P-糖蛋白介导的肿瘤多药耐药逆转机制研究进展

多药耐药（Multidrug resistance，MDR）是肿瘤细胞对种化疗药物产生抗药性的同时，对其它结构和作用机制不同的抗肿瘤药产生交叉耐药性，是最重要、最常见的肿瘤耐药现象。人类MDR基因家族含mdr1和mdr3（或mdr2）两种基因，但仅人类的mdr1基因可产生MDR现象。mdr1基因及其表达产物P糖蛋白（P-glycoprotein，P—gp）的过度表达是导致肿瘤MDR发生的重要原因。逆转MDR，尤其是mdr1基因编码生成的P—gP介导的MDR，可从RNA和蛋白质两个水平进行。     

介导肿瘤多药耐药的ATP结合盒转运体的研究进展

多药耐药（MDR）是阻碍肿瘤化疗成功的一大障碍,其机制之一就是耐药的肿瘤细胞高表达三磷酸腺苷（ATP）结合盒（ABC）转运体。依据此机制提出克服肿瘤细胞耐药的策略即开发外排转运体抑制剂,以期逆转MDR。最近的研究发现肿瘤干细胞也可能是通过表达外排转运体天然耐药,这就提供了一个新的抗癌药物作用靶点。对介导肿瘤细胞多药耐药的ABC转运体及其抑制剂的开发作一综述。     

介导肿瘤多药耐药的ATP结合盒转运体的研究进展

多药耐药（MDR）是阻碍肿瘤化疗成功的一大障碍,其机制之一就是耐药的肿瘤细胞高表达三磷酸腺苷（ATP）结合盒（ABC）转运体。依据此机制提出克服肿瘤细胞耐药的策略即开发外排转运体抑制剂,以期逆转MDR。最近的研究发现肿瘤干细胞也可能是通过表达外排转运体天然耐药,这就提供了一个新的抗癌药物作用靶点。对介导肿瘤细胞多药耐药的ABC转运体及其抑制剂的开发作一综述。     

肿瘤耐药机制研究进展

肿瘤的耐药又分为原发耐药（primary drug resistance,PDR）和多药耐药（mutidrug resistance,MDR）,PDR只对诱导药物产生耐药性,MDR则是指肿瘤细胞对一种抗肿瘤药产生耐药性后,对结构与作用机制不同的抗肿瘤药也产生交叉耐药性。肿瘤MDR是导致肿瘤化疗失败的最主要原因。本文就其耐药机制作一综述。     

肿瘤多药耐药机制及其逆转剂研究进展

肿瘤细胞多药耐药性（multidrug resistance,MDR）的产生是导致肿瘤化疗失败的主要原因之一。MDR是指肿瘤细胞对一种抗肿瘤药物产生耐药性的同时,对结构和作用机制完全不同的其他抗肿瘤药物产生交叉耐药性的现象。因此,研究MDR产生的机制、寻求有效的耐药逆转剂及逆转措施,克服MDR现象已成为国内外的研究热点。本文就MDR产生的机制、目前国内外逆转耐药的研究进展做一综述。     

外排型转运体与肿瘤多药耐药

肿瘤多药耐药（MDR）是导致肿瘤化疗失败的主要原因之一。肿瘤MDR的机制有多种,其中外排型转运体的过表达是导致MDR的主要机制,因此研究外排型转运体介导的肿瘤MDR机制和发现可以逆转肿瘤MDR的抑制剂成为国内外研究的热点。就目前研究的3种三磷酸腺苷结合盒转运体：P-糖蛋白、多药耐药相关蛋白、乳腺癌耐药蛋白介导的MDR及逆转MDR的机制进行综述,以期为提高肿瘤治疗疗效提供依据。     

