肿瘤多药耐药机制及逆转药物的研究进展

导致肿瘤多药耐药的机制很复杂,主要涉及有：ATP结合盒型转运蛋白超家族、DNA甲基化、细胞凋亡、拓扑异构酶Ⅱ、谷胱甘肽解毒系统及相关多药耐药信号通路等,这些机制单独或共同存在而导致耐药。逆转肿瘤多药耐药的方法主要有：化疗增敏剂、中药逆转剂和基因工程技术逆转耐药等。本文就肿瘤多药耐药机制的研究进展及逆转耐药的方法作一综述。     

白血病多药耐药研究进展

近年来肿瘤药物治疗效果多不理想,主要是由于肿瘤细胞发生了多药耐药.即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亦产生耐药性.目前,这方面的研究已经成为了肿瘤研究领域的热点.已知的多药耐药机制包括P-糖蛋白(P-gp)、多药耐药相关蛋白(MRP)、肺相关蛋白(LRP)的增多、乳腺癌耐药蛋白;拓扑异构酶II(Topo-II)活力降低;谷胱甘肽-S-转移酶以及还原型谷胱甘肽(GST)升高;肿瘤某些生化特征的改变:膜离子通道、蛋白激酶(PKC).     

非经典肿瘤多药耐药逆转剂的研究进展

化疗是肿瘤综合治疗的主要手段之一,多药耐药性的产生是肿瘤化疗中存在的主要问题。开发多药耐药逆转剂逆转肿瘤细胞对现有化疗药物的耐药性将是一种有效的治疗方法。目前已有多种多药耐药逆转剂处于基础和临床试验阶段。主要从谷胱甘肽S转移酶、蛋白激酶C、凋亡通路受阻、拓扑异构酶和DNA修复能力增强等方面介绍非经典的多药耐药逆转剂。     

多药耐药逆转剂的研究进展

<正> 化疗是提高恶性肿瘤疗效的一个重要手段,然而肿瘤细胞对化疗药物产生的多药耐药性往往导致化疗的失败,多药耐药性(multidrug resistance,MDR)是指肿瘤细胞能对多种结构、功能及杀伤机制均不同的化疗药物产生耐受。目前认为多药耐药与下列因素有关:多药耐药基因(MDR1)及其编码的细胞膜P—糖蛋白(P—GP)表达增加;谷胱甘肽解毒酶系统(GST)活性增高;DNA拓朴异构酶Ⅱ(ToP_0Ⅱ)活性减低或结构异常;DNA损伤后修复能力增强;蛋白激酶C活性增强;多药耐药相关蛋白(MRP)基因的扩增或过度表达;肺阻蛋白(LRP)的表达。根据耐药产生的机制不同,逆转剂可分以下几种。     

贲门腺癌经典多药耐药机制的研究

目的研究贲门腺癌经典多药耐药机制。方法用流式细胞术检测55例贲门腺癌患者癌组织和距离肿瘤5cm以上癌旁正常组织P糖蛋白。结果55例贲门腺癌组织P糖蛋白阳性表达率为50.9%,癌旁正常组织未见P170表达,两者差别有统计学意义。结论贲门腺癌存在经典多药耐药机制,检测癌组织P糖蛋白对化疗药物选择及逆转多药耐药具有重要意义。     

中药逆转肿瘤多药耐药的研究进展

多药耐药（multidrug resistance,MDR）是目前造成肿瘤化疗失败的重要原因,寻找合适的MDR逆转剂已成为肿瘤药物学研究的关键性问题。国内学者进行了大量的工作,在中药中筛选高效低毒的多药耐药逆转剂。总结了肿瘤多药耐药产生的经典机制及近年来中药逆转肿瘤多药耐药的研究进展。     

泌尿系肿瘤多药耐药的研究进展

多药耐药(MDR)是导致临床化疗失败的重要原因，对MDR及其逆转药的研究成为克服肿瘤耐药和提高化疗疗效的关键所在。泌尿系常见肿瘤MDR的形成机制复杂，可能与P 糖蛋白(P gp)、多药耐药相关蛋白(MRP)等过度表达、凋亡基因的缺失或抗凋亡基因的过度表达等有关。逆转药有P gp抑制药、细胞因子等。     

