核基质成分-拓扑异构酶Ⅱ与肿瘤耐药

DNA拓扑异构酶(topoisomerase,Topo)是核基质成分之一,是一种调整DNA拓扑结构的核酶,在DNA的复制和转录过程中发挥着重要作用,故而成为许多抗肿瘤化疗药物的靶.针对Topo Ⅱ的抗肿瘤化疗药物同样面临着耐药问题.简要综述了近年来Topo Ⅱ与肿瘤耐药关系方面的研究进展.     

核基质成分—拓扑异构酶Ⅱ与肿瘤耐药

DNA拓扑异构酶（topoisomerase,Topo）是核基质成分之一，是一种调整DNA拓扑结构的核酶，在DNA的复制和转录过程中发挥着重要作用。故而成为许多抗肿瘤化疗药物的靶，针对Topo II的抗肿瘤化疗药物同样面临着耐药问题，简要综述了近年来Topo II与肿瘤耐药关系方面的研究进展。     

拓扑异构酶Ⅱ和肿瘤多药耐药

拓扑异构酶Ⅱ和肿瘤多药耐药张文卿，综述，刘叙仪韩复生审核北京市肿瘤防治研究所（北京市１０００３４）ＤＮＡ拓扑异构酶Ⅱ（ＤＮＡＴｏｐｏｉｓｏｍｅｒａｓｅⅡ，ＴｏｐｅⅡ）是活细胞不可缺少的核酶，是与细菌ＤＮＡ回旋酶（ｇｙｒａｓｅ）具有同源性的同型二聚体蛋...     

DNA拓扑异构酶与肿瘤化疗

ＤＮＡ拓扑异构酶与肿瘤化疗郑国强综述韩复生徐光炜审校北京医科大学临床肿瘤学院（北京市１０００３６）ＤＮＡＴｏｐｏｉｓｏｍｅｒａｓｅａｎｄＣａｎｃｅｒＣｈｅｍｏｔｈｅｒａｐｙ￥ＺｈｅｎｇＧｏｕ－ＱｉａｎｇＨａｎＦｕ－ｓｈｅｎｇＸｕＧｕａｎｇ－Ｗｅｉ目前...     

拓扑异构酶与肿瘤多药耐药及耐药逆转

多约耐药(MDR)的产生是肿瘤化疗失败的主要原因，拓扑异构酶Ⅱ(topoⅡ)介导的MDR为MDR的重要途径：耐药逆转剂的应用是克服肿瘤临床耐药．提高化疗效果的一种潜在的重要手段：现综述topoⅡ与肿瘤MDR及耐药逆转研究进展。     

拓扑异构酶与肿瘤多药耐药及耐药逆转

多药耐药(MDR)的产生是肿瘤化疗失败的主要原因.拓扑异构酶Ⅱ(topoⅡ)介导的MDR为MDR的重要途径.耐药逆转剂的应用是克服肿瘤临床耐药,提高化疗效果的一种潜在的重要手段.现综述topoⅡ与肿瘤MDR及耐药逆转研究进展.     

肿瘤化疗的重要靶点—DNA拓扑异构酶

DNA 拓扑异构酶是近年来新发现的肿瘤化疗的重要靶点,它涉及到抗癌药作用的许多环节,如 DNA 复制、DNA 损伤与修复、基因的重组和转录、细胞有丝分裂及分化等。本文列举了一些临床上广泛使用的以 DNA 拓扑异构酶为靶点的化疗药物,着重介绍了拓扑酶抑制剂作用的分子基础及其与耐药的关系。事实证明拓扑酶抑制剂能促进酶介导的 DNA 切割复合物的形成,阻断正常基因及癌基因的表达。另一方面,对拓扑酶抑制剂耐药的细胞常表现为酶活性及酶量的下降,这种变化与拓扑酶基因的突变有关。     

DNA拓扑异构酶Ⅱ抑制剂与肿瘤不典型多药耐药

无论真核细胞还是原核细胞内的DNA分子，在细胞周期的G0和G1期主要以超螺旋形式存在，而在S、G2和M期，需要解开这种紧凑缠绕的DNA结构，以便DNA复制、转录、修复、重组、染色体分离等细胞生命活动得以顺利进行DNA拓扑异构酶(DNA topoisomerase,Topo)可以催化DNA的超螺旋     

肿瘤多药耐药机制的研究进展

多药耐药(Multi-drug resistance，MDR)是肿瘤化疗失败的主要原因之一。从药物转运、药物代谢、药物靶、细胞凋亡及凋亡相关基因4个方面，全面复习近年来有关MDR的机制，为肿瘤临床化疗及临床MDR研究提供重要的理论依据。     

