FG020327逆转肿瘤多药耐药性的作用及其机制

背景与目的肿瘤细胞过量表达P鄄糖蛋白穴P-glycoprotein.P-gp雪导致多药耐药穴multidrug resistance,MDR雪是目前肿瘤化疗的一大障碍,使用多药耐药逆转剂与抗癌药物联合化疗是克服临床多药耐药的重要方法。本研究对一种新的多芳基取代咪唑化合物FG020327的体外逆转活性及其逆转机制进行了探讨。方法以MTT法检测FG020327对多药耐药肿瘤细胞MCF-7/ADR及KBv200的耐药逆转活性;以荧光分光光度计法检测FG020327对MCF-7/ADR细胞内抗癌药物阿霉素累积的影响;以罗丹明蓄积实验检测该化合物对P-gp功能的影响。结果FG020327在体外具有较强的逆转活性,在5μmol/L浓度下使多药耐药细胞KBv200对长春新碱的敏感性增加44.9倍,逆转活性是公认的强逆转剂维拉帕米的3倍熏但它对敏感株对抗癌药物的敏感性基本无影响。2.5、5和10μmol/L的FG020327使MCF-7/ADR细胞中阿霉素的累积分别增加2.3、2.7和3.7倍,但是在敏感株MCF鄄7细胞却观察不到阿霉素累积的增加。FG020327浓度依赖性增加KBv200细胞内的罗丹明蓄积,但对敏感株KB细胞内的罗丹明蓄积无影响。结论FG020327具有较强的体外逆转MDR的活性,它可能通过抑制P鄄gp功能及增加MDR细胞内抗癌药物的累积逆转MDR。     

人参皂甙Rh2逆转P-gp介导的MCF-7/ADM多药耐药性的基础研究

目的：研究人参皂甙Rh：在逆转多药耐药（MDR）方面的作用及其机理。方法：Rh：和阿霉素单独或联合作用于MCF-7及MCF-7／ADM细胞，应用MTT法确定各组细胞的IC50。罗丹明123加入各组细胞，流式细胞仪分析Rh2和维拉帕米抑制罗丹明123外排的情况。RT—PCR检测各组mdrl mRNA表达量及流式细胞仪检测各组P—gP的表达情况。结果：Rh2可以显著降低MCF-7／ADM的ADM IC50（P〈0．05），对MCF-7细胞没有影响。Rh2和维拉帕米可以增加MCF-7／ADM细胞内罗丹明123荧光表达率（P〈0．05），Rh3比维拉帕米抑制罗丹明123外排作用更强。在MCF-7细胞内Rh2和维拉帕米无此作用。Rh2对MCF-7／ADM细胞mdrl mRNA表达及P—gP表达没有影响。结论：人参皂甙Rh2可以有效逆转P—gP介导的人乳腺癌细胞耐药细胞系MCF-7／ADM的耐药性。     

siRNA逆转乳腺癌细胞系MCF-7/ADR耐药

背景与目的：肿瘤的多药耐药性常导致乳腺癌化疗失败,多约耐药基因1(multidrug resistance 1、mdr1)编码的P-糖蛋白(P-glycoprotein．P-gP)过度表达是重要的耐药机制。本研充拟探讨siRNA抑制耐药乳腺癌细胞系MCF-7／ADR mdr1基因表达的可行性。方法：选择耐阿毒素人乳腺癌细胞系MCF-7／ADR技其敏感细胞系MCF-7作为研究对象,将预先设计的siRNA包装入质粒载体,然后转化质粒刮大肠杆菌中,经过克隆、扩增、纯化后转染到MCF-7／ADR细胞中,潮霉素筛选,流式细胞仪检测P-gP的表达率,实时定量PCR俭测,mdr1基因的表达率,并对转染后的细胞作阿霉素耐药实验。结果：流式细胞仪榆测结果显示,MCF-7／ADR细胞经特异性siRNA作用后,P-gP的表达率由99．8％下降到12．3％：实时相对定量PCR检测结果显示．MCF-7／ADR细胞经特异性siRNA作用后其Ct值由25．22增加到30．64．阿霉素耐药实验显示,转染siRNA的MCF-7／ADR细胞IC50为0．51μmol／L,而术转染组的IC50为17．88μmol／L。结论：siRNA能引发人乳腺癌多耐药细胞系MCF-7／ADR内mdr1基因沉默,从而为siRNA作为一种可能的治疗手段提供了理论依据。     