多药耐药基因1甲基化与多药耐药及逆转的研究进展

近年来,新的化疗药物应用于肿瘤的临床治疗,大大提高了化疗疗效。然而,对大多数的肿瘤患者来说,化疗仍然是一种姑息的治疗方法。肿瘤细胞对抗肿瘤药物产生的多药耐药性（MDR）严重地影响了化疗的有效率。其中对于由多药耐药基因1（mdrl）基因编码的P-糖蛋白（P-gp）介导的MDR研究最早也较多。mdrl基因的过表达是肿瘤预后的不良因素之一,它参与了大多数肿瘤的耐药机制。     

mdr1及P-gp与脑胶质瘤耐药关系的研究

恶性胶质瘤患者平均生存期较短,通常手术切除肿瘤组织并不能从根本上延长患者的生存时间,而且应用药物化疗易产生多药耐药性(multidrug resistance,MDR),使化疗失败。P-糖蛋白(P-glycoprotein,P-gp)和多药耐药相关蛋白(multidrug resistance associated protein,MRP)介导的药物外排是产生MDR的主要机制,其编码基因分别为mdr1和     

肿瘤耐药逆转剂研究进展

肿瘤细胞对化疗药物产生耐药性是临床肿瘤化疗失败的重要原因[1～2],因此,寻找肿瘤耐药逆转剂是抗肿瘤药物研究的重要策略之一. 1MDR产生的生化机制 肿瘤耐药性分为多药耐药性(MDR)和单药耐药性.MDR是指肿瘤细胞对一种抗肿瘤药物产生抗药性的同时,对结构和作用机制不同的抗肿瘤药物产生交叉耐药性.     

Ras蛋白活化与肿瘤发生多药耐药的研究进展

Ras蛋白的异常激活或表达升高可能导致肿瘤的发生。近10年来人们在Ras活化与肿瘤发生多药耐药（MDR）关系的研究方面取得了明显进展。Ras活化诱发肿瘤MDR的机制主要集中在三个方面；（1）Ras诱发P-糖蛋白高表达；（2）Ras破坏细胞增殖与凋亡的稳态平衡；（3）Ras诱发谷胱甘肽S-转移酶高表达。     

Overcoming drug resistance by regulating nuclear receptors

Drug resistance involves multiple mechanisms. Multidrug resistance (MDR) is the leading cause of treatment failure in cancer therapy. Elevated levels of MDR proteins [members of the ATP-binding cassette (ABC) transporter family] increase cellular efflux and decrease the effectiveness of chemotherapeutic agents. As a salvage approach to overcome drug resistance, inhibitors of MDR proteins have been developed, but have had limited success mainly due to undesired toxicities. Nuclear receptors (NRs), including pregnane X receptor (PXR), regulate the expression of proteins (including MDR proteins) involved in drug metabolism and drug clearance, suggesting that it is possible to overcome drug resistance by regulating NR. This review discusses the progress in the development of MDR inhibitors, with a focus on MDR1 inhibitors. Recent development of PXR antagonists to pharmacologically modulate PXR is also reviewed. The review proposes that selectively preventing the elevation of MDR levels by regulating NRs rather than non-selectively inhibiting the MDR activity by using MDR inhibitors can be a less toxic approach to overcome drug resistance during cancer therapy.     

Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters

Chemotherapy is one of the three most common treatment modalities for cancer. However, its efficacy is limited by multidrug resistant cancer cells. Drug metabolizing enzymes (DMEs) and efflux transporters promote the metabolism, elimination, and detoxification of chemotherapeutic agents. Consequently, elevated levels of DMEs and efflux transporters reduce the therapeutic effectiveness of chemotherapeutics and, often, lead to treatment failure. Nuclear receptors, especially pregnane X receptor (PXR, NR1I2) and constitutive androstane activated receptor (CAR, NR1I3), are increasingly recognized for their role in xenobiotic metabolism and clearance as well as their role in the development of multidrug resistance (MDR) during chemotherapy. Promiscuous xenobiotic receptors, including PXR and CAR, govern the inducible expressions of a broad spectrum of target genes that encode phase I DMEs, phase II DMEs, and efflux transporters. Recent studies conducted by a number of groups, including ours, have revealed that PXR and CAR play pivotal roles in the development of MDR in various human carcinomas, including prostate, colon, ovarian, and esophageal squamous cell carcinomas. Accordingly, PXR/CAR expression levels and/or activation statuses may predict prognosis and identify the risk of drug resistance in patients subjected to chemotherapy. Further, PXR/CAR antagonists, when used in combination with existing chemotherapeutics that activate PXR/CAR, are feasible and promising options that could be utilized to overcome or, at least, attenuate MDR in cancer cells.     

