P-gp 、GST-Л、p53 和CD44v6 在肺癌中的表达

 目的探讨多药耐药基因（MDR）产物P-糖蛋白（P-gp）、谷胱甘肽-S-转移酶π（GST-π）及p53、CD44V6在肺癌组织中的表达及其相互关系。方法采用免疫组化SP方法检测60例肺癌组织中p-gP、GST-π和p53、CD44v6的表达情况。结果①肺癌组织中P-gp、GST-π阳性表达率分别为63．3％、66．7％。GST-π和P-gp在非小细胞肺癌（NSCLC）中的表达率分别为69．8％和73．6％，在小细胞肺癌（SCLC）的阳性表达率均为14．3％，两者比较均有显著性差异（P〈0．05，P〈0．01）。GST-π和P-gp在肺腺癌中的表达明显高于肺鳞癌和小细胞癌组（P〈0．05，P〈0．01）②CD44v6在肺癌的阳性表达率为65．0％，在有淋巴结转移组的表达明显高于无淋巴结转移组（P〈0．05）。③P-gp和GST-π在肺癌中的共表达率为41．7％，P-gp表达和GST-π表达呈正相关性（P〈0．05）。P-gp和p53在肺癌中的共表达率为48．3％，P-gp表达和p53表达呈显著正相关性（P〈0．01）。结论P—gp、GST—π和p53在肺癌组织中的表达对肿瘤的耐药起重要作用，CD44v6是预测肺癌侵袭转移及估计预后的一个重要指标。     

P-gp、GST—π、p53和CD44v6在肺癌中的表达

目的探讨多药耐药基因（MDR）产物P-糖蛋白（P-gp）、谷胱甘肽-S-转移酶π（GST-π）及p53、CD44V6在肺癌组织中的表达及其相互关系。方法采用免疫组化SP方法检测60例肺癌组织中p-gP、GST-π和p53、CD44v6的表达情况。结果①肺癌组织中P-gp、GST-π阳性表达率分别为63．3％、66．7％。GST-π和P-gp在非小细胞肺癌（NSCLC）中的表达率分别为69．8％和73．6％，在小细胞肺癌（SCLC）的阳性表达率均为14．3％，两者比较均有显著性差异（P〈0．05，P〈0．01）。GST-π和P-gp在肺腺癌中的表达明显高于肺鳞癌和小细胞癌组（P〈0．05，P〈0．01）②CD44v6在肺癌的阳性表达率为65．0％，在有淋巴结转移组的表达明显高于无淋巴结转移组（P〈0．05）。③P-gp和GST-π在肺癌中的共表达率为41．7％，P-gp表达和GST-π表达呈正相关性（P〈0．05）。P-gp和p53在肺癌中的共表达率为48．3％，P-gp表达和p53表达呈显著正相关性（P〈0．01）。结论P—gp、GST—π和p53在肺癌组织中的表达对肿瘤的耐药起重要作用，CD44v6是预测肺癌侵袭转移及估计预后的一个重要指标。     