shRNA逆转耐阿霉素人乳腺癌细胞株（MCF-7/AdrR）的多药耐药性

目的〖HT5"SS〗： 利用短发夹RNA（short hairpin RNA,shRNA）表达载体逆转耐阿霉素人乳腺癌细胞株(MCF7/AdrR)的多药耐药性（multidrug resistance,MDR）。〖HT5W〗方法〖HT5"SS〗： 构建2个MDR1基因shRNA表达质粒,稳定转染MCF7/AdrR细胞。RTPCR分析MDR1基因mRNA的表达,Western blotting检测P糖蛋白(Pgp)的表达,流式细胞术和MTT法分别检测乳腺癌细胞的凋亡和对阿霉素的敏感     

补骨脂素逆转人乳腺癌细胞多药耐药性的研究

目的研究中药补骨脂素对人乳腺癌细胞多耐药性的逆转作用.方法用MTT法测定药物的细胞毒性和IC50用流式细胞仪测定耐药细胞P170糖蛋白表达,并选异搏定作阳性对照,观察具有钙拮抗作用的补骨脂素对MCF-7/ADR多药耐药性的逆转作用.结果补骨脂素在非细胞毒性剂量下能使MCF-7/ADR对阿霉素的浓度升高,但对细胞表面的糖蛋白P-170却没有影响.结论补骨脂素具有逆转人乳腺癌MCF-7/ADR多药耐药性的作用.     

阿帕替尼逆转P-gp转运体介导的乳腺癌化疗多药耐药性的作用及其机制

目的 探讨阿帕替尼对人乳腺癌化疗多药耐药性的逆转作用及其机制。方法 不同浓度的阿帕替尼作用于体外培养的人乳腺癌MCF-7及MCF-7/ADR细胞48 h,MTT法检测阿帕替尼对两种细胞的细胞毒性;低毒浓度的阿帕替尼与化疗药物紫杉醇及阿霉素联用,探讨阿帕替尼对两种细胞化疗耐药性的影响;采用流式细胞术检测阿帕替尼对罗丹明123在MCF-7及MCF-7/ADR细胞内蓄积的影响;采用Pgp-Glo? Assay Systems试剂盒观察阿帕替尼对多药耐药相关蛋白P-gp的ATPase活性的影响;采用Western blot法检测阿帕替尼对P-gp表达及AKT磷酸化的影响。结果 阿帕替尼可浓度依赖性地逆转乳腺癌MCF-7/ADR细胞对紫杉醇及阿霉素的多药耐药性（P<0.05）、增加罗丹明123在MCF-7/ADR细胞内的蓄积（P<0.05）及激活P-gp转运体的ATPase活性（P<0.05）,而对P-gp的表达没有影响;此外,阿帕替尼不改变AKT的磷酸化水平。结论 阿帕替尼可能通过抑制P-gp转运体的外排功能逆转P-gp转运体介导的乳腺癌化疗多药耐药性。     

GCS在人乳腺癌细胞多药耐药中的作用及与P-gP的关系

目的探讨葡萄糖神经酰胺合成酶（GCS）在人乳腺癌细胞多药耐药中的作用及其与P-糖蛋白（P-gP）的关系。方法采用MTT法检测多柔比星（阿霉素）对人乳腺癌耐药细胞株MCF-7／Adr和敏感株MCF-7的抑制率和IC50。以GCS抑制剂D，L-threo-1-phenyl-2-decanoyl—amino-3-morpholino-1-propanol（PDMP）预处理MCF-7／Adr后检测抑制率和IC50。运用流式细胞术（FCM）检测人MCF-7及MCF-7／Adr中GCS、P-gp的表达，以PDMP预处理细胞后检测GCS、P-gP的表达。FCM法检测细胞中ADM的荧光强度。结果MCF-7／Adr对MCF-7的耐药倍数为22．7倍，PDMP作用后阿霉素对MCF-7／Adr的抑制率升高，IC50下降（P〈0．05）。MCF-7／Adr中GCS和P-gp的表达均高于MCF-7，PDMP使MCF-7／Adr中GCS表达下降（P〈0．05），对P—gp表达无明显影响（P〉0．05）。FCM检测显示PDMP可使阿霉素在MCF-7内潴留增多。结论GCS在MCF-7／Adr多药耐药中起重要作用，PDMP能影响P-gP功能，GCS与P-gP有-定关系。     