多药耐药相关基因表达的研究现状

多药耐药（MDR）指癌细胞发生对许多结构不相关的化疗药物交叉抵抗的现象，是有效化疗的主要障碍之一。据美国癌症协会估计，９０％以上肿瘤患者死亡在不同程度上受耐药的影响。多药耐药是１９７０年Bicdler等用中国仓鼠肺细胞系和骨髓纤维母细胞系与放线菌素D（ACTD）接触培养诱导耐药时首次发现的，后被称为多药耐药性（MDR）。MDR的形成机制可分为：①多药耐药基因及其所编码的细胞膜蛋白过度表达；②谷胱甘肽转移酶（GST）活性增强；③DNA拓扑异构酶Ⅱ（TOPOⅡ）含量减少或性质改变；④DNA修复能力增强等。如何及早发现耐药…     

乳腺癌耐药蛋白（BCRP/ABCG2）的研究进展

肿瘤细胞的多药耐药严重影响肿瘤化疗的疗效,研究肿瘤细胞耐药相关蛋白的生理功能及其转运药物的机制,寻找高效的多药耐药蛋白抑制剂是提高肿瘤化疗效果的重要途径。乳腺癌耐药蛋白（BCRP／ABCG2）是一种介导乳腺癌细胞耐药的重要蛋白,在乳腺癌细胞多药耐药的形成中起关键作用。本文将就BCRP／ABCG2蛋白的结构特点、生理功能、在多药耐药中的作用及其抑制剂等方面的研究进展作一综述。     

肺癌化疗耐药分子标志及其逆转研究

目的:探讨肺癌化疗耐药分子标志及其逆转的临床与基础应用评价。方法:采用国内外相关文献,结合我们在这一领域长期研究,深入归纳与分析。结果与结论:肺癌化疗耐药主要分子标志有多药耐药基因(MDR1)表达增加,多药耐药相关蛋白(MRP)基因表达增加,谷胱甘肽解毒酶系统活性增强和线粒体凋亡途径异常,综合采用逆转耐药分子,耐药基因siRNA和中医药结合的逆转耐药策略,为彻底攻克肺癌耐药奠定坚实研究基础。     

Bacterial resistance to antibiotics: active efflux and reduced uptake

Antibiotic resistance of bacterial pathogens is a fast emerging global crisis and an understanding of the underlying resistance mechanisms is paramount for design and development of new therapeutic strategies. Permeability barriers for and active efflux of drug molecules are two resistance mechanisms that have been implicated in various infectious outbreaks of antibiotic-resistant pathogens, suggesting that these mechanisms may be good targets for new drugs. The synergism of reduced uptake and efflux is most evident in the multiplicative action of the outer membrane permeability barrier and active efflux, which results in high-level intrinsic and/or acquired resistance in many clinically important Gram-negative bacteria. This review summarizes the current knowledge of these two important resistance mechanisms and potential strategies to overcome them. Recent advances in understanding the physical structures, function and regulation of efflux systems will facilitate exploitation of pumps as new drug targets.     

P-糖蛋白抗凋亡机制及相关药物

由P-糖蛋白的过度表达而产生的抗细胞凋亡作用是导致肿瘤细胞多药耐药的重要原因之一。综述P-糖蛋白抗细胞凋亡的机制，并介绍几种目前正在开发研制中的对P-糖蛋白抗细胞凋亡有抑制作用的药物，如能下调mdr-1基因的ET-742与沙尔威辛，诱导非caspase依赖型细胞凋亡的SAHA和金雀异黄素，以及蛋白酶体抑制剂PS-341等。     

Bacterial resistance to antibiotics: enzymatic degradation and modification

Antibiotic resistance can occur via three general mechanisms: prevention of interaction of the drug with target, efflux of the antibiotic from the cell, and direct destruction or modification of the compound. This review discusses the latter mechanisms focusing on the chemical strategy of antibiotic inactivation; these include hydrolysis, group transfer, and redox mechanisms. While hydrolysis is especially important clinically, particularly as applied to beta-lactam antibiotics, the group transfer approaches are the most diverse and include the modification by acyltransfer, phosphorylation, glycosylation, nucleotidylation, ribosylation, and thiol transfer. A unique feature of enzymes that physically modify antibiotics is that these mechanisms alone actively reduce the concentration of drugs in the local environment; therefore, they present a unique challenge to researchers and clinicians considering new approaches to anti-infective therapy. This review will present the current status of knowledge of these aspects of antibiotic resistance and discuss how a thorough understanding of resistance enzyme molecular mechanism, three-dimensional structure, and evolution can be leveraged in combating resistance.     