P-gp、GST-π、Topo-Ⅱ在宫颈癌组织中的表达及意义

目的探讨P-糖蛋白（P-gp）、谷胱甘肽S-转移酶-π（GST-π）和DNA拓扑异构酶Ⅱ（TopoⅡ）在宫颈癌组织中的表达及其临床意义。方法采用免疫组化方法检测20例正常宫颈、30例宫颈上皮内瘤变（CIN）、60例初治宫颈癌及10例复发宫颈癌组织中P-gp、GST-π、TopoⅡ的表达，分析P-gp、GST-π、Topo-Ⅱ的表达与宫颈癌患者临床病理特征及3年生存率之间的关系。结果 ①P-gp、GST-π、Topo-Ⅱ在正常宫颈、CIN、初治宫颈癌及复发宫颈癌组织中均有表达，表达强弱顺序依次为：复发宫颈癌〉初治宫颈癌〉CIN〉正常宫颈。②宫颈癌组织中存在3种耐药蛋白的共表达，P-gp与、GST-π、Topo-Ⅱ的表达呈正相关（P〈0．05）；GST-π与Topo-Ⅱ的表达无显著性相关（P〉0．05）。P-gp、GST-π与初治宫颈癌临床分期，组织学类型和病理分级无关（P〉0．05）；TopoⅡ在宫颈腺癌中的表达水平明显低于鳞癌（P〈0．05）。④P-gp、GST-π、Topo-Ⅱ低表达者3年生存率优于高表达者，差别有统计学意义（P〈0，05）；TopoII低表达者与高表达者3年生存率差别无统计学意义（P〉0．05）。结论P-gp、GST-π、Topo-Ⅱ可能与宫颈癌的发生发展相关。P-gp、GST-π、Topo-Ⅱ表达强度的增加不仅可为宫颈癌化疗用药提供参考，而且可作为宫颈癌判断预后的指标。     

人肺癌细胞株化疗敏感性与基因表达的关系

目的探讨人肺癌细胞株对化疗药物的敏感性与多药耐药相关基因和凋亡调控基因表达的关系。方法采用MTT法检测5株肺癌细胞SPCA1、NCI-H446、SH-77、95C和95D对阿霉素(ADM)、顺铂(DDP)、丝裂霉素(MMC)、5-氟尿嘧啶(5-Fu)、卡氮芥(BCNU)的敏感性。流式细胞术检测多药耐药基因P-糖蛋白(P-gp)、谷胱甘肽-S-转移酶-π(GST-π)、肺耐药蛋白(LRP)、多药耐药相关蛋白(MRP)和甲基鸟嘌呤甲基转移酶(MGMT)等耐药相关基因和Fas、bcl-2、p53和p16等凋亡调控基因的表达。结果不同肺癌细胞株对同一药物敏感性有较大差异。相关分析显示,肺癌细胞株对MMC的敏感性与GST-π和bcl-2的表达呈负相关,P值分别为0.040和0.030,GST-π和bcl-2的表达水平较高者,MMC的IC50较高,敏感性较低;对DDP的敏感性与p53蛋白表达水平呈负相关(P=0.036);对其余药物的敏感性与所检基因的表达水平无关(P>0.05)。结论人肺癌细胞株对不同化疗药物敏感与否有不同的机制,对MMC的敏感性与GST-π和bcl-2的表达有关,对DDP的敏感性与p53的表达有关。     

24例原发性肝癌患者的肿瘤药敏结果分析

目的通过测定原发性肝癌患者对5-氟脲嘧啶(5-Fu)、顺铂(DDP)、阿霉素(ADM)、丝裂霉素(MMC)、氨甲喋呤(MTX)、长春新碱(VCR)6种化疗药物的体外敏感性试验,探讨肿瘤药敏试验对原发性肝癌个体化疗的应用价值。方法采用组织块培养-终点染色-计算机图像分析法(TECIA)。结果24例原发性肝癌细胞对6种化疗药物的敏感性由高到低依次为5-Fu、MMC、DDP、ADM、MTX、VCR。结论TECIA法的体外肿瘤药敏试验在原发性肝癌的临床用药及个体化化疗方面具有重要的指导意义。     

