肿瘤多药耐药分子机制研究进展

化疗是治疗恶性肿瘤主要方法之一。然而不幸的是,先天或获得性耐药尤其是多药耐药的发生,最终导致化疗失败。因此,深入探讨多药耐药发生的分子机制,寻找可以有效预测肿瘤化疗敏感性的分子标志物以及逆转多药耐药的分子靶点,是提高化疗效果的有效途径。肿瘤多药耐药分子机制错综复杂,本文主要从DNA损伤修复、ABC转运蛋白家族表达和功能异常、肿瘤干细胞、拓扑异构酶活性改变、上皮间质转分化、谷胱甘肽-S-转移酶表达改变、表观遗传学修饰以及缺氧等方面对肿瘤多药耐药分子机制进行阐述。     

多药耐药基因与子宫颈癌化疗

肿瘤细胞对化疗药物产生多药耐药性是化疗失败的主要原因之一,肿瘤多药耐药的机制十分广泛,其中P-gp/mdrl介导的多药耐药是最经典的耐药机制.故本文就MDR1与宫颈癌化疗的关系进行回顾和总结.     

多药耐药基因产物在宫颈癌中的研究进展

化疗多药耐药是影响宫颈癌化疗疗效的重要因素.目前关于多药耐药(multidmgresistance,MDR)产生机制的研究报道很多,主要包括以下几个方面:(1)典型性多药耐药:如多药耐药基因1(multidrug resistance gene 1,MDRI)及其编码的蛋白P糖蛋白(P-glycoprotein,P-gp)、多药耐药相关蛋白(multidrug resistance-associated protein,MRP)和肺耐药蛋白(lung resistance-related protein,LRP)基因及其编码的蛋白的过度表达;(2)谷胱苷肤-S-转移酶-π的表达;(3)非典型性多药耐药:由拓扑异构酶Ⅱ(Topo Ⅱ)介导的耐药机制;(4)细胞凋亡抑制(例如:突变型P53和癌基因Her-2/neu/C-erbB-2表达增加)等.这些因素之问还可以相互影响、共同作用,造成宫颈癌对多种抗肿瘤药物的耐药[2].本文就多药耐药基因产物在宫颈癌中的研究进展进行综述.     

逆转肿瘤多药耐药策略进展

多药耐药MDR是肿瘤治疗的一大障碍 ,本文简述了MDR的可能机制与逆转克服策略及开发临床可应用的低毒有效逆转剂的新方向     

基因逆转肿瘤多药耐药的研究进展

化疗在恶性肿瘤的综合治疗中占有非常重要的地位,而耐药性是严重影响肿瘤病人化疗效果及生存的主要原因之一,其中多药耐药(multi-drug resistance,MDR)最具临床意义。多药耐药是指肿瘤细胞对某一化疗药物产生耐药性后,对其他化学结构及机理不同的化疗药物也产生交叉耐药性。研究表明MDR是一个多阶段发展、多因素参与的复杂事件。逆转肿瘤多药耐药是目前肿瘤化疗的研究热点之一。近年随着基础科学研究的不断深入,基因逆转肿瘤多药耐药的研究已从分子水平上,定点、多位点阻断多药耐药基因的表达,已取得一些显著的进展。本文对肿瘤多药耐药机制以及逆转肿瘤多药耐药性的相关基因做一简要综述。     

新辅助化疗对骨肉瘤多药耐药相关蛋白表达的影响

目的:探讨不同新辅助化疗方案对多药耐药相关蛋白在骨肉瘤组织中表达的影响。方法:采用RP-PCR技术以及免疫组化技术检测48例骨肉瘤患者在不同新辅助化疗方案实施前后多药耐药相关蛋白在mRNA以及蛋白水平的表达变化。结果:在同一新辅助化疗方案实施前后以及不同新辅助化疗方案之间,肿瘤组织的多药耐药蛋白的mRNA及蛋白表达均无显著性差异。结论:不同新辅助化疗方案的实施对骨肉瘤多药耐药蛋白表达的影响有限,其多药耐药性可能主要决定于肿瘤本身,检测多药耐药蛋白的表达有利于制定个体化化疗方案。     