miR-490-3p逆转MCF-7／ADM细胞对阿霉素耐药性的影响

【摘 要】目的 探讨miR-490-3p在阿霉素（ADM）耐药乳腺癌细胞系MCF-7／ADM中的表达情况及其对MCF-7／ADM细胞增殖、凋亡和ADM耐药的影响。方法 以野生型人乳腺癌细胞系MCF-7及其耐药型细胞系MCF-7／ADM为研究对象,用实时荧光定量PCR（qPCR）比较两种细胞中miR-490-3p的表达水平,将miR-490-3p的过表达载体pcDNA1（+）miR-490-3p瞬时转染至MCF-7／ADM细胞（过表达组）后采用qPCR检测转染效果,同时设pcDNA3.1（-）空载体对照组和空白对照组;采用MTT法测定转染pcDNA3.1（+）miR-490-3p对各组MCF-7/ADM细胞增殖能力的影响,测定ADM对MCF-7／ADM细胞的增殖抑制率并计算半数抑制浓度（IC50）及逆转倍数以评价对ADM敏感性的变化;分别于瞬时转染48 h后用Annexin V／FITC流式细胞术检测各组MCF-7/ADM细胞的凋亡率,Western blotting检测耐药蛋白P-糖蛋白（P-gp）,乳腺癌耐药蛋白（BCRP）和多药耐药相关蛋白1（MRP1）的表达,荧光分光光度计检测胞内ADM药物浓度,流式细胞仪检测P-gp活性。结果 MCF-7／ADM细胞中miR-490-3p的表达水平为0.24±0.07,显著低于野生型MCF-7细胞的1.02±0.03（P＜0.05）;过表达组瞬时转染24～96 h的miR-490-3p水平持续升高,均高于空载体对照组和空白对照组（P＜0.05）;过表达组的增殖抑制率随转染时间的延长而增加,转染24、48、72和96 h的增殖抑制率依次为（17.52±1.87）％、（31.67±2.79）％、（45.09±1.88）％和（61.82±2.52）％,高于空载体对照组（P＜0.05）;ADM对过表达组的IC50值为（11.27±2.34）μg／ml,低于空白对照组的和空载体对照组（P＜0.05）,且过表达组相对于空白对照组和空载体对照组的逆转倍数分别为3.35倍和3.39倍;与其余两组相比,过表达组的MCF-7/ADM细胞早、晚期凋亡率和细胞内药物浓度均升高,P-gp、BCRP和MRP1表达及P-gp活性均降低,差异均有统计学意义（P＜0.05）。结论 上调miR-490-3p可逆转MCF-7／ADM细胞对ADM的耐药性,可能通过降低耐药蛋白表达及抑制P-gp活性有关,且升高其水平可抑制细胞增殖并诱导凋亡。     

microRNA-21对乳腺癌MCF-7/ADR细胞株多柔比星耐药性影响的研究

目的:探讨microRNA-21(miR-21)基因表达改变对乳腺癌细胞多柔比星化疗耐药的影响.方法:人工合成miR-21模拟序列或干扰序列,以脂质体为载体,转染乳腺癌细胞MCF-7及其多柔比星耐药细胞株MCF-7/ADR;应用荧光定量RT-PCR检测miR-21的表达;应用MTT法检测细胞转染前后对多柔比星的耐药性;应用流式细胞仪检测细胞凋亡;应用蛋白质印迹法检测PTEN、BAX及Bcl-2蛋白的表达.结果:MTT检测结果示,MCF-7及其耐药株MCF-7/ADR细胞多柔比星半数抑制浓度(IC50)分别为(0.28±0.03)和(17.5±0.12) μmol/L.miR-21表达上调,MCF-7细胞对多柔比星的IC50明显增高为(3.65±0.12) μmol/L;miR-21表达下调,MCF-7/ADR细胞对多柔比星的IC50明显降低为(7.53±0.11) μmol/L.流式细胞分析显示,miR-21下调后MCF-7/ADR细胞凋亡率明显增加.同时,细胞内PTEN、BAX蛋白表达水平增加,Bcl-2表达降低.结论:miR-21在乳腺癌化疗耐药中具有重要作用,抑制miR-21的表达可以逆转乳腺癌多柔比星耐药细胞株对多柔比星的耐药性.     

