肺癌多药耐药的监测与评价

国内外研究表明多药耐药(MDR)的产生是导致肺癌化疗乏效的主要原因,试验研究证实,参与体内外肺癌细胞耐药机制主要有多药耐药基因(MDR1)及其编码的细胞膜蛋白P-糖蛋白(P-gp)过表达,多药耐药相关蛋白(MRP)表达增加,谷胱甘肽解毒酶系统活性增强,拓扑异构酶活性降低及结构异常,DNA损伤的修复能力增强等.因此充分了解耐药机制可为临床肺癌治疗提供决策.     

非小细胞肺癌多药耐药机制研究进展

肿瘤的多药耐药(MDR)是导致肺癌化疗失败的主要原因,也是肺癌化疗亟待解决的问题[1].研究肺癌细胞的相关耐药机制及寻找逆转耐药的药物已经成为肿瘤研究的热点.肺癌MDR的机制非常复杂,多数是由多蛋白、多种酶、多基因综合作用的结果.现将非小细胞肺癌(NSCLC) MDR机制研究进展综述如下.     

依托泊苷对耐药和非耐药肺癌细胞survivin基因、端粒酶活性及其亚基表达的影响

肺癌的耐药机制系多因素参与。以往人们主要注意Ｐ 糖蛋白、多药耐药蛋白、肺癌耐药蛋白、谷胱甘肽 /谷胱甘肽 Ｓ 转移酶、拓扑异构酶Ⅱ以及Ｂｃｌ 2等在肺癌多药耐药(ＭＤＲ)中的作用[1] ,而对端粒酶和新的凋亡抑制蛋白ｓｕｒｖｉｖｉｎ在肺癌ＭＤＲ发生机制中的作用知之甚少。为此 ,我们用由顺铂 (ＤＤＰ)诱导的多药耐药Ａ5 49细胞模型研究依托泊苷(ＶＰ16 )对耐药和非耐药肺癌Ａ5 49细胞株ｓｕｒｖｉｖｉｎ基因、端粒酶活性和端粒酶各亚基表达影响的差异 ,以进一步探讨肺癌多药耐药的发生机制。材料与方法　 (1)细胞培养 :耐药肺腺癌Ａ5 …     

MDR1、CyclinD1和Bax与肺癌的预后

影响肺癌预后的因素较多,包括临床因素、癌基 因与抑癌基因,生长因子和细胞因子、基质蛋白酶 端粒酶、细胞增生和凋亡凋控因子、黏连分子等。本 文就MDR1、CyclinD1和Bax三个方面与肺癌的预 后关系进行讨论。 1　MDR1 多药耐药基因(MDR),在人类存在两种亚型 MDR1和MDR2,多药耐药主要与MDR1有关,而与 MDR2无关;MDR1编码的P 糖蛋白(P gp)是多药 耐药的基本功能单位。 1.1　MDR1基因和P gp的结构功能关系　人类的 MDR1基因位于第7号染色体,含有28个外显子 全长4.5kb,仅有一个开放阅读框,5′和3′非编码区 有调节基因,5′非编…     

大肠癌多药耐药性的逆转

大肠癌化疗失败的主要原因是肿瘤细胞对分子结构不同、作用机制各异的抗肿瘤药物产生交叉耐药,即多药耐药性(multidrug resistance,MDR)的产生。其形成机制复杂,主要包括多药耐药基因(mdrl基因)及其编码的P-糖蛋白过度表达;谷胱甘肽及相关酶的改变;拓扑异构酶II(TopoII)的改变;DNA损伤修复能力增强;多药耐药相关蛋白(multidrug     

MRP1与肺癌耐药

肺癌是最常见的恶性肿瘤之一,约80％的患者就诊时已属中、晚期,化疗成为其主要治疗手段,而多药耐药现象的产生是目前影响化疗效果的主要原因。多药耐药(multidrug resistance,MDR)是指肿瘤细胞对一种抗肿瘤药物产生耐药的同时,对结构和作用机制迥然不同的抗肿瘤药物产生交叉耐药的现象。典型的MDR机制是指MDR1基因编码的P—gP致药物外流而产生的多药耐药,但多数学者发现它们在肺癌中的表达水平并不高,     