洛贝林逆转肿瘤细胞多药耐药机制新进展

洛贝林,是从半边莲的品种中提取的一种哌啶生物碱。近期发现洛贝林可以逆转肿瘤细胞的多药耐药,可能作为新型、低毒、有效的耐药逆转剂。研究其作用机理、体内实验等将有助于探讨其临床实用性。     

洛贝林逆转肿瘤细胞多药耐药机制新进展

洛贝林,是从半边莲的品种中提取的一种哌啶生物碱。近期发现洛贝林可以逆转肿瘤细胞的多药耐药,可能作为新型、低毒、有效的耐药逆转剂。研究其作用机理、体内实验等将有助于探讨其临床实用性。     

蛋白激酶C对多药耐药调控作用

化疗是目前治疗恶性肿瘤的主要手段之一 ,尽管新的抗癌药物及化疗方案不断推出 ,但治疗效果仍无显著提高 ,其主要原因之一是肿瘤细胞对化疗药物产生多药耐药 (ｍｕｌ ｔｉｄｒｕｇｒｅｓｉｓｔａｎｃｅ ,ＭＤＲ)。ＭＤＲ是指对一种药物耐药的肿瘤 ,同时对另一些与之化学结构、作用机制完全不同的药物产生交叉耐药。其发生机制复杂 ,其中ｍｄｒ1基因编码的Ｐ 糖蛋白 (Ｐ ＧＰ)表达是ＭＤＲ产生的主要机制之一。近年来的研究表明 ,蛋白激酶Ｃ(ｐｒｏｔｅｉｎｋｉｎａｓｅＣ ,ＰＫＣ)参与了调控ＭＤＲ形成过程。蛋白激酶Ｃ是一种钙离子、磷脂依…     

纳米载药系统在肿瘤多药耐药中的应用

当今世界,肿瘤已经成为威胁人类健康的重大疾病。在肿瘤疾病中,化疗可控制肿瘤的生长和转移,增强放疗的疗效,是治疗肿瘤疾病的主要手段之一。而肿瘤多药耐药是影响化疗药物疗效、引起化疗失败的重要原因,影响肿瘤患者的治愈效果,降低生存率。如何提高化疗的疗效,延长肿瘤患者的寿命成为医学界的难题。纳米载药系统是生物医学领域研究的热点,相对于单一药物,纳米载药体现了许多优越性,具有良好的应用前景。纳米级颗粒更有利于药代动力学,这些纳米载药颗粒通过被动和主动的机制表现出在全身血液循环寿命延长,持续的药物释放动力,使其能更好的在肿瘤细胞中积累而发挥作用,提高化疗的疗效。本文综述了肿瘤多药耐药研究中主要的纳米载体以及它们在逆转多药耐药方面的应用,并展望载药系统的有更多更好的发展趋势。     

Multidrug resistance ABC transporters

Clinical multidrug resistance is caused by a group of integral membrane proteins that transport hydrophobic drugs and lipids across the cell membrane. One class of these permeases, known as multidrug resistance ATP binding cassette (ABC) transporters, translocate these molecules by coupling drug/lipid efflux with energy derived from the hydrolysis of ATP. In this review, we examine both the structures and conformational changes of multidrug resistance ABC transporters. Together with the available biochemical and structural evidence, we propose a general mechanism for hydrophobic substrate transport coupled to ATP hydrolysis.     

Multidrug resistance evaluation by confocal microscopy in primary urothelial cancer explant colonies

Assessing functional multidrug resistance (MDR) status in clinical biopsy material using drug autofluorescence has potential applications to clinical management. The small size of many cystoscopy specimens has led us to develop, as an alternative to flow cytometry, a protocol for studying epirubicin accumulation in adherent colonies of primary bladder cancer cells viewed live andin situ by confocal microscopy. The limitations to quantitation inherent in this technique are compensated for by preservation of cellular organisation and the elimination of non-malignant cells. Biopsy material is disaggregated and explanted into culture-grade petri dishes. After incubation for three to seven days plaques of epithelial cells have developed. Classical patterns of sensitive and resistant drug distribution are observed. Cells of the rolled edges of the colony accumulate more drug than those of the inner epithelial monolayer. Some central areas of larger colonies give the appearance of drug arrested at the intercellular junctions to give a fenestrated pattern. These observations contribute to the understanding of mechanisms in MDR as well as forming the basis for a clinical urological MDR evaluation protocol.     