胆囊和胆管癌组织中多药耐药相关蛋白和GST-π的表达及意义

背景与目的：多药耐药性（MDR）被认为是导致胆囊癌和胆管癌化疗疗效不佳的主要原因，本实验通过免疫组织化学的方法检测胆囊癌、胆管癌组织中MRP1、MRP2和谷胱甘肽S-转移酶-π（GST-π）的表达情况，并探讨其与耐药的关系。方法：采用免疫组化的方法（IHC）检测复旦大学附属中山医院普外科自2000年2月—2006年11月收治的并行手术切除的18例胆囊癌和36例胆管癌中MRP1、MRP2及GST-π的表达情况，并以胆囊炎和胆管炎13例为对照。结果：MRP1、MRP2和GST-π在胆囊癌组织中的表达阳性率分别72．2％、72．2％和61．1％，在胆管癌组织中的表达阳性率为86．1％、80．6％和69．4％，显著高于对照组的23．1％、15．4％和23．1％（P〈0．05）。上述指标与性别、年龄、病理分期、病理类型、分化程度淋巴结转移均无关（P〉0．05）；MRP1和GST-π、MRP2在胆囊癌和胆管癌的表达具有相关性（P〈0．05）。结论：MRP1、MRP2、GST-π在未经过化疗的胆囊癌和胆管癌组织中均有不同程度的高表达；胆囊癌和胆管癌的原发性多药耐药可能与MRP1、MRP2、GST-π有关。     

非小细胞肺癌多药耐药性病理学检测的临床意义

 目的 检测113例非小细胞肺癌（NSCLC）中谷胱甘肽巯基转移酶π（GST-π）、肺耐药相关蛋白（LRP）、DNA拓扑异构酶Ⅱa（TopoⅡa）、多药耐药相关蛋白（MRP）和多药耐药基因（MDRt）的表达，观察上述指标与肿瘤I临床病理因素的关系及各指标表达之间的相关性。方法 采用免疫组化SP法检测GST-π、LRP、TopoⅡa蛋白的表达；应用原位杂交技术检测MRP和MDR1 mRNA表达。结果 （1）GST-π、LRP、TopoⅡa蛋白及MRP、MDR1 mRNA在113例NSCLC中的阳性表达率分别为75.2％、80．5％、60．2％、79．6％、51．3％。其中LRP表达最高，MDR1表达最低。（2）LRP、TopoⅡa和MRP的表达分别与肿瘤组织学类型有关。（3）GST-π与MRP（P〈0．05）、LRP与MRP（P〈0．01）、MDR，与MRP（P〈0．01）的表达间具有相关性。结论 （1）多种耐药相关基因的过度表达及其相互作用可能是NSCLC产生原发MDR的重要原因。（2）LRP和MRP过度表达，TopoⅡa高表达和MRP低表达可能分别与肺腺癌、鳞癌的化疗敏感性有关。     

特异性核酶增强宫颈癌细胞对多种化疗药物的敏感度研究

目的研究抗HPV16E6核酶（Ribozyme）在宫颈癌CaSKi细胞对多种化疗药物在体内外敏感度的影响。方法以脂质体法将抗HPV16E6-Ribozyme、空载体质粒分别导入CaSKi细胞,命名为CaSKi、CaSKi-R、CaSKi-P细胞。MTT敏感实验检测多种化疗药物对三种细胞的抑制率;建立三种宫颈癌细胞移植瘤裸鼠模型,检测顺铂(DDP)对其抑制作用;透射电镜观察顺铂作用后的三种细胞形态。结果与CaSKi-P、CaSKi细胞比较,DDP、VCR、5-Fu、MMC对 CaSKi-R细胞的抑制率明显增加（P<005）,CaSKi-R细胞对 DDP、VCR、5-Fu、MMC的敏感度明显增加; ADM、MTX、INF、Taxol、Ara-C、CTX对 CaSKi-R细胞的抑制率无明显变化（P>0.05）,敏感度无明显变化;顺铂作用后CaSKi-R、CaSKi-P和CaSKi细胞裸鼠移植瘤的重量分别为（0.09±0.03）g、（0.26±0.07）g和（0.26±0.05）g（P＜005）,抑制率分别为81.63%、62.32%和63.38%;顺铂作用后CaSKi-R细胞出现明显的凋亡改变, 而CaSKi、CaSKi-P细胞不明显。结论抗HPV16E6-Ribozyme增加了CaSKi细胞对DDP、VCR、5-Fu、MMC的敏感度,抑制了宫颈癌细胞裸鼠移植瘤的生长并增加对DDP的敏感度。     