胃癌细胞的体外药敏试验与多药耐药基因表达的关系

目的:分析胃癌细胞的体外药敏试验与多药耐药基因的表达之间的相关性。方法:采用MTT法测定化疗药物对胃癌肿瘤细胞的敏感性;用逆转录聚合酶链反应(RT-PCR)测定胃癌组织中多药耐药基因(MDR1,MRP1,ABCG2,Topo-2mRNA)的表达水平。结果:单药组抑制率最高为5-FU(36.51%),联合用药组抑制率最高为DCF(56.80%);多药耐药基因(MDR1,MRP1,ABCG2,Topo-2mRNA在胃癌组织中的阳性率分别为33.3%,42.9%,52.4%,66.7%。结论:体外药敏试验测定并结合多药耐药基因表达的相关性可提高预测肿瘤的敏感性或发现其耐药性,为临床实现个体化治疗提供参考依据。     

黄芪皂苷Ⅱ对人肝癌多药耐药细胞BEL-7402/FU 的逆转耐药作用

摘要目的：探讨黄芪皂苷II（AstragalosideII,ASⅡ）对肝癌多药耐药性的逆转作用。方法：MTT法检测人肝癌多药耐药细胞BEL-7402／FU对化疗药物的敏感性和逆转耐药倍数,RT-PCR法检测多药耐药蛋白-1（MDRl）基因表达,免疫细胞化学法检测P一糖蛋白（P-gP）蛋白表达水平,流式细胞仪检测AS1I对细胞内Rhodaminel23的蓄积影响。结果：BEL-7402／FU细胞对5-氟尿嘧啶（5-FU）、阿霉素、丝裂霉素的耐药倍数分别为19．64、1．98、1．92。0．04、0．08mg／mL的ASⅡ能增强5-FU对BEL-7402／FU的细胞毒作用,逆转耐药倍数分别为1．49,1．81。0．08、0．16mg／mL的ASⅡ作用BEL-7402／FU细胞24h后,能下调MDRlmRNA和P-gP蛋白表达水平,提高细胞内Rhodaminel23的荧光表达率。结论：ASⅡ能部分逆转肝癌多药耐药性,其机制可能与下调MDRl1TIRNA表达及抑制P-gP的功能与表达有关。     

人早幼粒白血病HL60细胞及其亚系中mdr－1基因和癌基因表达的关系

人早幼粒白血病ＨＬ６０细胞及其亚系中ｍｄｒ１基因和癌基因表达的关系周卫东，张鸿卿，方敏，薛绍白（北京师范大学生物系，北京１００８７５，中国）关键词癌基因；多种抗药性；流式细胞计量术；急性早幼粒白血病目的：研究人早幼粒白血病ＨＬ６０细胞系及其分别抗Ｈ...     

Regulation of drug and bile salt transporters in liver and intestine

Major determinants of the bioavailability of drugs are the degree of intestinal absorption and the hepatic first-pass effect. Drugs need to overcome several membrane barriers before reaching the systemic circulation, each of which expresses an array of specialized transport proteins for drug uptake or efflux. The P-glycoprotein MDR1 (multidrug resistance gene product, ABCB1) is expressed at the apical surface of enterocytes, where it mediates the efflux of xenobiotics into the intestinal lumen before these can access the portal circulation. Increased expression of MDR1 reduces the bioavailability of MDR1 substrates such as digoxin, cyclosporin, and taxol. Numerous xenobiotics can induce the MDR1 gene through activation of the nuclear pregnane X receptor (PXR). This explains the risk for drug interactions that is inherent to pharmacotherapy with PXR ligands such as rifampin, phenobarbital, statins, and St. John's wort. Other PXR-regulated genes include cytochrome P450 3A4, the digoxin and bile salt transporter Oatp2 (organic anion transporting polypeptide 2, Slc01a4) of the basolateral hepatocyte membrane, and the xenobiotic efflux pump Mrp2 (multidrug resistance associated protein 2, Abcc2) of the canalicular hepatocyte membrane. A second orphan nuclear receptor that is activated by xenobiotics is the constitutive androstane receptor (CAR), which induces Mrp2 and Mrp3 (Abcc3). The PXR and CAR are thus important "xenosensors" that mediate drug-induced activation of the detoxifying transport and enzyme systems in liver and intestine.