ZD6474 reverses multidrug resistance by directly inhibiting the function of P-glycoprotein

P-glycoprotein (P-gp) pumps multiple types of drugs out of the cell, using energy generated from ATP, and confers multidrug resistance (MDR) on cancer cells. ZD6474 is an orally active, selective inhibitor of the vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection tyrosine kinases. This study was designed to examine whether ZD6474 reverses P-gp-mediated MDR in cancer cells. Here, we show that clinically achievable levels of ZD6474 reverse P-gp-mediated MDR of the P-gp-overexpressing cell lines derived from breast cancer, MCF-7/adriamycin (ADR), and human oral epidermoid carcinoma, KBV200 to ADR, docetaxel, and vinorelbine. This ability to reverse the P-gp-mediated resistance is comparable to that of another frequently used reversal agent known as verapamil. ZD6474 itself moderately inhibits the proliferation of both MCF-7 and MCF-7/ADR cells with almost equal activity, but its inhibitory effect is not altered by co-incubation with verapamil, suggesting that ZD6474 may not be a substrate of P-gp. In addition, ZD6474 increases the intracellular accumulation of the P-gp substrate, rhodamine-123, and ADR, by enhancing the uptake and/or decreasing the efflux of these compounds in resistant cells. Further studies show that ZD6474 stimulates ATPase activity in a dose-dependent manner, which is required for the proper function of P-gp. In contrast, ZD6474 does not inhibit the expression level of P-gp. Our results suggest that ZD6474 is capable of reversing MDR in cancer cells by directly inhibiting the function of P-gp, a finding that may have clinical implications for ZD6474.     

雷公藤红素逆转K562/A02细胞多药耐药的实验研究

目的探讨雷公藤红素逆转人慢性粒细胞白血病红白血病急变细胞株K562/A02多药耐药的效果。方法采用CCK-8法测定细胞的药敏性及耐药逆转性,应用流式细胞术检测细胞内ADM浓度、P-gp蛋白表达。结果雷公藤红素对K562/A02、K562的半数抑制率浓度（IC50）分别为（295.58±23.288）μmol/L、（411.59±26.551）μmol/L。K562/A02细胞对ADM的耐药性是K562细胞的79.78倍。细胞毒剂量的雷公藤红素作用后,ADM对K562/A02细胞的IC50显著下降（P〈0.05）,逆转倍数为117.860倍。细胞毒剂量（IC50）和非细胞毒剂量（IC10）的雷公藤红素处理后的K562/A02细胞内的ADM浓度显著增加（P〈0.05）,增加倍数分别为1.537倍和1.102倍。雷公藤红素能明显下调K562/A02细胞的P-gp表达。结论雷公藤红素对逆转K562/A02细胞的耐药性有一定的作用,其机制可能与下调P-gp表达有关。     

逆转胶囊含药血清对人乳腺癌耐药株MCF-7／ADR细胞P—gp蛋白表达的影响

目的探讨逆转胶囊在乳腺癌多药耐药中的应用。方法应用流式细胞技术。测定逆转胶囊含药血清对人乳腺癌耐药株MCF-7／ADR细胞P—gp蛋白表达的影响。结果阿霉素单用对P—gp表达无明显影响,其余各处理组与对照组（正常鼠血清组）比较P-gp的荧光表达率均有所下降;逆转胶囊含药血清能显著抑制MCF-7／ADR细胞P—gp表达;阿霉素与10％含药鼠血清合用,对人乳腺癌耐药MCF-7／ADR细胞P—gp蛋白表达的抑制效果良好,P—gp荧光表达率的下降幅度大,与异博定＋阿霉素＋10％正常鼠血清组无明显差异。结论逆转胶囊含药血清能显著抑制MCF-7／ADR细胞P—gp表达;并有耐药逆转作用。     

