脂质体逆转肿瘤多药耐药研究进展

本文就肿瘤细胞多药耐药机理、脂质体的一般特点、脂质体逆转肿瘤细胞多药耐药的机理以及近年来脂质体应用于逆转肿瘤细胞多药耐药的研究进行综述。     

脂质体逆转肿瘤多药耐药研究进展

本文就肿瘤细胞多药耐药机理、脂质体的一般特点、脂质体逆转肿瘤细胞多药耐药的机理以及近年来脂质体应用于逆转肿瘤细胞多药耐药的研究进行综述.       

脂质体阿霉素逆转肿瘤多药耐药的活性和机制研究

目的 探讨脂质体阿霉素( PLD)逆转肿瘤多药耐药(MDR)的活性及其逆转机制.方法 以噻唑蓝(MTT)方法检测PLD对多药耐药肿瘤细胞MCF-7/ADR及KBv200的耐药逆转活性.结果 PLD在体内具有较强的逆转活性,逆转活性大于公认的强逆转剂维拉帕米的活性;在5.0μmol/L浓度下使多药耐药细胞KBv200对长春新碱的敏感性增加了45倍.PLD浓度依赖性增加(0、2.5、5.0、10 μmol/L)KBv200细胞内的罗丹明蓄积.PLD的心脏毒性、骨髓抑制以及脱发等不良反应显著降低.结论 脂质体阿霉素具有较强的逆转MDR的活性,主要通过持续向肿瘤组织聚集,肿瘤局部药物浓度升高,抗肿瘤的活性增强.     

川芎嗪脂质体对人白血病细胞株K562多药耐药逆转作用的研究

目的:研究川芎嗪脂质体在体外对肿瘤细胞的细胞毒作用和对多药耐药的逆转作用,并研究脂质体剂型对上述作用的影响.方法:MTT法检测川芎嗪脂质体以及川芎嗪原料对照组、空白脂质体对照组对耐阿霉素的人白血病细胞株(K562/ADM)的细胞毒性和多药耐药逆转作用.结果:川芎嗪脂质体对K562/ADM有明显的细胞毒作用.非细胞毒性剂量(生长率≥95%)为2.0μg·ml-1,该浓度下可显著降低ADM对K562/ADM细胞的IC50(P＜0.01),抗药性逆转为11.2倍.低毒剂量(生长率85～90%)为2.6μg·ml-1,抗药性逆转为178倍.2.0μg·ml-1的川芎嗪原料对照组可显著降低ADM对K562/ADM细胞的IC50(P＜0.01),抗药性逆转为7.9倍;同比稀释的空白脂质体对照组可显著降低ADM对K562/ADM细胞的IC50(P＜0.01),抗药性逆转为4.9倍.结论:川芎嗪脂质体体外对人白血病细胞K562/ADM有明显的细胞毒作用和MDR逆转作用;在一定浓度范围内川芎嗪脂质体的细胞毒性与逆转作用有剂量依赖性;脂质体本身对逆转有增效作用.     

纳米制剂克服肿瘤多药耐药的研究进展

多药耐药性是肿瘤治疗的重要障碍。靶向性、协同载药能力等功能使纳米制剂成为克服肿瘤多药耐药的理想载体。本文首先介绍了多药耐药性的主要产生机制,然后着重介绍了基于抑制外排、诱导细胞程序性死亡的多功能纳米制剂,用于逆转肿瘤多药耐药性的研究进展,以期为耐药性肿瘤治疗提供思路和方法。     

阿霉素纳米粒对MRP介导的膀胱肿瘤多药耐药细胞株EJ/MRP多药耐药性的逆转作用

目的 研究阿霉素纳米粒对多药耐药相关蛋白(MRP)介导的膀胱肿瘤多药耐药的逆转作用.方法 采用四甲基偶氮唑盐(MTT)法测定药物的体外杀伤作用,应用流式细胞术测定细胞内药物浓度.结果 阿霉素纳米粒对EJ细胞的细胞毒作用与阿霉素相似,EJ/MRP 细胞对阿霉素纳米粒较阿霉素敏感4.00倍.结论 阿霉素纳米粒通过增加耐药细胞内阿霉素浓度而有效逆转多药耐药.     

脂质体阿霉素抗肿瘤药的作用及评价

目的 阐述脂质体阿霉素的药理学和在卵巢癌化疗中的作用及疗效评价.方法 对本院2004年6月至2009年12月共212例应用脂质体阿霉素治疗卵巢癌的综合评价.结果 共212例卵巢癌患者中,完全缓解15例,部分缓解72例,无变化111例及进展14例.总有效率达41.04%.常见的不良反应是心脏毒性,发生率为47%;其次是骨...     