肝癌体外药物敏感性试验

目的 通过测定肝癌对阿霉素（ADM）、顺铂（DDP）、氟尿嘧啶（FU）、长春新碱（VCR）、丝裂霉素C（MMC）及噻替哌（TSPA）的体外药物敏感性，为肝癌化疗用药提供参考依据。方法 采用滤纸支持组织块培养－MTT终点－计算机图像分析体外药物敏感性试验法。结果 在1倍血浆峰浓度（1 PPC）时作用最强的药物为MMC，其抑制率中位数（MIR）为26．5％，其次是ADM为13．0％，DDP、TSPA、5－FU和VCR为4．0－8．5％。在5倍血浆峰浓度（5PPC）时作用最强的药物亦为MMC，其MIR为92．0％，次为ADM、DDP和TSPA为41－50％，5－FU和VCR为16．0－17．0％，DDP和TSPA在5PPC的MIR比在1PPC时大5．0和5．8倍以上，MMC、ADM帮VCR则大2－3．5倍，5－FU只增大1倍左右。结论 结果提示MMC对肝癌抑制作用较强，DDP和TSPA剂量增加与疗效提高可能有较大的关系。天然来源的药物ADM、MMC和VCR之间，无论在1PPC或5PPC水平，其相关系数均较大（r=0.5539-0.7208)，表明部分肝癌具有多药耐药性。     

P-gp和GSTπ对结直肠癌埋植式给药装置化疗的指导作用

 目的 探索耐药标记P-gp和GSTπ对结直肠癌埋植式给药装置化疗的指导作用。方法 研究对象为近3年来经结直肠镜活检确诊为结直肠腺癌患者，并按根治术标准宽切病灶，选择相应供血动脉插管，接埋植式给药装置（药壶，IDDS）埋植于皮下。标本用SP法检测P-gp和GSTπ的表达并按结果采用推荐方案P-gp+／GSTπ-：A（即5-Fu，DDP）；P-gp-／GSTπ+：B（即VCR，HCPT）；P-gp+／GSTπ+：C（即5-Fu，HCPT）；P-gp-／GSTπ-：D（即VCR，DDP）；化疗药均经术中留置的IDDS施药；给药剂量为5-Fu 500 mg，DDP 50 mg，VCR 2 mg，HCPT 4 mg。观察记录疗效及毒副反应、随访结果。结果 初治有效率（CR+PR）93.5 %（29／31例）；随访3年生存率为93.5 %，PD2例：1例9个月后黏液腺癌腹壁转移，腹腔积液1 000 ml中查见转移癌细胞后改造瘘术；1例1年后出现肝、腰椎、肺广泛转移；2例均死于衰竭。结论 P-gp和GSTπ对结直肠癌埋植式给药装置化疗具指导意义，可提高疗效及3年生存率并降低毒副反应。     

P糖蛋白、谷胱甘肽-S-转移酶和拓扑异构酶Ⅱ在胃癌组织中的表达

背景与目的:P糖蛋白(P-gp)、谷胱甘肽-S-转移酶(GST-π)和拓扑异构酶Ⅱ(Topo-Ⅱ)等多种细胞内物质是恶性肿瘤产生多药耐药的物质基础,胃癌是比较常见的恶性肿瘤,应用免疫组化方法检测化疗前P-gp、GST-π和Topo-Ⅱ三因素在胃癌中表达的报告还比较少,为此,本文检测P-糖蛋白(P-gp)、谷胱甘肽-S-转移酶(GST-π)和拓扑异构酶II(Topo-Ⅱ)在胃癌组织中的表达,探讨其与胃癌分化、转移的关系。方法:应用免疫组化方法,检测75例术前未进行化疗的胃癌患者癌组织中P-gp、GST-π和Topo-Ⅱ的表达。结果:P-gp、GST-π及Topo-Ⅱ在75例胃癌组织中表达率分别为76.0%、85.3%和68.0%,与患者的年龄、性别、肿瘤发生部位及浸润深度无关,其在胃癌组织中的表达管状腺癌分别与粘液腺癌、印戒细胞癌及未分化癌比较差异均有显著性(P<0.05)。P-gp、GST-π高表达及Topo-Ⅱ低表达与其淋巴结转移有显著相关性。结论:P-gp、GST-π及Topo-Ⅱ的表达与胃癌组织类型有关,其表达可能还与胃癌细胞的分化、转移有关。     

