复发难治性急性白血病多药耐药性及耐药逆转的体内外研究

目的 :探讨复发难治性急性白血病多药耐药性及耐药性的逆转。方法 :采用RT PCR法检测白血病细胞的多药耐药性 ,采用MTT法进行体外药敏及耐药逆转试验。结果 :35例患者中MDR1mRNA阳性表达例数为 2 6例(74.3% ) ,体外耐药逆转环胞素组逆转率 6 4.7%、异搏定组 41.2 %、两药合用组 76 .5 % ;临床耐药逆转环胞素组逆转率 14.3%、异搏定组 45 .8%、两药合用 37.5 % ;结论 :复发难治性急性白血病MDR1mRAN高表达 ,环胞素和异搏定单用及两药联合应用体外逆转效果明显优于临床疗效 ,耐药逆转药物的剂量及给药方式可能是影响逆转疗效的重要因素     

与逆转肿瘤多药耐药相关的研究进展

本文针对多药耐药(MDR)的主要机制,对MDR1介导的多药耐药的逆转方法、MDR1基因的检测、逆转剂对化疗药物的药代学影响、逆转的相关毒性等方面的研究进展进行综述。     

与逆转肿瘤多药耐药相关的研究进展

本文针对多药耐药（ＭＤＲ）的主要机制,对同介导的多药耐药的逆转方法、ＭＤＲ１基因的检测、逆转剂对化疗药物的药代学影响、逆转的相关毒笥等方面的研究进展进行综述。     

环孢菌素A逆转白血病多药耐药成功一例

近年来的研究表明 ,环孢菌素Ａ(ＣｓＡ)及其衍生物可有效逆转Ｐ ｇｐ介导的多药耐药[1 ,2 ] 。我们采用ＣｓＡ与化疗并用治疗 1例Ｐ ｇｐ过表达的复发难治性急性髓系白血病 (ＡＭＬ)患者 ,取得较好效果 ,报告如下。病例和方法1　病例资料与治疗经过　患者 ,女 ,32岁。因乏力伴胸痛 2周于 1998年 6月入院。外周血检查 :ＷＢＣ 16 .0× 10 9 Ｌ ,原始粒细胞 0 .38。骨髓增生极度活跃 (无核红细胞∶有核细胞 =9∶1) ,原始粒细胞 0 .6 0 0 ,过氧化物酶阳性率 30 % ,诊断为ＡＭＬ Ｍ2ａ。予ＤＡ方案 [柔红霉素 (ＤＮＲ) 6 0ｍｇ ｄ ,静脉注射 ,连…     

浙贝母碱逆转白血病细胞多药耐药的研究

浙贝母因其以化痰散结为主要药用功能,我们常常配合化疗药物治疗复发和难治性白血病（或）肿瘤,往往获得理想疗效。浙贝母中含有多种活性成分,其中浙贝母碱（贝母素甲,Ｐｅｉｍｉｎｅ）是其主要活性成分之一,属异甾类生物碱中的瑟文类（Ｃｅｖｉｎｅｇｒｏｕｐｓ）生物碱［１］。为了探讨浙贝母抗白血病的作用机制,我们研究了浙贝母碱逆转白血病细胞多药耐药作用。材料和方法１　细胞株　Ｋ５６２／Ａ０２：多药耐药细胞株,以Ｐ糖蛋白（Ｐｇｐ）蛋白升高为主要耐药机制。由中国医学科学院血液学研究所药物室提供。对阿霉素耐药４０…     

急性白血病的治疗及逆转多药耐药的研究

白血病(leukemia)是造血系统的一种恶性肿瘤，临床上分为急性和慢性两型，以急性白血病为多。其多见于儿童及青少年，该病起病急，不治疗一般病程不超过6个月，是小儿时期最常见的恶性肿瘤。15岁以下儿童白血病的发病率为4／10万左右。其特点是白血病细胞在骨髓中恶性增生，并浸润至其他组织与器官，从而产生一系列临床症状。     

单克隆抗体逆转多药耐药性研究进展

体我及动脉实验发现抗Ｐ－糖蛋白单抗ＭＲＫ１６，ＭＲＫ１７等能与Ｐ－糖蛋白表达细胞膜表面的抗原决定族结合，使Ｐ－糖蛋白构象改变，阻止药物外流，增加细胞的内药物浓度。     

以K562/MDR细胞为模型的白血病多药耐药逆转研究

白血病细胞多药耐药（ＭＤＲ）是导致化疗失败的主要原因,其中ｍｄｒ１基因产物Ｐ糖蛋白（Ｐｇｐ）起着重要作用。多种Ｐｇｐ拮抗剂可逆转ＭＤＲ从而改善化疗结果。目前ＭＤＲ逆转研究多以药物加压筛选的耐药变异株为模型,但除其表达ｍｄｒ１基因外,尚有多种与耐...     