脂质体载药提高阿霉素抗淋巴瘤活性的体内外研究

脂质体载药提高阿霉素抗淋巴瘤活性的体内外研究吴开达，范健，高雪芝，金宝翠（南京铁道医学院血液室，普外科．江苏２１０００９）阿霉素是一种抗瘤谱广、活力强．对多种肿瘤有效的强力抗癌剂．但由于其毒性较大而限制了临床广泛应用。脂质体是近年来发展较快的一种药物...     

多柔比星-五味子乙素共载脂质体克服多药耐药的机制研究

目的 探讨多柔比星-五味子乙素共载脂质体克服肿瘤多药耐药机制。方法 制备多柔比星-五味子乙素共载脂质体,以人慢性髓系白血病耐药细胞株K562/DOX为模型细胞,分别探讨不同温度、内吞抑制剂存在下的细胞摄取药物的情况,并检测耐药细胞P-gp表达和细胞凋亡情况。结果 共载脂质体在4℃及氯喹、叠氮钠和甘露醇内吞抑制剂存在下进入耐药细胞的药物量明显减少;流式细胞仪检测多柔比星-五味子乙素共载脂质体可抑制P-gp表达且诱导凋亡。结论 多柔比星-五味子乙素共载脂质体进入K562/DOX细胞主要通过耗能的内吞途径;而多柔比星-五味子乙素共载脂质体克服肿瘤多药耐药可能是通过抑制P-gp表达和促进凋亡双通道途径。     

Multifunctional micelle delivery system for overcoming multidrug resistance of doxorubicin

Doxorubicin (DOX), as an anthracycline, plays an important role in chemotherapy. But multidrug resistance (MDR) tremendously retards the anticancer effect of DOX and results in the failure of chemotherapy. Multifunctional micelles emerge as a valid strategy to load DOX by physical encapsulation or chemical binding to be delivered to cancer cells against MDR. In this review, mechanism of MDR of DOX is simply described. Multifunctional co-delivery micelles of DOX and main MDR modulators have been summarised in detail. DOX-loaded multifunctional polymeric micelles are also introduced to alleviate MDR of DOX, in which polymers act as MDR modulators.     

氟哌啶醇对人红白血病耐多柔比星细胞株多药耐药性的逆转及其机制

目的　从临床常用药物中探寻逆转肿瘤耐药性的活性物质。方法　应用MTT法测定不同浓度Hal处理的瘤细胞对 0～ 2 0 μmol·L- 1多柔比星 (Dox)的敏感性的影响。RT PCR法分析 12 .5 μmol·L- 1氟哌啶醇 (Hal)处理后多药耐药基因 (MDR1) ,多药耐药相关蛋白 (MRP)和谷胱甘肽S转移酶Pi(GSTπ)mRNA表达的变化。通过流式细胞术观察 0 ,6 .2 5 ,12 .5 ,2 5 μmol·L- 1Hal对细胞内药物蓄积和细胞周期进程的影响。结果　Hal对K5 6 2 /Dox的耐药性具有明显的逆转作用。在 12 .5 ,6 .2 5及 3.12 5 μmol·L- 1时的逆转倍数分别为 8.35 ,4 .2 1及 2 .16。用 12 .5μmol·L- 1Hal处理后 ,MDR1及MRP的mRNA表达水平均呈现时间依赖性明显降低 ,分别较原水平下降76 .3%及 6 4.6 %。药后d 2GSTπmRNA表达下降6 6 .1% ,于d 3回升。Hal处理细胞lh后 ,Dox在细胞内蓄积量明显增加 ,并呈浓度依赖性 ;此外 ,Hal可明显增强Dox对K5 6 2 /Dox细胞的G2 /M阻滞作用 ,12 .5 μmol·L- 1浓度可以使 5 μmol·L- 1Dox的G2 /M阻断由单独应用时的 9.9%± 4 .3%增加到2 3.4 %± 3.0 %。结论　Hal具有较强的逆转K5 6 2 /Dox细胞MDR的作用 ,其逆转机制为多种途径 ,包括相关基因mRNA的表达下调 ,增加细胞内药物蓄积 ,增强Dox对K5 6 2 /Dox在G2     

Partial circumvention of P-glycoprotein-mediated multidrug resistance by doxorubicin-14-O-hemiadipate