Chromosomally-encoded resistance mechanisms of Pseudomonas aeruginosa: therapeutic implications

Pseudomonas aeruginosa is an important nosocomial pathogen that presents a difficult therapeutic challenge. Although P. aeruginosa has been shown to acquire resistance mechanisms encoded on plasmids, this pathogen comes armed with multiple chromosomally-encoded mechanisms of resistance that can provide impressive intrinsic resistance, as well as the potential to mutate to high-level multi-drug resistance. Recent analysis of the sequenced genome of P. aeruginosa PAO1 suggested that we have just started to unlock the resistance potential of this pathogen. One of the most serious threats to the usefulness of beta-lactams against P. aeruginosa is the chromosomal AmpC cephalosporinase. When AmpC production increases through mutational events, overproduction of this cephalosporinase provides high-level resistance to all beta-lactams except the carbapenems. Carbapenem resistance typically requires down-regulation of the outer membrane protein (OprD), which serves as the primary route of entry for carbapenems. Perhaps the most threatening of the resistance mechanisms encoded on the P. aeruginosa chromosome are the multi-drug efflux pumps. These pumps have the ability to extrude multiple classes of antibiotics from the periplasmic space, as well as the cytoplasm. Natural expression of efflux pumps in 'wild-type' cells plays an important role in the relatively decreased susceptibility of P. aeruginosa to antibiotics. However, the greatest therapeutic problems occur when these pumps are overproduced in mutants and high-level, multi-drug resistance develops. Although the development of infections with highly resistant strains of P. aeruginosa can present serious therapeutic challenges, the most troublesome threat associated with the chromosomally-encoded resistance mechanisms is the potential for high-level resistance to emerge during the course of therapy. When resistance emerges during therapy, clinical failure can occur and the therapeutic options for second-line therapy can become severely limited. Unfortunately, the emergence of resistance during therapy is not a rare event with P. aeruginosa and these three resistance mechanisms. Therefore, clinicians must be mindful of this threat when choosing an appropriate therapy, and usually appropriate therapy includes a combination of drugs. Since the standard combination of an aminoglycoside and a beta-lactam has been shown to be ineffective in preventing the emergence of some resistance problems, the search for more effective combinations must be a priority.     

Bacterial Efflux Pumps Involved in Multidrug Resistance and their Inhibitors: Rejuvinating the Antimicrobial Chemotherapy

Active efflux of antibiotics is one of the major mechanisms of drug resistance in bacteria. The efflux process is mediated by membrane transporters with a large variety of unrelated compounds as their substrates. Though these pumps are responsible for the low intrinsic resistance of a bacterium to a drug, their overexpression, accumulation of mutations in these proteins and their synergy with other drug resistance mechanisms hampers effective antimicrobial treatment. As efflux pumps have been reported to play vital roles in mediating multidrug resistance in clinical isolates from varied geographic locations and varied populations, the inhibition of efflux pumps appears to be an attractive approach to combat the problem of drug resistance. Efflux pump inhibitors can be utilized for increasing the antibiotic concentration inside a pathogenic cell making these drugs more effective, reduce the accumulation of other resistance mechanisms in a cell and for diagnostic purposes to evaluate the presence and contribution of the efflux mechanism in a pathogen. A large number of inhibitors have been discovered and patented in last two decades but the process of discovery, testing and commercialization is rather slow. Some of the important inhibitors include the energy decouplers, phenothiazines, analogs of popular antibiotics, inhibitors of serotonin re-uptake, to name a few, that have been used as adjuvants in the antimicrobial chemotherapy to potentiate the activity of some important antimicrobials in deadly pathogens that have worried the mankind since long. This review describes the role of efflux pumps in governing the resistance phenotype of a pathogen, efflux pumps found in bacteria and the efflux pump inhibitors that have been studied and patented so far.     