儿茶素单体对胃癌细胞热休克蛋白70和多药耐药蛋白1的影响

热休克蛋白70（HSP70）可抑制细胞凋亡，降低肿瘤热疗、化疗疗效，但其与化疗耐受性的关系不甚明确。多药耐药基因1（MDR1）的蛋白产物P-糖蛋白（P-gp）是一种耐药蛋白，在肿瘤耐药中起重要作用。本实验观察儿茶素单体（EGCG）及热休克对胃腺癌SGC7901细胞HSP70和P-gp表达的影响及其增强肿瘤化疗疗效的作用。     

非小细胞肺癌P-糖蛋白及耐药相关蛋白的表达与临床意义

化疗成为晚期肺癌的主要治疗方法。然而非小细胞肺癌(NSCLC)对化疗多不敏感,多药耐药的产生是化疗失败的主要原因。研究发现多药耐药糖蛋白的过度表达与MDR具有相关性,但在临床中发现有部分P-糖蛋白(Pgp)表达阴性的患者仍有MDR产生,所以推测MDR是多种复杂机制共同作     

膜糖蛋白介导的肺癌耐药与逆转机制的研究现状

尽管近年来肺癌的诊疗技术有了很大提高，但5年生存率仍不足15％，其主要原因是化疗对肺癌，尤其是非小细胞肺癌（non-small-cell lung cancer，NSCLC）效果不佳，多药耐药（muhidrug resistance，MDR）是其主要原因。MDR是指肿瘤细胞对一种化疗药物产生耐药现象后，对其他结构、细胞靶点和作用机制迥然不同的化疗药物产生交叉耐药。肺癌的耐药机制比较复杂，     

肺耐药蛋白与肺癌

肺耐药蛋白(LRP)是新近发现的一种与多药耐药性(MDR)相关的蛋白,被认为是人的穹窿体主蛋白(MVP),它可以阻止以胞核为效应点的药物通过核孔进入细胞核,并将进入细胞核的药物转运到胞浆中和/或将进入胞浆的药物转运到运输囊泡中,隔绝药物作用,并以胞吐的方式将其排出细胞外,从而介导P-gp阴性的肿瘤耐药。本文复习近年文献,对LEP的作用机制及其研究进展,LRP在肺癌中的表达对于肺癌化疗药物的选择、化疗方案的制定、新型化疗药物的研制开发以及LRP与肺癌的预后进行了综述。     

Biology of multiple drug resistance in acute leukemia

Since the early 1970s, multiple drug resistance (MDR) has been known to exist in cancer cells and is thought to be attributable to a membrane-bound, energy-dependent pump protein (P-glycoprotein [P-gp]) capable of extruding various related and unrelated chemotherapeutic drugs. P-gp is coded for by the MDR1 gene, which in the human genome is located on the long arm of chromosome 7 (7q21-31). At the cellular level, the function of P-gp has been extensively investigated in human cancer. Although innumerable reports have been published in which P-gp has been shown to confer MDR to malignant (including leukemia) cells, so far, large-scale studies in the clinical setting have not convincingly proven that MDR1 plays a major role in clinical drug resistance when the influence of other known prognostic factors in human leukemia are taken into account. At present, results from phase 3 clinical trials evaluating the efficiency of inhibiting (or reversing) the function of P-gp in hematologic malignancies are eagerly awaited. Moreover, the horizon of cellular drug resistance in human cancer has during recent years widened dramatically. Thus, an array of different molecules and mechanisms by which resistant cells can escape the cytotoxic effect of anticancer drugs has now been identified. These molecules and mechanisms include apoptosis-related proteins. In this article, we review the different methods for determining MDR and, in particular, methods for determining P-gp/MDR1, with special reference to their potential importance for therapeutic strategies in human acute leukemia.     