Previously, we have reported partial circumvention ofP-glycoprotein (Pgp)-associated resistance to doxorubicin(Dox) in MCF7/R human breast carcinoma and P388/R murineleukemia cell lines by doxorubicin-14-O-hemiadipate (H-Dox)[Povarov L.S. et al. (1995) Russian J. Bioorganic Chemistry21: 797–803]. We felt that these changes were due toalterations in the cellular pharmacokinetics of the analog inmultidrug (MDR) resistant cells, as compared to that of Dox.To address this hypothesis, we performed comparative studiesof the accumulation, retention and intracellular localizationof H-Dox and Dox in Dox-sensitive murine leukemia cell lineP388/S and its Dox-selected, Pgp-positive drug resistantP388/R subline. These studies were performed in the presenceor absence of cyclosporin A (CsA), a competitive inhibitor ofPgp. Flow cytometric analysis revealed significant differencesin Dox and H-Dox accumulation in P388/R cells when compared toP388/S cells. In P388/R versus P388/S cells, there was a 38-fold decrease in Dox accumulation, but only a 5-fold decreasein H-Dox accumulation, indicating over a 7-fold increase in H-Dox buildup in resistant cells. CsA did not affect uptake orretention of either drug by sensitive cells. However,coincubation with CsA resulted in a 54-fold increase in Doxaccumulation and only a 5-fold increase in H-Dox uptake inP388/R cells, restoring anthracycline levels in P388/R to100% of that found in P388/S cells. Once internalized by theresistant cells, H-Dox was retained better than Dox regardlessof presence or absence of CsA. Confocal microscopic analysisrevealed the presence of H-Dox but no Dox in cellular nucleiof P388/R cells. Thus, increased activity of H-Dox towardP388/R cells was correlated with its enhanced ability to enterand be retained in these cells, and also with redistributionof H-Dox into the nuclei of the resistant cells as compared toDox. Overall, our findings support our initial hypothesis andprovide evidence that H-Dox, a 14-O-hemiadipate ofdoxorubicin, is affected by Pgp-mediated MDR to a lesserextent than parental Dox due to changes in the cellularpharmacokinetics of the analog.     

蛋白酶体抑制剂逆转肿瘤多药耐药的研究进展

肿瘤多药耐药是肿瘤治愈的主要障碍之一。肿瘤细胞对抗癌药物诱导的凋亡的耐受是多药耐药形成的重要原因。蛋白酶体抑制剂可选择性地促进肿瘤细胞凋亡，逆转多药耐药。蛋白酶体被认为是肿瘤治疗的新靶点。     

盐酸多柔比星脂质体注射液药效学研究

目的比较盐酸多柔比星脂质体注射液与市售楷莱注射液的体内抗肿瘤作用。方法建立小鼠实体型S180肿瘤模型、小鼠腹水型S180、L1210肿瘤模型和静脉注射L1210的小鼠肝转移模型,探讨盐酸多柔比星脂质体与市售楷莱注射液的抗肿瘤作用。结果盐酸多柔比星脂质体注射液与市售楷莱注射液单次以16.0mg/kg静脉注射,对小鼠S180实体型的抑瘤率分别为95.4%和87.9%,二者差异无统计学意义(P>0.05);单次以8.0和12.0mg/kg静脉注射,仅盐酸多柔比星脂质体注射液12.0mg/kg对腹水型S180小鼠有治疗作用,且疗效明显优于市售楷莱注射液组(P<0.05);单次以8.0和12.0mg/kg静脉注射,与空白组相比均可显著延长腹水型L1210肿瘤模型和肝转移模型小鼠的生存时间,二者差异无统计学意义(P>0.05),但与等剂量的盐酸多柔比星注射液组比较差异有统计学意义(P<0.05)。结论相同给药剂量下,盐酸多柔比星脂质体注射液的体内抗肿瘤作用与市售楷莱注射液等效,并显著优于盐酸多柔比星注射液。     

The effect of crown ethers, tetraalkylammonium salts, and polyoxyethylene amphiphiles on pirarubicin incorporation in K562 resistant cells

The basic distinguishing feature of all cells expressing functional P-glycoprotein-multidrug resistance (P-gp-MDR) is a decrease in steady-state accumulation drug levels as compared to drug-sensitive controls. In an attempt to identify mechanism(s) by which MDR can be circumvented, we examined the cellular accumulation, in resistant cells, of 4′-O-tetrahydropyranyl-doxorubicin (pirarubicin) alone and in conjunction with various molecules belonging to three different classes: the crown ethers, the tetraalkylammonium salts, and the polyoxyethylene amphiphiles. The present study was performed using a spectrofluorometric method which enabled us to follow the uptake and release of fluorescent molecules by living cells while the cells were being incubated with the drug. Erythroleukemia K562 cell lines were used. Our data show that the compounds of these three completely different classes were able to increase the incorporation of pirarubicin provided they had a minimum degree of lipophilicity. Study of the growth inhibitory activity of these compounds revealed that cross-resistance to the tetraalkyl ammonium salt increased with the lipophilicity and was equal to 58 for tetraoctylammonium salt, the most lipophilic compound of this series. This demonstrates that neither the presence of a positive charge nor an aromatic moiety is required for MDR recognition.     