Exploiting nanotechnology to overcome tumor drug resistance: Challenges and opportunities

Tumor cells develop resistance to chemotherapeutic drugs through multiple mechanisms. Overexpression of efflux transporters is an important source of drug resistance. Efflux transporters such as P-glycoprotein reduce intracellular drug accumulation and compromise drug efficacy. Various nanoparticle-based approaches have been investigated to overcome efflux-mediated resistance. These include the use of formulation excipients that inhibit transporter activity and co-delivery of the anticancer drug with a specific inhibitor of transporter function or expression. However, the effectiveness of nanoparticles can be diminished by poor transport in the tumor tissue. Hence, adjunct therapies that improve the intratumoral distribution of nanoparticles may be vital to the successful application of nanotechnology to overcome tumor drug resistance. This review discusses the mechanisms of tumor drug resistance and highlights the opportunities and challenges in the use of nanoparticles to improve the efficacy of anticancer drugs against resistant tumors.     

A redox pathway leading to the alkylation of nucleic acids by doxorubicin and related anthracyclines: application to the design of antitumor drugs for resistant cancer

Doxorubicin has been a constituent of antitumor drug protocols for a broad spectrum of cancers for more than two decades. Side effects and resistance continue to be important limitations. Drug targets responsible for both side effects and anti-tumor activity are cell membrane receptors, cell membrane lipids, nucleic acids and topoisomerase. Induction of oxidative stress is responsible for most if not all biological activity. An important consequence of oxidative stress is the production of formaldehyde which can subsequently be utilized by the drug for covalent bonding to nucleic acids and other targets as shown by in vitro experiments. Multidrug resistance mechanisms inhibit drug-induced DNA damage, drug uptake, and drug-induced oxidative stress. Synthetic anthracyclines conjugated to formaldehyde circumvent some if not all of the resistance mechanisms. Consequently, anthracycline-formaldehyde conjugates have potential for the treatment of resistant cancer.     

Resistance to tyrosine kinase inhibitors: calling on extra forces.

Over the past 5 years, small molecule tyrosine kinase inhibitors have been successfully introduced as new cancer therapeutics. The pioneering work with the ABL inhibitor imatinib (Glivec, Gleevec) was rapidly extended to other types of leukemias as well as solid tumors, which stimulated the development of a variety of new tyrosine kinase inhibitors. Unfortunately, oncogenic tyrosine kinases seem to have little problem to develop resistance to these inhibitors, and there is good evidence that this is not limited to imatinib, but also occurs with other inhibitors, such as FLT3 and EGFR inhibitors. Based on studies with imatinib, mutation and amplification of the target kinase seem to be the most important mechanisms for the development of resistance, but these mechanisms alone cannot explain all cases of resistance. A better understanding of the resistance mechanisms will be required to design improved treatment strategies in the future. In this review, we summarize the current insights in the different mechanisms of resistance to small molecule tyrosine kinase inhibitors, and discuss future improvements that might limit or even overcome resistance.     

念珠菌ERG11基因耐药机制研究进展

近年来,随着医疗技术与经济的发展,侵袭性真菌感染尤其是念珠菌感染病例持续增高。由于唑类药物的广泛应用,临床念珠菌耐药菌株不断出现,使得对耐药机制的深入研究迫在眉睫。在念珠菌对唑类药物的耐药机制中,麦角甾醇合成通路上ERG11基因的突变和高表达被视为念珠菌最重要的耐药机制之一,而ERG11基因突变和高表达可能是多种机制共同作用的结果。     

可溶性钙结合蛋白与肿瘤多药耐药

可溶性钙结合蛋白sorcin主要作用是调节细胞内的钙平衡,在肿瘤多药耐药（MDR）中起重要作用。Sorcin不仅自身可导致耐药,而且可通过增加P-糖蛋白（P-gp）表达等途径间接导致耐药,因此可能在临床对肿瘤的治疗中成为逆转肿瘤MDR的靶点。与sorcin相关的治疗MDR的新方法包括反义寡核苷酸转染技术、二氢杨梅素和钙通道阻滞剂治疗等。针对sorcin的作用机制和治疗方法做一综述,为临床逆转MDR提供依据。