环孢霉毒A逆转急性髓系白血病多药耐药一例

报道一例急性髓系白血病（Ｍ＿（４ｂ）患者，经ＨＡＤ方案全量化疗两疗程无效，实验室检查示ｍｄｒｌｍＲＮＡ（＋），ｐ１７０阳性率３１％，多药耐药细胞群占４１．７６％，证实为多药耐药。第３疗程用环孢霉素Ａ（ＣｓＡ，４ｍｇ／ｋｇ，每日两次，第１～３天；２．５ｍｇ／ｋｇ，每日两次，第４～５天）加类似剂量的ＨＡＤ方案化疗，取得完全缓解，同时ｍｄｒｌｍＲＮＡ和ｐ１７０转阴，耐药细胞群消失。     

环孢霉素A对K562／DOX细胞药物积聚和外排的影响

目的：寻找克服肿瘤细胞多药耐药的方法。方法：以环孢霉素Ａ（ＣｓＡ）作为耐药逆转剂，用ＭＴＴ法体外药物敏感试验，观察ＣｓＡ对多药耐药白血病细胞株Ｋ５６２／ＤＯＸ的药物敏感性、细胞内药物的积聚和外排的影响。结果：ＣｓＡ可增强阿霉素（ＤＯＸ）对Ｋ５６２／ＤＯＸ的细胞毒作用，且存在剂量依赖关系。ＣｓＡ≥２μｇ／ｍｌ能较明显提高Ｋ５６２／ＤＯＸ对ＤＯＸ的敏感性。用２μｇ／ｍｌＣｓＡ处理后，Ｋ５６２／ＤＯＸ细胞内ＤＯＸ外排速度明显减慢，ＤＯＸ含量仅减少１２．３％，但对Ｋ５６２细胞内药物外排无影响。结论：ＣｓＡ能有效地减慢Ｋ５６２／ＤＯＸ细胞内ＤＯＸ外排速度，增加细胞内ＤＯＸ积聚。ＣｓＡ对Ｋ５６２细胞药物敏感性、细胞内药物外排和积聚均无影响。     

多药耐药基因反义寡核苷酸逆转肿瘤细胞耐药的初步研究

目的：克服肿瘤细胞的多药耐药（ＭＤＲ）。方法：用人工合成互补于ｍｄｒ１基因５′端转录起始部位的反义寡核苷酸（ＯＤＮ），直接转染耐药细胞株ＫＢ－８－５细胞，或以脂质体ｌｉｐｏｆｅｃｔｉｎ为载体进行基因转染实验，通过ＭＴＴ法检测细胞对柔红霉素（ＤＮＲ）的敏感性，流式细胞仪分析细胞内ＤＮＲ含量及免疫组化方法确定细胞表面糖蛋白（Ｐｇｐ）的表达水平。结果：ＯＤＮ可增加ＫＢ－８－５细胞内的ＤＮＲ浓度从而提高耐药细胞对ＤＮＲ的敏感性，ｌｉｐｏｆｅｃｔｉｎ进一步加强上述作用。在ＤＮＲ浓度为３．０ｍｇ／Ｌ组中，约有７４．４３％的被转染细胞对ＤＮＲ敏感而致死，基本达到药物敏感细胞株ＫＢ－３－１的水平。ＯＤＮ转染的ＫＢ－８－５细胞的Ｐｇｐ为弱阳性表达，低于阳性对照ＫＢ－８－５细胞的Ｐｇｐ表达水平。结论：ＯＤＮ的逆转作用可能与其互补结合的ｍｄｒ１ｍＲＮＡ降解或直接阻滞了Ｐｇｐ合成使其表达降低有关。     