Reversal of Multidrug Resistance of Adriamycin-resistant Gastric Adenocarcinoma Cells Through the Up-regulation of DARPP-32

We have investigated the roles of dopamine and cAMP-regulated phosphoprotein (DARPP-32) in the multidrug resistance (MDR) of gastric cancer cells and the possible underlying mechanisms. The up-regulation of DARPP-32 was found to significantly enhance the sensitivity of cells of human adriamycin (ADR)-resistant gastric adenocarcinoma cell line SGC7901/ADR to vincristine, ADR, 5-fludrouracil and cisplatin. The results of an in vivo drug sensitivity assay confirmed that DARPP-32 may play a specific role in the MDR of gastric cancer. DARPP-32 significantly down-regulated the expression of P-glycoprotein and zinc ribbon domain-containing 1 (ZNRD1), but did not alter the expression of MDR-associated protein or glutathione-S-transferase. The up-regulation of ZNRD1 significantly inhibited the drug sensitivity of gastric cancer cells over-expressing DARPP-32, indicating that ZNRD1 may be important in the DARPP-32-mediated MDR of gastric cancer. DARPP-32 was also able to significantly decrease the anti-apoptotic activity of SGC7901/ADR cells. Further study of the biological functions of DARPP-32 may be helpful for understanding the mechanisms of MDR of gastric cancer cells and developing possible strategies to treat gastric cancer. Liu Hong, Yunping Zhao and Jin Wang contribute equally to the work.     

敲除Linc00152对丝裂霉素耐药胃癌细胞NCI-N87/MMC的化疗耐药性影响及机制

背景 长基因间非编码RNA 152(long intergenic noncoding RNA 152,Linc00152)在胃癌组织中高表达,且其能促进胃癌细胞增殖、迁移与侵袭,而Linc00152对胃癌化疗耐药的影响和机制并不清楚.目的 探究Linc00152对人胃癌细胞系NCI-N87化疗耐药性的影响及相关的作用...     

肺癌患者外周血中MDR1的表达及临床意义

目的 检测多药耐药基因-1（MDR1）在肺癌患者外周血中的表达,探讨MDR1的表达水平与肺癌病理类型及临床化疗进程之间的关系.方法 应用荧光定量PCR（qRT-PCR）技术,动态监测45例肺癌患者化疗前后外周血中MDR1的表达水平,并与48例健康者进行对照比较.结果 肺癌组化疗前MDR1的阳性率28.89%（13/45）,明显高于健康对照组2.08%（1/48）,差异显著（P〈0.05）;各种病理类型的肺癌随着化疗次数的增多MDR1的表达均增强;化疗前后各期MDR1的表达程度：非小细胞肺癌（NSCLC,肺鳞癌和肺腺癌）明显高于小细胞肺癌（SCLC）,差异具有统计学意义（P〈0.05）,而肺鳞癌和肺腺癌之间MDR1的表达程度相当,无显著差异,（P＞0.05）.结论 化疗可诱导各种病理类型肺癌MDR1表达增加;病理类型不同诱导化疗耐药的机制可能不同：NSCLC可能为原发性MDR,SCLC可能为获得性MDR;动态检测肺癌患者外周血中MDR1的表达水平,有利于进行肺癌耐药的监测与评价.     

Modulation of drug resistance transporters as a strategy for treating myelodysplastic syndrome

Resistance to chemotherapy is an obstacle to the successful treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The failure of therapeutic treatment may be due to the development of multidrug resistance (MDR), mechanisms of which include upregulation of membrane-resident transporters which efflux chemotherapeutic drugs from tumor cells, and failure of the cancer cell to undergo apoptosis in response to chemotherapy. Membrane transporter-based drug efflux transporters have been extensively studied, and agents that block drug efflux have been found and investigated. Presence of P-glycoprotein (Pgp, MDR1, ABCB1), a member of the ATP-binding cassette (ABC) transporter family, has been reported to correlate with poor prognosis in AML and MDS. In MDS, Pgp expression increases as the disease progresses. Overexpression of other transporters, such as the multidrug resistance protein (MRP1, ABCC1), and the vault-associated transporter lung resistance protein have been shown as well in both MDS and AML, but their prognostic relevance is not clear. Recently, a novel ABC half-transporter, the breast cancer resistance protein (ABCG2) has been found in approximately 30% of AML cases, and may play a role in resistance to chemotherapy. In clinical trials in MDS, first-generation Pgp blockers, such as cyclosporin-A and verapamil, were minimally effective, non-specific, and toxic. However, another first-generation blocker, quinine, was used in MDS and may specifically benefit MDS patients overexpressing Pgp. A second-generation drug, the non-immunosuppressive cyclosporine analog valspodar (PSC833), was studied in AML and MDS, and was highly toxic, resulting in the need to reduce the dosage of the chemotherapeutic drugs as a result of valspodar reducing the clearance of the chemotherapeutic agents. Third-generation drugs, which are highly specific for Pgp and which seem to have only modest effects on drug clearance, include tariquidar, zosuquidar, laniquidar, and ONT-093. These are all in phase I/II trials and show promise for future treatment.     