化疗药物杀伤原代胃癌细胞效应与P-糖蛋白和GST-π表达的关系

背景与目的:化疗耐药是影响进展期胃癌疗效的主要原因之一。本研究旨在评价不同化疗药物对原代胃癌细胞的体外杀伤效应及其诱导凋亡能力,同时研究上述效应与胃癌组织P鄄糖蛋白(P鄄gp)和谷胱甘肽S转移酶π(GST鄄π)表达的关系。方法:39例分离纯化后的人新鲜胃癌细胞,分别暴露于血浆峰浓度的5鄄氟尿嘧啶(5鄄FU)、顺铂(DDP)、丝裂霉素(MMC)、阿霉素(ADM)及羟基喜树碱(HCPT)。用台盼蓝染色法和MTT法检测经上述药物作用后肿瘤细胞活力及代谢活性的变化;用原位末端转移酶标记法(TdT法)检测胃癌细胞凋亡率;并用免疫组化染色检测胃癌组织中GST鄄π和P鄄gp的表达。结果:经化疗药物作用后,体外培养的胃癌细胞出现不同程度的形态学改变、代谢活性下降及细胞凋亡。不同个体肿瘤细胞对不同化疗药物的敏感性不同。MTT结果提示,所测药物对胃癌细胞的平均抑制率由高到低依次为MMC[(38.6±7.7)%],DDP[(38.1±8.8)%],5鄄FU[(37.8±10.3)%],ADM[(31.9±10.4)%],HCPT[(29.9±10.2)%]。MMC、DDP及5鄄FU的平均抑制率明显高于HCPT及ADM(P<0.01)。TdT结果提示,诱导胃癌细胞凋亡率由高到低的药物依次为DDP[(32.1±7.7)%],5鄄FU[(31.1±8.8)%],MMC[(29.8±6.3)%],HCPT[(21.9±7.4)%],ADM[(19.9±7.4)%]。本组病例GST鄄π和P鄄gp的     

多药耐药基因产物表达和细胞凋亡对胃癌影响的研究

目的　探讨多药耐药 (MDR)基因产物和细胞凋亡指数 (AI)表达与胃癌分型、分期、预后的关系。方法　应用免疫组化及原位末端标记法 (TUNEL) ,对 80例胃癌标本进行MDR指标 (P gp、GST π、TOPOⅡ )及AI检测。结果　P gp表达与临床分期有关 (P <0 .0 5 ) ,正常组织P gp表达高者生存期长 (P <0 .0 5 ) ;GST π表达强度与预后有关 ,高表达者生存期短 (P <0 .0 5 ) ;TOPOⅡ表达与分型有关 (P <0 .0 5 ) ,低分化癌表达高于高中分化癌 ;凋亡指数表达与临床分期有关 (P <0 .0 5 ) ,高表达者其临床分期越晚。结论　MDR与细胞凋亡都属细胞正常基因组表达的一部分 ,在正常组织及癌组织均可有表达。正常组织P gp、GST π的表达与预后有关 ,不同生存期的MDR与细胞凋亡表达差异无显著性 (P >0 .0 5 ) ,但MDR与AI的表达与胃癌的生物学行为有关     