Reversal effect of Tween-20 on multidrug resistance in tumor cells in vitro

Multidrug resistance (MDR) is a major barrier for chemotherapy of many cancers. Non-ionic surfactants have great potential to reverse the MDR by preventing onset or delay progression of the carcinogenic process. However, the role of Tween-20 in the development of MDR remains unknown. The aim of this study was to explore the reversal effect and potential mechanism of Tween-20 on tumor cells in vitro. Alamar Blue assay was used to examine the reversal index of Tween-20 to vincristine (VCR), doxorubicin (DOX) and 5-fluorouracil (5-FU) in KBv200, HepG2/R and Bel-7402/5-FU, respectively. Morphological change was determined by Gimsa and Hoechst 33258 staining. The acumulation of DOX was confirmed by spectrofluorimetric assay. Cell cycle analysis was performed using flow cytometry. The mRNA and protein expression levels of MDR were assessed by semiquantitative RT-PCR and dot blot, respectively. The results showed that Tween-20 at concentrations of 0.0025%, 0.005%, 0.01% had little cytotoxicity. When combined with the cancer drugs, it significantly promoted the sensitivity of MDR cells. Fluorescence staining confirmed that the percentage of apoptotic cell increased when combined with Tween-20. This notion was further supported by the observation that Tween-20 treatment potentiated VIN-induced G2/M arrest of the cell cycle. Furthermore, Tween-20 treatment increased significantly intracellular accumulation of DOX. RT-PCR and dot blot revealed that Tween-20 could downregulate the expression of MDR and P-glycoprotein. Low concentrations of Tween-20 can efficiently reverse the multidrug resistance phenotype by enhancing accumulation of the anticancer drugs. The potential mechanism may be via inhibiting the multidrug-resistant gene expression.     

Recent attempts at RNAi-mediated P-glycoprotein downregulation for reversal of multidrug resistance in cancer

Multidrug resistance (MDR) is among the major mechanisms leading to failure in chemotherapy of cancer patients. The ATP‐binding cassette proteins are major contributors to MDR, involved in the active efflux of xenobiotics out of cancer cells. Among them, P‐glycoprotein (P‐gp) is the most dominant protein involved in the efflux of drugs. For more than 30 years, scientists have searched for the ideal P‐gp inhibitor to modulate drug resistance activity of P‐gp. This inhibitor should be tissue and cell specific with side effects on other tissues, must not provoke immune responses from the host, should provide sustained inhibition, and must be synthesized readily with low cost. Chemical P‐gp inhibitors tested to date, have shown nonspecific toxic effects limiting their clinical applications. Sequence‐specific P‐gp gene silencing by RNA interference (RNAi) may provide a more effective approach for downregulation of specific protein targets due to high specificity, limited toxicity and immunogenicity, and relative ease in synthesis. RNAi can be implemented by delivery of synthetic small interfering RNAs (siRNAs) or by gene expression of short hairpin RNAs using gene expressing vectors. Specific delivery systems and expression vectors have been designed for this purpose and many researchers have explored their effectiveness for P‐gp downregulation. In this report, we review the efficiency of various methods for siRNA delivery and transfection for P‐gp downregulation in cancer cells for MDR reversal. Novel ideas and observations by different research groups were discussed for future improvement in this essential field. © 2011 Wiley Periodicals, Inc. Med Res Rev     

难治与复发急性白血病p170和p26与多药耐药关系的分析

目的：探讨ｐ１７０和ｐ２６两种膜蛋白在临床耐药中的作用及相互关系。方法：用流式细胞仪技术检测了３９例急性白血病患者骨髓细胞的ｐ１７０和ｐ２６表达率。结果：两者在初治敏感组分别为１５．８９％±４．４１％和１７．３２％±１０．２０％，在难治复发组分别为３１．０２％±１４．３３％和３３．７８％±１５．９７％，两组差别均有显著性（Ｐ均＜０．０５），ｐ１７０与ｐ２６的相关性，ｒ＝－０．１５７８，Ｐ＞０．５。结论：两者均与临床多药耐药相关，但它们之间无明显相关性，揭示其耐药机制不同。     

拓扑替康为主联合方案治疗难治性和复发性急性淋巴细胞白血病的临床探讨

目的 探讨以拓扑替康为主的治疗方案对难治及复发性急性淋巴细胞白血病(ALL)的疗效及毒性反应。方法 拓扑替康联合顺铂或异环磷酰胺及阿糖胞苷治疗预后差的难治性及复发性ALL8例。结果 经1个疗程治疗后判断疗效，完全缓解(CR)5例，CR率62．5％；部分缓解(PR)1例，PR率12．5％；未缓解(NR)2例，NR率25％；总有效率75％。不良反应主要表现为白细胞及血小板明显减少的骨髓抑制。结论 拓扑替康对预后不良、难治及复发性ALL具有肯定疗效，是一种很有前途的治疗药物。不良反应主要为骨髓抑制，非血液系统毒性轻微。     

Cyclosporine diminishes multidrug resistance in K562/ADM cells and improves complete remission in patients with acute myeloid leukemia