ATP1B1协同阿霉素抑制乳腺癌细胞MCF-7生长及逆转耐药的作用

背景与目的：Na^＋-K^＋ATP酶（Na^＋-K^＋泵）是细胞能量转换的重要系统,可能与肿瘤转移有关,其B1亚基基因ATP1B1在高分化的肿瘤细胞中表达高,低分化细胞中表达低。本实验研究ATP1B1协同阿霉素（ADM）在人乳腺癌细胞株MCF-7和其耐药株MCF-7／ADM中的作用以及其逆转耐药效应的影响。方法：将重组质粒PEGFP—ATP1B1转染到MCF-7和MCF-7／ADM细胞,MTT法检测质粒及其B1亚基因沉默后ADM抑瘤效应,荧光显微镜和流式细胞术分析细胞内药物荧光强度,定磷法检测ATP酶活性,RT—PCR和real-timePCR检测MDR1 mRNA的表达,Western blot法检测P—gP蛋白的表达。结果：转染PEGFP-ATP1B1的MCF-7和MCF-7／ADM细胞对ADM的敏感性相对阴性对照ADM—C3组（pEGFP—C3空载体转染）和空白对照ADM—RPMI-1640组均明显增加,且ADM各浓度梯度ADM—ATP1B1组与ADM—RPMI-1640组比较差异有统计学意义（P〈0．05）;而B1亚基沉默后阴性对照组ADM-shNC,相对实验组ADM—shATP1B1和空白对照ADM—RPMI-1640组细胞对ADM的敏感性明显偏高。荧光显微镜下观察ADM-ATP1B1组MCF-7和MCF-7／ADM细胞ADM红色荧光均高于对照组。流式细胞术显示,ADM—ATP1B1组MCF-7细胞中ADM平均荧光强度较对照组高（P〈0．05）,ADM—ATPlBl组MCF-7／ADM细胞中ADM平均荧光强度高于对照组（P〈0．05）。MCF-7和MCF-7／ADM细胞的ADM-ATP1B1组ATP酶活性均高于ADM—RPMI-1640组（P〈0．05）．而ADM-C3组与ADM-RPMI-1640组相比差异无统计学意义（P〉0．05）。RT—PCR和real-time PCR检测结果显示,MCF-7／ADM细胞ADM—ATP1B1组MDR1 mRNA相对表达水平与两对照组相比差异均无统计学意义（P〉0．05）。Western blot显示P-gp蛋白的表达水平差异无统计学意义（P〉0．05）。结论：ATP1B1对ADM抑制乳腺癌细胞生长具有协同作用,并可逆转耐药细胞MCF-7／ADM对ADM的耐药效应,其机理与MDR1基因无明显的相关性,?     

Lack of modulation of MDR1 gene expression by dominant inhibition of cAMP-dependent protein kinase in doxorubicin-resistant MCF-7 breast cancer cells.

The drug transporter P-glycoprotein (P-gp) appears to play an important role in the ability of tumor cells to evade killing by chemotherapeutic agents. Using pharmacological inhibitors of cAMP-dependent protein kinase (PKA), it has been suggested that, similar to rodent model systems, the human P-gp gene (MDR1) is also under PKA-dependent control and that PKA inhibition may prove useful in reducing drug resistance in human cancer cells. To test this hypothesis, we stably transformed doxorubicin (Adriamycin)-resistant human MCF-7 breast cancer cells (MCF-7(ADR)) with a vector that inhibits PKA activity by inducing over-expression of mutant type Ialpha PKA regulatory (RIalpha) subunits. Two transformants (MCF-7(ADR-A) and MCF-7(ADR-B)) were found to express mutant RIalpha subunits and to possess markedly reduced PKA activity; another transformant (MCF-7(ADR-9)) lacked mutant RIalpha subunit expression and exhibited no inhibition of PKA activity. In contrast with findings in Chinese hamster ovary and Y1 adrenal cells, P-gp levels and cellular sensitivity to drugs which are P-gp substrates were unchanged in the PKA-inhibited transformants, suggesting that P-gp expression and function are not under PKA-dependent control in MCF-7(ADR) cells. Growth and saturation densities of the cell lines were highly correlated with level of PKA catalytic activity, suggesting that PKA inhibition may prove useful in inhibiting growth of breast tumor cells, even upon establishment of resistance to doxorubicin. However, our results challenge current proposals that drug sensitivity in P-gp-expressing human tumor cells may be restored by blocking MDR1 gene expression through inhibition of PKA activity.     

Reversal of doxorubicin resistance in breast cancer cells by photochemical internalization

Multiple drug resistance (MDR) is a problem that seriously reduces the efficacy of many chemotherapy agents. One mechanism for MDR is increased acidification of endocytic vesicles and increased cytosol pH, so weak base chemotherapeutic agents, including doxorubicin, are trapped in endocytic vesicles and exhibit a drug resistant phenotype. Treatments that selectively reverse this accumulation may therefore reverse the MDR phenotype. Photochemical internalization (PCI) is a novel technology developed for site-specific enhancement of the therapeutic efficacy of macromolecules by selective photochemical rupture of endocytic vesicles and consequent release of endocytosed macromolecules into the cytosol. This study evaluates PCI for release of doxorubicin from endocytic vesicles in MDR cells. Two breast cancer cell lines, MCF-7 and MCF-7/ADR (the latter resistant to doxorubicin), were selected. They were found equally sensitive to photochemical treatment with the photosensitiser TPPS(2) (a) (disulfonated meso-tetraphenylporphine) and light. On exposure to doxorubicin alone, the IC(50) (drug concentration for 50% reduction in colony formation) was 0.1 microM for MCF-7 and 1 microM for MCF-7/ADR. After PCI (photochemical treatment followed by doxorubicin), the IC(50) concentration was 0.1 microM for both cell lines. Comparable changes were seen with assay of cell viability using 3-(4,5-dimethyltiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). On fluorescence microscopy in MCF-7/ADR cells, doxorubicin localised in granules identified as lysosomes. After PCI, doxorubicin was released into the cytosol and entered cell nuclei, as was seen in MCF-7 cells without PCI. In conclusion, PCI reversed the MDR phenotype of doxorubicin resistant breast cancer cells by endo-lysosomal release of the drug. The technique is a promising new approach to tackling the problem of MDR.     

