （P-gp, MRP and LRP） between lung cancer tissues and paratumor tissues （P 〈 0.05）. The expression of proteins P-gp, LRP in lung adenocarcinoma were higher than that in other pathological carcinomas （P 〈 0.05）. The expression of protein MRP was not related to pathological type, clinical stage and classification of histodifferentiation （P 〉 0.05）. Conclusion： Multidrug resistance is more common in NSCLC. The proteins of P-gp, MRP and LRP participated in the formation of multidrug resistance in lung cancer. Detection of multidrug resistance-related proteins in lung cancer tissues may be useful to choice drugs.     

Is multidrug resistance relevant in breast cancer?

The multidrug resistance phenotype is associated with expression of P-glycoprotein (P-gp), an energy-dependent drug efflux pump. P-gp is expressed in several clinically resistant human cancers. This article discusses the evidence that P-gp expression may be implicated in the development of clinical drug resistance in patients with breast cancer.     

乳腺癌组织多药耐药相关蛋白表达及其与化疗疗效的相关性研究

目的:探讨乳腺癌组织中多药耐药蛋白(P-gp)、乳腺癌耐药蛋白(BCRP)和肺耐药蛋白(LRP)的表达及其与乳腺癌化疗疗效的关系。方法:免疫组化法检测126例乳腺癌和42例癌旁组织中P-gp、BCRP和LRP蛋白的表达。结果:乳腺癌组织中P-gp、BCRP及LRP阳性表达率分别为41.26%(52/126)、38.89%(49/126)和65.87%(83/126),明显高于癌旁组织的14.28%(6/42)、16.67%(7/42)和19.05%(8/42),χ2值分别为10.147、7.020和27.820,P<0.05;5年内复发转移和无复发转移者P-gp阳性表达率差异有统计学意义(P=0.001),BCRP及LRP阳性表达率差异均无统计学意义,P>0.05。5年总生存率及无病生存率P-gp和BCRP阴性表达者明显高于阳性,χ2值分别为24.17、4.43、12.13和4.22,P值均<0.05;伴有2及3个耐药相关蛋白共表达的乳腺癌患者5年无病生存期及总生存期均较1或3个者明显缩短,χ2值分别为7.43和14.30,P值均<0.05。结论:P-gp、BCRP和LRP均参与了乳腺癌多药耐药,P-gp阳性...     

Prognostic significance of multidrug resistance-related proteins in childhood acute lymphoblastic leukaemia

An important problem in the treatment of children with acute lymphoblastic leukaemia (ALL) is pre-existent or acquired resistance to structurally and functionally unrelated chemotherapeutic compounds. Various cellular mechanisms can give rise to multidrug resistance (MDR). Best studied is the transmembrane protein-mediated efflux of cytotoxic compounds that leads to decreased cellular drug accumulation and toxicity. Several MDR-related efflux pumps have been characterised, including P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), breast cancer resistance protein (BCRP) and lung resistance protein (LRP). P-gp expression and/or activity has been associated with unfavourable outcome in paediatric ALL patients, whereas MRP1 and BCRP do not seem to play a major role. LRP might contribute to drug resistance in B-lineage ALL, but larger studies are needed to confirm these results. The present review summarises the current knowledge concerning multidrug resistance-related proteins and focuses on the clinical relevance and prognostic value of these efflux pumps in childhood ALL.     

人卵巢癌多细胞球体的P-gp蛋白表达与p27蛋白表达的相关性研究

目的:检测人卵巢癌多细胞球体中p27和P-gp的表达。观察P27反义寡核苷酸(p27-ASON)抑制p27表达前后人卵巢癌多细胞球体多药耐药P-糖蛋白(P-gp)的表达,探讨P-gp蛋白表达与p27蛋白表达的相关性及p27反义寡核苷酸对卵巢癌细胞多药耐药的逆转作用。方法:以单层细胞为对照,以三维培养方法获得的人卵巢癌A2780、CAOV3多细胞球体(MCS)为模型,通过脂质体将p27-ASON转染入两卵巢癌细胞株,采用流式细胞仪(FACS)、蛋白质免疫印迹法(Westernblot)检测p27、P-gp蛋白水平的表达;激光共聚焦显微镜(Confocal)检测p27、P-gp蛋白的亚细胞分布。结果:FACS、Westernblot、Confocal检测提示单层细胞低表达p27,低表达P-gp,而在MCS中p27和P-gp表达明显升高。p27-ASON转染后培养的MCS,p27表达明显下调,同时P-gp表达下调。结论:卵巢癌多细胞球体中P-gp和p27的表达呈相关性,多药耐药性可能和p27的表达上调有关,p27-ASON可下调多细胞球体中P-gp的表达,从而可一定程度的逆转卵巢癌多药耐药性。     

阿帕替尼逆转P-gp转运体介导的乳腺癌化疗多药耐药性的作用及其机制

目的 探讨阿帕替尼对人乳腺癌化疗多药耐药性的逆转作用及其机制。方法 不同浓度的阿帕替尼作用于体外培养的人乳腺癌MCF-7及MCF-7/ADR细胞48 h,MTT法检测阿帕替尼对两种细胞的细胞毒性;低毒浓度的阿帕替尼与化疗药物紫杉醇及阿霉素联用,探讨阿帕替尼对两种细胞化疗耐药性的影响;采用流式细胞术检测阿帕替尼对罗丹明123在MCF-7及MCF-7/ADR细胞内蓄积的影响;采用Pgp-Glo? Assay Systems试剂盒观察阿帕替尼对多药耐药相关蛋白P-gp的ATPase活性的影响;采用Western blot法检测阿帕替尼对P-gp表达及AKT磷酸化的影响。结果 阿帕替尼可浓度依赖性地逆转乳腺癌MCF-7/ADR细胞对紫杉醇及阿霉素的多药耐药性（P<0.05）、增加罗丹明123在MCF-7/ADR细胞内的蓄积（P<0.05）及激活P-gp转运体的ATPase活性（P<0.05）,而对P-gp的表达没有影响;此外,阿帕替尼不改变AKT的磷酸化水平。结论 阿帕替尼可能通过抑制P-gp转运体的外排功能逆转P-gp转运体介导的乳腺癌化疗多药耐药性。     

PSC-833, a frontier in modulation of P-glycoprotein mediated multidrug resistance

The expression of drug efflux mechanisms by cancer cells during chemotherapy leads to multidrug resistance (MDR) and constitutes a major obstacle in the effective treatment of cancer. The most widely characterized drug efflex pump is P-glycoprotein (P-gp) and efforts are being directed towards identifying agents that reverse P-gp mediated drug resistance. PSC-833 is a non-immunosuppressive cyclosporin derivative that potently and specifically inhibits P-gp. The current review focuses on the elucidation of the mechanism of action of PSC-833 as a potential MDR reversing agent, using syngeneic multidrug resistant sublines of MDA435 human breast adenocarcinoma cell line that express increasing levels of P-gp. In vitro experiments indicate that PSC-833 interacts directly with P-gp with high affinity and probably interferes with the ATPase activity of P-gp. Studies in multidrug resistant tumor models confirm P-gp as the in vivo target of PSC-833 and demonstrate the ability of PSC-833 to reverse MDR leukemias and solid tumors in mice. Presently, PSC-833 is being evaluated in the clinic.