Multidrug resistance in fungi

Antibiotic and synthetic chemotherapeutic resistance in pathogenic yeast becomes one of the biggest challenges for the modern chemotherapy. An increasing number of pathogenic yeast and filamentous fungi resistant to the action of the majority of currently used drugs is isolated in clinics nowadays. Among variety of the resistance mechanisms, the most dangerous grows to be the multidrug resistance. The most important mechanism of the multidrug resistance is the overexpression of membrane proteins participating in the active efflux of drugs out of the cells subjected to chemotherapy. Representatives of two classes of multidrug efflux transporters, ABC and MFS, have been identified in fungi. One of the most important strategies for overcome the phenomenon of multidrug resistance in pathogenic fungi, is the use of chemical compounds co-administrated with chemotherapeutics which are able to restore drug susceptibility in multidrug resistant cells. Mode of action of these chemical compounds may be very diverse, from the substrate competition, through the influence on the membrane fluidity, to the multidrug transporters activity modulation. This paper presents a review of the current knowledge on proteins contributing to fungal multidrug resistance and strategies for overcoming multidrug resistance by pharmacological intervention.     

Multidrug resistance increment in a human colon carcinoma cell line by colchicine

The most important mechanism in drug resistance is the multidrug resistance (MDR) phenomenon. It is possible to select MDR cells by in vitro exposure to cytotoxic agents. The resistance is due to the hyperexpression of the P-glycoprotein (P-Gp) that take drugs out from the cells. In this study, a colchicine resistant subline (HCA-2/1cch) was selected from a human colon adenocarcinoma after a short period of drug exposure, as an in vitro model of drug resistance selection. These cells showed cross-resistance to other drugs, which were not present in the medium during selection. The relative resistance was 3.32 for colchicine, 3.15 for vinblastine, 2.62 for vincristine and 5.22 for mitomycin C. P-glycoprotein levels were assayed by flow cytometry. It was found that a significant increase of 2.35 and 1.59 had occurred in the peak and mean channel of fluorescence, respectively, indicating an increment of P-glycoprotein expression in relation to the parental line. Moreover, verapamil (10 microg/ml) produced a partial reversion of multidrug resistance. The sensitisation rates were 7.41 for colchicine, 1.25 for vinblastine, 2.36 for vincristine and 1.17 for mitomycin C. The data obtained suggest that colchicine exposure period (10 weeks) and dose (0.5 microg/ml) assayed were sufficient to produce an increment in multidrug resistance. This resistance could be due to higher level of P-Gp expression.     

Multidrug resistance in Gram-negative bacteria

Broadly specific, so-called multidrug, efflux mechanisms are now known to contribute significantly to intrinsic and acquired multidrug resistance in a number of Gram-negative bacteria, and the boom in bacterial genomics has confirmed the distribution of these systems in all bacteria. This broad distribution of multidrug transporters lends a certain credibility to suggestions that they play a housekeeping role in the cell, beyond any contributions they may make to antimicrobial efflux and resistance. In many instances, these transporters are dispensable, arguing against their carrying out essential cellular functions; nevertheless, the multiplicity of these broadly specific export systems within a given microorganism, often with overlapping substrate specificity, may explain the dispensability of individual exporters. Whatever their intended function, however, their conservation in so many organisms highlights their probable general importance in antimicrobial resistance, particularly in Gram-negative bacteria whose outer membranes work synergistically with many of these export systems to promote drug exclusion.     

Multidrug resistance in Entamoeba histolytica

Drug resistance in protozoan parasites has been emerging in the past decade as an obstacle to their control. Amoebiasis, caused by Entamoeba histolytica, is a worldwide disease that provokes high rates of morbidity and mortality. Reports of failed drug treatment and differences in drug susceptibilities among E. histolytica strains probably herald the development of drug resistance in this parasite. In this review, Esther Orozco and co-workers summarize recent progress on the elucidation of physiological and molecular evidence of multidrug resistance in this parasite.