肿瘤耐药及其逆转策略

恶性肿瘤是当今威胁人类健康的重大疾病,肿瘤化疗是治疗恶性肿瘤最有效、最广泛应用的手段之一,但肿瘤的耐药性却严重影响了抗肿瘤药物的治疗效果。肿瘤耐药是一个复杂的,多因素的,并且不断发展变化问题,始终是肿瘤研究的热点领域。本文将对肿瘤耐药的机制及其逆转策略的研究进展作一综述。     

P-糖蛋白抑制性纳米载体逆转肿瘤多药耐药的研究进展

P-糖蛋白(P-glycoprotein,P-gp)的过表达导致细胞外排泵活性增强,将抗肿瘤药物泵出胞外,从而导致多药耐药(multidrug resistance,MDR)的产生和化疗的失败.纳米药物载体的优势表现在减少药物外排、增加药物在肿瘤部位的蓄积、增强药物的靶向作用、下调P-gp的表达、协同逆转多药耐药等.本...     

法尼基转移酶抑制剂在抗肿瘤和逆转肿瘤耐药中的作用

法尼基转移酶抑制剂(FTI)是一类靶向作用于肿瘤细胞增殖、细胞信号转导途径的新药.它通过抑制细胞内包括Ras在内的蛋白法尼基化修饰,诱导细胞凋亡及抑制血管生成从而发挥抗肿瘤作用;通过抑制P糖蛋白(Pgp)的功能来逆转肿瘤的多药耐药(MDR).     

肿瘤耐药逆转剂的研究进展

肿瘤细胞对多种多种化疗药物产生交叉抗药性（ＭＤＲ）是造成肿瘤化疗失败的主要原因，Ｐ糖蛋白（Ｐｇｐ）高表达是ＭＤＲ的主要机制，逆转ＭＤＲ成为肿瘤治疗亟待解决的问题，现已发现许多化合物具有ＭＤＲ逆转作用，少数已进入临床应用。为了发现效果更强，副作用更小的耐药逆转剂，研究者对许多化合物进行了研究，本文综述了近年来Ｐｇｐ有关的耐药逆转剂的研究进展。     

乙二醛酶抑制剂逆转肿瘤耐药研究进展

糖代谢的衍生物甲基乙二醛等可通过糖化作用产生细胞毒性。乙二醛酶(GLO)Ⅰ是降解甲基乙二醛过程中起主要作用的酶,在多种肿瘤细胞内高表达,并导致肿瘤耐药。GLOⅠ抑制剂具有抗癌及逆转耐药作用,有望成为新的靶向抗肿瘤药,但其具体作用机制仍有待进一步阐明。     

乙二醛酶抑制剂逆转肿瘤耐药研究进展

糖代谢的衍生物甲基乙二醛等可通过糖化作用产生细胞毒性。乙二醛酶（GLO）Ⅰ是降解甲基乙二醛过程中起主要作用的酶，在多种肿瘤细胞内高表达，并导致肿瘤耐药。GLOⅠ抑制剂具有抗癌及逆转耐药作用，有望成为新的靶向抗肿瘤药，但其具体作用机制仍有待进一步阐明。     

卵巢癌化疗耐药及逆转耐药基因水平研究进展

卵巢癌细胞对化疗产生耐药的机制主要有肿瘤细胞内有效药物浓度降低、DNA损伤修复功能异常和细胞凋亡调控异常3个方面.逆转卵巢癌细胞耐药主要包括反义基因治疗、RNA干预、化疗药物的联合应用等.     

肿瘤耐药逆转剂研究新进展

肿瘤耐药逆转剂研究新进展陆东东肿瘤细胞对多种化疗药物产生交叉抗药性是造成肿瘤化疗失败的主要原因。多药耐药（ＭＤＲ）的发生机制十分复杂，其中多药耐药基因编码的Ｐ－糖蛋白（ＰｇＰ）高表达是多药耐药的主要机制。人类ｍｄｒ１基因编码的ＰｇＰ是一种能量依赖性“...     

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。     

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。     

上皮-间质转化与肿瘤耐药性的研究进展

上皮-间质转化（EMT）是上皮细胞表型向间质细胞表型转变的过程,在肿瘤发生及其演变中发挥着重要的作用。近期研究表明,EMT在多种肿瘤的化疗耐药中发挥重要作用,而化疗药物也能增强肿瘤的恶性程度包括诱导EMT表型的产生。本文结合国内外最新报道,对EMT与肿瘤耐药关系的研究进展进行综述。      

Hypoxia and drug resistance

Biologically and therapeutically important hypoxia occurs in many solid tumor masses. Hypoxia can be a direct cause of therapeutic resistance because some drugs and radiation require oxygen to be maximally cytotoxic. Cellular metabolism is altered under hypoxic conditions. Hypoxia can result in drug resistance indirectly if under this condition cells more effectively detoxify the drug molecules. Finally, there is evidence that hypoxia can enhance genetic instability in tumor cells thus allowing more rapid development of drug resistance cells. The current review describes the effects of hypoxia on tumor response to a variety of anticancer agents and also describes progress toward therapeutically useful methods of delivering oxygen to tumors in an effort to overcome therapeutic resistance due to hypoxia. Finally, the use of hypoxic cell selective cytotoxic agents as a means of addressing hypoxic drug resistance is discussed.     