Vitamin E derivative-based multifunctional nanoemulsions for overcoming multidrug resistance in cancer

The multidrug resistance (MDR), including intrinsic and acquired multidrug resistance, is a major problem in tumor chemotherapy. Here, we proposed a strategy for modulating intrinsic and/or acquired multidrug resistance by altering the levels of Bax and Bcl-2 expression and inhibiting the transport function of P-gp, increasing the intracellular concentration of its substrate anticancer drugs. Vitamin E derivative-based nanoemulsions containing paclitaxel (MNEs-PTX) were fabricated in this study, and in vitro anticancer efficacy of the nanoemulsion system was evaluated in the paclitaxel-resistant human ovarian carcinoma cell line A2780/Taxol. The MNEs-PTX exhibited a remarkably enhanced antiproliferation effect on A2780/Taxol cells than free paclitaxel (PTX) (p?<?0.01). Compared with that in the Taxol group, MNEs-PTX further decreased mitochondrial potential. Vitamin E derivative-based multifunctional nanoemulsion (MNEs) obviously increased intracellular accumulation of rhodamine 123 (P-gp substrate). Overexpression of Bcl-2 is generally associated with tumor drug resistance, we found that MNEs could reduce Bcl-2 protein level and increase Bax protein level. Taken together, our findings suggest that anticancer drugs associated with MNEs could play a role in the development of MDR in cancers.     

R-dl-型维拉帕米调低KBv200肿瘤细胞对长春新碱和多柔比星的多药抗药性

目的:研究R-型维拉帕米对多药耐药的降低作用及其急性动物毒性,并与消旋维拉帕米的相应结果作比较。方法:细胞毒性的测定用MTT法;细胞内多柔比星积累的测定用萤光分光光度计法。急性毒性试验用BALB/c小鼠腹腔注射法。结果:R-型维拉帕米部分调低KBv200细胞对长春新碱和多柔比星的耐药性,其调低效应与作用浓度和作用时间有关。1.25μmol·L~(-1)的R-型维拉帕米与长春新碱对细胞作用24h,能够显著增加KBv200细胞对长春新碱的敏感性。在增敏和增加细胞内多柔比星累积方面,R-型维拉帕米与消旋维拉帕米效果一样,但R-型维拉帕米的急性动物毒性明显低于消旋维拉帕米。结论:R-型维拉帕米1.25μmol·L~(-1)提高耐药肿瘤细胞对长春新碱和多柔比星的敏感性,增加对长春新碱敏感性所需的药物作用时间可缩短至24h。     

外排型转运体与肿瘤多药耐药

肿瘤多药耐药（MDR）是导致肿瘤化疗失败的主要原因之一。肿瘤MDR的机制有多种,其中外排型转运体的过表达是导致MDR的主要机制,因此研究外排型转运体介导的肿瘤MDR机制和发现可以逆转肿瘤MDR的抑制剂成为国内外研究的热点。就目前研究的3种三磷酸腺苷结合盒转运体：P-糖蛋白、多药耐药相关蛋白、乳腺癌耐药蛋白介导的MDR及逆转MDR的机制进行综述,以期为提高肿瘤治疗疗效提供依据。     

马蔺子甲素抗多药抗药性肿瘤作用及其机制探讨

有报道马蔺子甲素（ｉｒｉｓｑｕｉｎｏｎｅ,ＩＲ）能抑制肿瘤细胞ＤＮＡ的合成及断裂后的修复,具抗肿瘤和放射增敏作用［１,２］。那么 ＩＲ对多药抗药性（Ｍｕｌｔｉｄｒｕｇ Ｒｅｓｉｓｔａｎｃｅ,ＭＤＲ）肿瘤是否有治疗作用或逆转肿瘤的ＭＤＲ作用？本文拟通过测定马蔺子甲素对多药抗药性（ＭＤＲ）肿瘤细胞的抑制作用及其对Ｐ－ｇｐ的影响,对这些问题进行探讨。１材料与方法１．１药物ＩＲ由山东新华制药厂提供,以二甲基亚砜溶解,用生理盐水配成所需浓度。１．２细胞培养ＭＣＦ－７和ＭＣＦ－７／ＡＤＲ细胞在含１０％小牛血清…