拓扑异构酶Ⅰ抑制剂与肿瘤耐药的相关性研究进展

TOPO Ⅰ是调节核酸拓扑构型的关键酶,已成为重要的抗癌药物研究新靶点。肿瘤对细胞TOPOⅠ抑制剂产生耐药是一个相当复杂的细胞生理化过程,也是化疗失败的重要原因。喜树碱类药物是经典的TOPO Ⅰ抑制剂,一些非喜树碱类TOPO Ⅰ抑制剂也见报道。     

Non-P-glycoprotein-mediated Atypical Multidrug Resistance in a Human Bladder Cancer Cell Line

A human bladder cancer cell line resistant to adriamycin (ADM), T24/ADM9 has been established in vitro by exposing T24 parent cells to progressively higher concentrations of the drug over a period of 12 months. The T24/ADM9 cells were found to be 9 times more resistant to ADM than the T24 parent, and showed various degrees of cross-resistance to an ADM derivative, vinca alkaloids and a DNA topoisomerase II (Topo ID-targeting agent, etoposide. No significant difference was observed in the cellular accumulation of ADM between the T24/ADM9 and T24 parent cells. A Northern blot analysis showed an overexpression of multidrug resistance-associated protein (MRP) mRNA, but no overexpression of multidrug resistance-1 (MDR1) mRNA was observed in the T24/ADM9 cells. A flow cytometric analysis showed that the MDR1 gene product, P-glycoprotein (Pgp), is not expressed on the T24/ADM9 cells. T24/ADM9 showed approximately the parental level of DNA Topo II catalytic activity. In Western blot and Northern blot analyses, however, the cellular level of DNA topo II was apparently much lower in T24/ADM9 than in the T24 parent. Thus, these results suggest that a decreased cellular level of DNA Topo II and an overexpression of MRP gene may be responsible for the expression of an MDR phenotype in the T24/ADM9 cells and that such non-Pgp-mediated, atypical MDR may develop in bladder cancer treated with chemotherapy including ADM.     

姜黄素逆转肿瘤多药耐药机制的研究进展

化学药物疗法是中晚期恶性肿瘤的主要治疗方法.然而,肿瘤细胞的多药耐药是导致肿瘤治疗困难及复发的主要因素,而且经常使预后较差.很多研究已经证实,姜黄素可在多种化疗药物引起的化学抵抗中成为强有力的化疗增敏剂.作为一种用药安全、成本低的化合物,姜黄素与多种化疗药联合应用可增强药物治疗指数.全文就肿瘤多药耐药发生机制及姜黄素逆转肿瘤多药耐药的机制展开论述.     

蛋白酶体抑制剂治疗多药耐药肿瘤机制的研究进展

多药耐药（multidrug resistance,MDR）是导致肿瘤化疗失败的重要原因,其复杂的机制中涉及许多蛋白的作用,这些蛋白多为蛋白酶体抑制剂的底物。通过蛋白酶体抑制剂可有效逆转MDR现象,它是目前抗癌药物研制领域的一个重要方向。介绍蛋白酶体的作用和MDR,综述近年来关于乳胞素、醛基肽、环孢菌素类似物和硼酸肽这4种蛋白酶体抑制剂对MDR的治疗机制。     

卵巢上皮癌组织中LRP和P—gp表达及其临床意义

目的：探讨卵巢上皮癌组织中肺耐药蛋白（lung resistrance protein,LRP)表达的临床意义。方法采用免疫组化S－P法对79例卵巢上皮性肿瘤（恶性54例、交界性5例、良性20例）和18例正常卵巢组织进行LRP和P－gp表达检测,并进行相关临床因素分析。结果LRP在正常卵巢组织、良性、交界性和恶性卵巢上皮性肿瘤组织中的表达阳性率分别为38．9％、30．0％、80．0％和75．9％。LRP的表达与卵巢癌理性类型,腹腔积液相关,化疗对LRP表达阳性和阴性卵巢上皮癌患者的有效率分别为50．0％和84．6％,有显著性差异（P＜0．05）。LRP表达阴性患者的预后优于阳性者（P＜0．05）,LRP与P-gp表达无相关性,两者可协同表达。结论LRP是评价卵巢上皮癌化疗耐药性和预后的可靠指标。     

Circumvention of Atypical Multidrug Resistance with Tumor Necrosis Factor

Some "multidrug-resistant" (MDR) cell lines are not associated with a defect in drug accumulation or with the overexpression of P-glycoprotein. These cell lines are defined as "atypical MDR" (at-MDR) and they often express altered or mutated topoisomerase II. We investigated the ability of tumor necrosis factor to reverse at-MDR (in the human ovarian cancer cell line A2780 DX3) on the basis of its efficacy in potentiating in vitro topoisomerase II-targeted drugs, and because there is convincing evidence that the synergy is due to an increased number of topoisomerase-associated strand-breaks as well as to an increased level of extractable topoisomerase     