卵巢癌中P-gp与GST-π的表达对化疗耐药的预测价值

目的 探讨卵巢癌内在性的耐药机制及其对化疗反应的影响。方法 运用免疫组织化学方法对74例术前未经治疗的上皮性卵巢癌进行P－糖蛋白（P-gp)与谷胱甘肽S－转移酶－π（GST－π）检测。结果（1）30例正常卵巢组织中,P－gp与GST－π染色无一例阳性;而74例卵巢癌组织中,P－gp阳性者为14例（18．9％）,GST－π阳性者为55例（74．3％）,这两种指标的表达具有显著的相关性（P＜0．01）。（2）P－gp与GST－π的表达与临床分期、组织学类型及细胞分级等临床病理参数均无相关性（P均＞0．05）。（3）对首次术后有残余病变的27例患者进行化疗评价,P－pg阳性组与阴性组对化疗的反应率为0及57．1%,GST－π阳性组与阴性组对化疗的反应率为13．3％和83．3％,两组比较,差异有显著性（P＜0．01）。GST－π阳性对耐药的预测值为86．7％,GST－π阴性对化疗反应的预测值为83．3％。（4）P－gp与GST－π阳性组的生存率也显著低于阴性组（P＜0．01,P＜0．05）。结论 术前未经治疗的卵巢癌中有一定程度上存在着由P－gp与GST－π介导的内在性的耐药机制,P－gp与GST－π的表达能较好地预测化疗反应及耐药,对预后也有一定的判断价值。     

A new quinoline derivative MS-209 reverses multidrug resistance and inhibits multiorgan metastases by P-glycoprotein-expressing human small cell lung cancer cells.

Development of distant metastases and acquired multidrug resistance (MDR) are major problems in therapy for human small cell lung cancer (SCLC). MS-209 is a novel quinoline compound, which reverses P-glycoprotein (P-gp)-mediated MDR. We previously reported that MS-209 reversed in vitro MDR of human SCLC (SBC-3 / ADM and H69 / VP) cells expressing P-gp. In the present study, we determined the therapeutic effect of MS-209 in combination with chemotherapy against multiorgan metastases of MDR SCLC cells. SBC-3 / ADM cells expressing P-gp were highly resistant to etoposide (VP-16), adriamycin (ADM), and vincristine (VCR) in vitro, compared with parental SBC-3 cells lacking P-gp expression. MS-209 restored chemosensitivity of SBC-3 / ADM cells to VP-16, ADM, and VCR in a dose-dependent manner in vitro. Intravenous injection with SBC-3 or SBC-3 / ADM cells produced metastatic colonies in the liver, kidneys and lymph nodes in natural killer (NK) cell-depleted severe combined immunodeficiency (SCID) mice, though SBC-3 / ADM cells more rapidly produced metastases than did SBC-3 cells. Treatment with VP-16 and ADM reduced metastasis formation by SBC-3 cells, whereas the same treatment did not affect metastasis by SBC-3 / ADM cells. Although MS-209 alone had no effect on metastasis by SBC-3 or SBC-3 / ADM cells, combined use of MS-209 with VP-16 or ADM resulted in marked inhibition of metastasis formation by SBC-3 / ADM cells to multiple organs. These findings suggest that MS-209 reversed the MDR of SBC-3 / ADM cells, but not SBC-3 cells, growing in the various organs, and inhibited metastasis formation in vivo. Therefore, this chemosensitizing agent, MS-209, may be useful for treatment of refractory SCLC patients with multiorgan metastases.     

A New Quinoline Derivative MS-209 Reverses Multidrug Resistance and Inhibits Multiorgan Metastases by P-glycoprotein-expressing Human Small Cell Lung Cancer Cells