This study was designed to investigate the effects of cyclosporine A (CsA) on a multidrug resistance cultured cell line, and its effect on complete remission in patients with acute myeloid leukemia (AML). A multidrug resistant K562/ADM cell line and drug-sensitive K562 cell line was used. The intracellular concentration of daunorubicin and the accumulation of Rhodamine 123 (Rh123) in the K562/ADM and K562 cells were evaluated. Clinical effects of CsA were also studied in 65 patients with AML. In the K562/ADM cells, the 50% of inhibition concentration (IC50) of daunorubicin only group was 23.0 ± 5.2 μmol/L, which was greater than in other groups co-administered with CsA (1.2 ± 4.8 μmol/L), verapamil (1.5 ± 5.4 μmol/L) or CsA + verapamil (1.4 ± 4.3 μmol/L) (all P < 0.01). The relative fluorescence intensity of Rh123 in the K562/ADM cells treated with CsA and daunorubicin was increased from 48.9% to 69.8% (P < 0.05). CsA also improved the complete remission rate in the AML patients (72.7% vs 21.9%, P < 0.01). We conclude that CsA can significantly diminish the multidrug resistance in K562/ADM cells. It also enhances the complete remission rates in patients with AML. CsA may be used as an integral part of the chemotherapy for AML.     

IL-2和α-IFN逆转人肺腺癌细胞A549／CDDP耐药性的研究

目的观察人重组白细胞介素2（IL-2）和α-干扰素（α-IFN）对人肺腺癌细胞A549／顺铂（CDDP）多药耐药（MDR）的逆转作用,并探讨其机制。方法四氮甲唑兰比色法（MTT法）检测IL-2、α-IFN及IL-2＋α-IFN处理前后A549／CDDP细胞对药物CDDP的敏感性．荧光分光光度法测定IL-2、α-IFN及IL～2＋α-IFN处理前后A549／CDDP细胞内罗丹明聚集量。流式细胞仪检测处理前后A549／CDDP细胞P-糖蛋白（P—gP）的表达。结果经IL-2、α-IFN及IL-2＋α-IFN处理48h后：①化疗药物CDDP对A549／CDDP细胞的半数抑制浓度（IC50）依次是（1．75±0．18）,（2．95±0．30）,（0．45±0．06）,同对照组（8．10±0．72）相比,差异有显著性（P〈0．05）,药物敏感性提高;②A549／CDDP细胞内罗丹明平均荧光强度依次为：（4．82±1．03）,（4．25±1．38）（9．13±1．86）,同对照组（2．38±0．26）相比,差异均有显著性（P〈0．05）;③A549／CDDP细胞P—gp平均荧光强度依次为（5．98±1．13）,（8．90±1．59）,（3．03±0．51）,同对照组（15．23±2．69）相比,差异均有显著性（P〈0．05）。结论IL-2、α-IFN及IL-2＋α-IFN能增加A549／CDDP细胞对CDDP的敏感性,可能机制为抑制P—gP表达,增加细胞膜的通透性,最终逆转了肿瘤细胞的多药耐药性。     

急性白血病多药耐药基因表达与化疗的关系--附25例临床分析

目的：了解急性白血病多药耐药基因表达情况与临床化疗的关系。方法：对２５例初治急性白血病人采用逆转录ＰＣＲ技术检测多药耐药基因（ＭＤＲ１），并对其阳性和阴性表达的２组病人化疗效果进行分析，结果；本组病例ＭＤＲ１阳性表达６例（２４％），以急性非淋巴细胞白血病为主，占５例，这６例ＭＤＲ１阳性的急性白血病患者，没有１例经１个疗程化疗即能完全缓解，ＭＤＲ１阳性的急性白血病患者，完全缓解率为２／６，ＭＤＲ１阴     

肺耐药蛋白基因在急性白血病中的表达及临床意义

目的　检测急性白血病患者肺耐药蛋白 (Lungresistanceprotein ,LRP)基因mRNA表达 ,探讨其与多药耐药和预后的关系。方法　采用半定量逆转录 聚合酶链反应 (RT PCR)技术检测 47例急性白血病患者及 7例正常对照骨髓细胞LRP基因的表达。结果　正常骨髓细胞LRP基因表达阴性 ,2 5例初治急性髓细胞白血病 (AML)患者中 1 7例LRP基因表达阳性 ,1 2例初治急性淋巴细胞白血病 (ALL)中仅 1例阳性 ,1 0例复发难治患者 8例阳性 ,初治AML组及复发难治组较正常对照组相比表达率明显升高 ,差异有显著性 (P =0 .0 0 1 ) ,LRPmRNA表达水平与初次化疗不敏感及预后差有关 ,LRPmRNA阳性患者的完全缓解率明显低于表达阴性者 (分别为 3/1 1 ,4/5 ,P <0 .0 5)。结论　LRP基因表达水平与急性髓细胞白血病化疗效果及预后密切相关 ,是一项新的耐药指标 ,检测LRP的表达可以指导治疗 ,估计预后