Bromocriptine Reverses P-Glycoprotein-mediated Multidrug Resistance in Tumor Cells

One of the most important causes of anticancer treatment failure is the development of multidrug resistance (MDR). The main characteristics of tumor cells displaying the MDR phenomena are cross-resistance to structurally unrelated cytotoxic drugs having different mechanisms of action and the overexpression of the MDR1 gene, which encodes a transmembrane glycoprotein named P- glycoprotein (P-gp). This study evaluated whether bromocriptine, a D₂ dopaminergic receptor agonist, influenced anticancer drug cytotoxicity and P-gp activity in a P-gp-expressing cell line compared to a non-expressing subline. The K_i values for P-gp of cyclosporine and verapamil were 1.09 and 540 μ M , respectively, and that of bromocriptine was 6.52 μ M in a calcein-AM efflux assay using porcine kidney epithelial LLC-PK1 and L-MDR1 cells, overexpressing human P-gp. Bromocriptine at 10 μ M reduced the IC₅₀ of doxorubicin (DXR) in K562-DXR from 9000 to 270 ng/ml and that of vincristine (VCR) in K562-VCR from 700 to 0.30 ng/ml, whereas the IC₅₀ values of DXR and VCR in the K562 subline were only marginally affected by these drugs. Bromocriptine restored the anticancer effect of DXR, VCR, vinblastine, vinorelbine and etoposide on MDR-tumor cells overexpressing P-gp. These observations suggest that bromocriptine has the potential to reverse tumor MDR involving the efflux protein P-gp in the clinical situation.     

Resistance to topoisomerase poisons due to loss of DNA mismatch repair

Sporadic breast carcinomas demonstrate microsatellite instability, reflecting the presence of DNA mismatch repair-deficient cells, in about one fourth of cases at the time of diagnosis. Loss of DNA mismatch repair has been reported to result in resistance not only to cisplatin and alkylating agents but also to the topoisomerase II poison doxorubicin, suggesting an association between DNA mismatch repair and topoisomerase II poison-induced cytotoxicity. Our study investigates the relationship between loss of MSH2 or MLH1 function and sensitivity to the topoisomerase I and II poisons, and to the taxanes, 2 classes of cytotoxic drugs commonly used in breast cancer. Two pairs of cell lines proficient and deficient in mismatch repair due to loss of either MSH2 or MLH1 function were used. Loss of either MSH2 or MLH1 function resulted in resistance to the topoisomerase II poisons doxorubicin, epirubicin and mitoxantrone, whereas only loss of MLH1 function was associated with low-level resistance to the topoisomerase I poisons camptothecin and topotecan. In contrast, there was no resistance to docetaxel and paclitaxel. Our data support the hypothesis that both MSH2 and MLH1 are involved in topoisomerase II poison-mediated cytotoxicity, whereas only MLH1 is involved in topoisomerase I poison-mediated cytotoxicity. Since our study shows that loss of DNA mismatch repair does not result in resistance to the taxanes, these drugs can be recommended for use in breast cancer deficient in mismatch repair.     

槲皮素逆转肿瘤多药耐药机制的研究进展

恶性肿瘤已成为当今威胁人类健康的重大疾病.目前,肿瘤的治疗主要是以手术为主的综合治疗,其中化疗药物的应用可明显抑制肿瘤生长、改善患者预后,但肿瘤的多药耐药严重阻碍了其治疗效果.槲皮素是广泛存在于植物中、具有生物活性的黄酮类化合物,具有抗肿瘤等多种药理学作用.目前,槲皮素逆转肿瘤多药耐药作用已引起广泛关注.研究发现,其可通过抑制多种耐药相关蛋白、诱导细胞凋亡、抑制热休克蛋白功能、逆转上皮间质转化等作用,从而逆转肿瘤多药耐药.本文主要综述槲皮素逆转肿瘤多药耐药的分子机制及其临床应用前景,以期为逆转肿瘤多药耐药的基础及临床研究提供新思路.     

多药耐药相关蛋白7及其抑制剂

多药耐药(MDR)的机制与转运蛋白有关,现在研究最多的为P-糖蛋白(P-gp)、多药耐药相关蛋白(MRP)1、乳腺癌耐药相关蛋白(BCRP)等的抑制剂.MRP7可介导对紫杉醇、长春新碱和长春碱等的耐药.MRP7抑制剂近年研究主要包括千斤藤素、酪氨酸酶抑制剂、环孢素A等,MDR是多种机制共同作用的结果,对其他转运体的研究会提供更全面、更广泛的MDR逆转途径.