Med19基因敲减增加乳腺癌细胞化疗敏感性及其可能的机制

目的:研究中介体(mediator,Med) 19对乳腺癌化疗敏感性的影响并分析其分子机制.方法:选用多柔比星(adriamycin,ADM)耐药的人乳腺癌细胞MCF-7/ADM和亲本细胞MCF-7(NC组),采用慢病毒载体介导RNA干扰方法构建Med9稳定低表达的MCF-7/ADM与MCF-7细胞株(KD组),并用Real-time PCR和Western blotting方法验证干扰效果.CCK-8法检测慢病毒介导的Med19敲减前后两种细胞对ADM、顺铂(cisplatin,DDP)和紫杉醇(taxinol,TAX)药物敏感性的变化.Real-time PCR和Western blotting检测Med19敲减对多药耐药基因1(multidrug resistance 1,MDR1)和细胞凋亡基因Bcl2、Bax及Caspase-3、active Caspase-3的表达的影响.流式细胞术检测敲减Med19及ADM处理对细胞凋亡的影响.结果:与MCF-7相比,MCF-7/ADM细胞对ADM、DDP和TAX均具有耐药性.成功构建Med19稳定低表达的MCF-7/ADM与MCF-7细胞株,并且其对ADM、DDP、TAX的敏感性增加,药物作用IC50显著降低(均P＜0.05).MCF-7/ADM细胞Med19 mRNA和蛋白表达显著高于MCF-7细胞,Med19的敲减可降低MCF-7/ADM细胞中MDR1 mRNA与蛋白表达水平(均P＜0.05)并可增加MCF-7/ADM及MCF-7细胞中凋亡相关active Caspase-3、Bax的蛋白表达,降低Bc12的蛋白表达(均P＜0.05).此外,与NC及NC+ ADM组相比,KD组及KD+ ADM组凋亡水平显著增加(均P＜0.05).结论:Med19高表达参与乳腺癌化疗耐药,其机制可能与Med19调节MDR1的表达并影响细胞凋亡有关.     

MS-209, a quinoline-type reversal agent, potentiates antitumor efficacy of docetaxel in multidrug-resistant solid tumor xenograft models.

The existence of multidrug-resistant (MDR) cells in cancer is a major obstacle to effective cancer chemotherapy. Expression of P-glycoprotein (P-gp) in cancer cells causes resistance against paclitaxel and docetaxel, as well as against vincristine and doxorubicin (ADM). MS-209 is a novel MDR-reversal agent currently under clinical evaluation, which is shown to be active against ADM and vincristine resistance in MDR cancer cells in vitro and in vivo. In this paper, we report the combined effect of MS-209 with docetaxel in various MDR cancer cell lines that express P-gp. MS-209 at 3 microM effectively overcame docetaxel resistance in MDR cancer cells, and this concentration was achieved in blood plasma for > 7 h without serious toxicity. To study the effect of MS-209 in a clinically relevant model, we compared the antitumor efficacy of docetaxel alone with that of docetaxel combined with MS-209 at equitoxic doses in established solid tumor xenograft models. Treatment with docetaxel alone at the maximal tolerated dose (MTD) showed an apparent antitumor activity to an intrinsically resistant HCT-15 tumor xenograft, and MS-209 additionally potentiated the antitumor activity of docetaxel. Against a MCF-7/ADM tumor xenograft expressing larger amounts of P-gp, docetaxel alone at the MTD showed no antitumor activity, whereas the MTD of docetaxel combined with MS-209 greatly reduced MCF-7/ADM tumor growth. These results indicate that MS-209 could be a clinically useful drug to modulate MDR in docetaxel therapy.