大肠癌耐药机制的研究进展

化疗药物的耐药较大程度地限制了大肠癌化疗的效果，其中约90％的转移性病例治疗失败可以归因于药物耐药。即使在辅助化疗中，耐药性微转移灶的存在也可能降低化疗的疗效。目前的研究表明，许多因素可以影响化疗药物的敏感性，包括药物的药代动力学、药物的激活或失活、药物作用靶点的变化、（药物诱导的DNA损伤修复、细胞凋亡的逃逸等。本文试从药物代谢、药物靶点、DNA损伤修复及细胞凋亡等方面叙述大肠癌对常规化疗药物的耐药机制，并对新的靶向药物可能的耐药机制作一简要介绍。     

pH-responsive mesoporous silica nanoparticles employed in controlled drug delivery systems for cancer treatment

In the fight against cancer, controlled drug delivery systems have emerged to enhance the therapeutic efficacy and safety of anti-cancer drugs. Among these systems, mesoporous silica nanoparticles （MSNs） with a functional surface possess obvious advantages and were thus rapidly developed for cancer treatment. Many stimuli-responsive materials, such as nanopartides, polymers, and inorganic materials, have been applied as caps and gatekeepers to control drug release from MSNs. This review presents an overview of the recent progress in the production of pH-responsive MSNs based on the pH gradient between normal tissues and the tumor microenvironment. Four main categories of gatekeepers can respond to acidic conditions. These categories will be described in detail.     

Stearoyl gemcitabine nanoparticles overcome obesity-induced cancer cell resistance to gemcitabine in a mouse postmenopausal breast cancer model

Obesity is associated with increased breast tumor aggressiveness and decreased response to multiple modalities of therapy in postmenopausal women. Delivering cancer chemotherapeutic drugs using nanoparticles has evolved as a promising approach to improve the efficacy of anticancer agents. However, the application of nanoparticles in cancer chemotherapy in the context of obesity has not been studied before. The nucleoside analog gemcitabine is widely used in solid tumor therapy. Previously, we developed a novel stearoyl gemcitabine solid-lipid nanoparticle formulation (GemC18-NPs) and showed that the GemC18-NPs are significantly more effective than gemcitabine in controlling tumor growth in mouse models. In the present study, using ovariectomized diet-induced obese female C57BL/6 mice with orthotopically transplanted MMTV-Wnt-1 mammary tumors as a model of postmenopausal obesity and breast cancer, we discovered that obesity induces tumor cell resistance to gemcitabine. Furthermore, our GemC18-NPs can overcome the obesity-related resistance to gemcitabine chemotherapy. These findings have important clinical implications for cancer chemotherapies involving gemcitabine or other nucleoside analogs in the context of obesity.     

表观遗传调控与肿瘤耐药

恶性肿瘤严重威胁着人类健康,抗肿瘤药物是目前治疗肿瘤最主要的方法,但肿瘤对药物不可避免的出现抗药,使其成为攻克肿瘤的最大难题之一。目前对肿瘤抗药的分子机制并不十分清楚,除了传统观点强调的基因突变,近年来越来越多的研究揭示了表观遗传调控在肿瘤耐药中的作用,本文从DNA甲基化,组蛋白修饰,非编码RNA和染色质重塑对抗肿瘤药物的治疗作用进行综述和分析,旨在为抗肿瘤药物安全有效的合理使用提供新的思路,以及为肿瘤个体化治疗提供更有效的治疗靶点。     

Overcoming drug efflux-based multidrug resistance in cancer with nanotechnology

Multidrug resistance(MDR),which significantly decreases the efficacy of anticancer drugs and causes tumor recurrence,has been a major challenge in clinical cancer treatment with chemotherapeutic drugs for decades.Several mechanisms of overcoming drug resistance have been postulated.Well known P-glycoprotein(P-gp) and other drug efflux transporters are considered to be critical in pumping anticancer drugs out of cells and causing chemotherapy failure.Innovative theranostic(therapeutic and diagnostic) strategies with nanoparticles are rapidly evolving and are anticipated to offer opportunities to overcome these limits.In this review,we discuss the mechanisms of drug efflux-mediated resistance and the application of multiple nanoparticle-based platforms to overcome chemoresistance and improve therapeutic outcome.     

Research progress in nanoparticles as anticancer drug carrier

Nanoparticles drug delivery system has sustained and controlled release features as well as targeted drug delivery, which can change the characteristics of drug distribution in vivo. It can increase the stability of the drug and enhance drug bioavailability. The selective targeting of nanoparticles can be achieved through enhanced permeability and retention effect and a conjugated specific ligand or through the effects of physiological conditions, such as pH and temperature. Nanoparticles can be prepared by using a wide range of materials and can be used to encapsulate chemotherapeutic agents to reduce toxicity, which can be used for imaging, therapy, and diagnosis. In this research, recent progress on nanoparticles as a targeted drug delivery system will be reviewed, including positive-targeting, negative-targeting, and physicochemical-targeting used as anticancer drug carriers.