Development of distant metastases and acquired multidrug resistance (MDR) are major problems in therapy for human small cell lung cancer (SCLC). MS-209 is a novel quinoline compound, which reverses P-glycoprotein (P-gp)-mediated MDR. We previously reported that MS-209 reversed in vitro MDR of human SCLC (SBC-3/ADM and H69/VP) cells expressing P-gp. In the present study, we determined the therapeutic effect of MS-209 in combination with chemotherapy against multiorgan metastases of MDR SCLC cells. SBC-3/ADM cells expressing P-gp were highly resistant to etoposide (VP-16), adriamycin (ADM), and vincristine (VCR) in vitro , compared with parental SBC-3 cells lacking P-gp expression. MS-209 restored chemosensitivity of SBC-3/ADM cells to VP-16, ADM, and VCR in a dose-dependent manner in vitro. Intravenous injection with SBC-3 or SBC-3/ADM cells produced metastatic colonies in the liver, kidneys and lymph nodes in natural killer (NK) cell-depleted severe combined immunodeficiency (SCID) mice, though SBC-3/ ADM cells more rapidly produced metastases than did SBC-3 cells. Treatment with VP-16 and ADM reduced metastasis formation by SBC-3 cells, whereas the same treatment did not affect metastasis by SBC-3/ADM cells. Although MS-209 alone had no effect on metastasis by SBC-3 or SBC-3/ADM cells, combined use of MS-209 with VP-16 or ADM resulted in marked inhibition of metastasis formation by SBC-3/ADM cells to multiple organs. These findings suggest that MS-209 reversed the MDR of SBC-3/ADM cells, but not SBC-3 cells, growing in the various organs, and inhibited metastasis formation in vivo. Therefore, this chemosensitizing agent, MS-209, may be useful for treatment of refractory SCLC patients with multiorgan metastases.     

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.     

Circumvention of multidrug resistance by a quinoline derivative, MS-209, in multidrug-resistant human small-cell lung cancer cells and its synergistic interaction with cyclosporin A or verapamil

Purpose and methods: To develop a clinically useful approach to circumvent P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in MDR human small-cell lung cancer (SCLC), we examined the ability of a novel quinoline compound, MS-209, to reverse MDR by inhibition of P-gp function in combination with other MDR-reversing drugs using a cytotoxicity assay. Results: We established MDR human SCLC cells by culture in medium with gradually increasing concentrations of adriamycin (ADM). Compared with the parental human SCLC cells, SBC-3, the MDR variant SBC-3 cells obtained (SBC-3/ADM) were highly resistant to various chemotherapeutic agents due to P-gp expression. MS-209 reversed the resistance to ADM and vincristine (VCR) of SBC-3/ADM and H69/VP cells in a dose-dependent manner. Moreover, MS-209 in combination with cyclosporin A (CsA) or verapamil (VER) synergistically enhanced the antitumor effects of ADM and VCR on SBC-3/ADM cells. MS-209 restored ADM incorporation and this effect was enhanced by CsA and VER, suggesting that these synergistic effects were due to competitive inhibition of P-gp function. Conclusion: MS-209 in combination with CsA or VER might increase the efficacy of these chemotherapeutic agents against MDR human SCLC cells. Received: 10 December 1997 / Accepted: 16 April 1998     

Expression of MDR1, GST-pi and topoisomerase II as an indicator of clinical response to adriamycin.

The usefulness of MDR1, GST-pi or topoisomerase II mRNA expression detected by dot blot analysis as an indicator of intrinsic resistance to adriamycin was investigated in 15 fresh human tumor specimens. MDR1 and GST-pi expression, which is known to be a marker for adriamycin resistance, was detected in six (66.7%) and seven (77.8%) of the nine clinically resistant tumors, respectively. However, in four of the six adriamycin responsive tumors, MDR1 and/or GST-pi expression were detected. Thus these two markers were not indicators of clinical response to adriamycin. In contrast, topoisomerase II mRNA expression was significantly correlated with clinical response (p less than 0.01, chi 2 test). The expression of topoisomerase II mRNA was detected at a high level in five (83.3%) of the 6 clinically responsive tumors, and the other nine tumors resistant to adriamycin treatment exhibited undetectable or low levels of topoisomerase II mRNA. We therefore suggest that the level of topoisomerase II mRNA expression is a useful marker of the clinical response to adriamycin.