Iron containing anti-tumoral agents: unexpected apoptosis-inducing activity of a ferrocene amino acid derivative

Purpose  

Due to the severe problems accompanied with multiple drug resistance (MDR), agents that can induce apoptosis independently of death-suppressing proteins are required. Here, we show that the ferrocene derivative HUNI 068 is active against cancer cells and overcomes different mechanisms of multiple drug resistance (MDR).     

Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein.

Multidrug-resistance-associated protein (MRP) is a plasma membrane glycoprotein that can confer multidrug resistance (MDR) by lowering intracellular drug concentration. Here we demonstrate that depletion of intracellular glutathione by DL-buthionine (S,R)-sulfoximine results in a complete reversal of resistance to doxorubicin, daunorubicin, vincristine, and VP-16 in lung carcinoma cells transfected with a MRP cDNA expression vector. Glutathione depletion had less effect on MDR in cells transfected with MDR1 cDNA encoding P-glycoprotein and did not increase the passive uptake of daunorubicin by cells, indicating that the decrease of MRP-mediated MDR was not due to nonspecific membrane damage. Glutathione depletion resulted in a decreased efflux of daunorubicin from MRP-transfected cells, but not from MDR1-transfected cells, suggesting that glutathione is specifically required for the export of drugs from cells by MRP. We also show that MRP increases the export of glutathione from the cell and this increased export is further elevated in the presence of arsenite. Our results support the hypothesis that MRP functions as a glutathione S-conjugate carrier.     

Multidrug resistance 1 gene expression in Indian patients with gastric carcinoma.

BACKGROUND: Gastric carcinoma is frequently refractory to chemotherapy. The multidrug resistance 1 gene (MDR1) encodes for a protein (p-glycoprotein) that functions as a drug efflux pump and thus contributes to resistance to chemotherapeutic agents. METHODS: We studied gastric tissues from 28 patients with gastric cancer for MDR1 expression, using immunohistochemistry. RESULTS: Sixteen (57%) of 28 cases showed MDR1 expression. Sections of normal mucosa away from the tumor showed perinuclear staining for MDR1 in surface epithelial cells, whereas tumor cells showed diffuse cytoplasmic positivity. CONCLUSIONS: Over one half of gastric carcinoma specimens at our center show MDR1 gene expression.     

MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia

Multi drug resistance (MDR) is a major obstacle for cancer therapy. The three major candidates accounting for the development of MDR in acute myeloid leukaemia (AML) are multi drug resistance gene (MDR1), multi drug resistance-related protein gene (MRP1) and lung resistance protein gene (LRP). So far, the differential impact of resistance gene expression on treatment outcome in AML is not clear. Therefore, we examined MDR1, MRP1 and LRP gene expression at diagnosis in 331 adult AML patients in the context of other known prognostic factors, such as age, disease status, cytogenetics and FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication mutational status. Median observation time was longer than 5 years [64.1 months (40.0-87.6)]. MDR1 expression proved to be an independent prognostic factor for outcome of induction therapy (P <0.001) and overall survival (P=0.02), whereas MRP1 expression was an independent predictor for disease-free survival (P=0.01) in the multivariate analysis. This prognostic impact of both resistance genes was also found in patients with intermediate risk cytogenetics. LRP expression, however, had no impact on treatment outcome in AML. Our study shows that resistance gene expression should be considered together with age, cytogenetics and FLT3 mutational status for risk-adapted treatment strategies in AML in the future.