肺癌组织中耐药相关蛋白和p53 bcl-2表达及其意义

目的:探讨肺癌组织中耐药相关蛋白和p53、bcl-2表达及其意义.方法:应用免疫组化技术检测治疗前73例肺癌组织标本中P-gp、MRP、LRP、GST-π、p53和bcl-2表达.结果:非小细胞肺癌组P-gp、LRP、MRP LRP、P-gp p53的蛋白表达明显高于小细胞肺癌组(P＜0.05).腺癌组MRP、LRP、MRP LRP、MRP LRP GST-π、MRP LRP P-gp GST-π蛋白阳性表达高于鳞状细胞癌组、小细胞肺癌组(P＜0.05),MRP GST-π共表达者高于鳞状细胞癌组(P＜0.01),P-gp-p53共表达者高于小细胞肺癌组(P＜0.05),bcl-2蛋白阳性表达低于鳞状细胞癌组、小细胞肺癌组(P＜0.05).鳞状细胞癌组P-gp、P-gp p53、P-gp bcl-2的蛋白表达明显高于小细胞肺癌组(P＜0.05).P-gp与p53、bcl-2蛋白阳性表达呈正相关(P＜0.05).p53与bcl-2蛋白阳性表达呈正相关(P＜0.01).MRP与GST-π蛋白阳性表达呈正相关(P＜0.05).结论:肺癌耐药为一多途径多基因参与的过程,P-gp、LRP、MRP、GST-π、p53、bcl-2表达及其共表达可作为监测肺癌细胞原发性耐药的指标.     

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。     

鲎素抑制多药耐药细胞HL-60/VCR生长的研究

目的：探讨鲎血细胞来源的多肽鲎素是否能够抑制白血病多药耐药细胞HL-60／VCR细胞的生长。方法：HL-60细胞采用持续低浓度和逐渐增加长春新碱（VCR）浓度间歇诱导，建立多药耐药细胞HL-60／VCR；MTT法检测细胞耐药性及鲎素对HL-60／VCR细胞和HL-60细胞生长的影响；流式细胞仪检测HL-60／VCR细胞P-糖蛋白（P-glycoprotein，P-gP）和多药耐药相关蛋白（multidrugresistance-associatedprotein，MRP）的表达水平。结果：HL~0／VCR细胞对多种化疗药物产生耐药；HL-60／VCR细胞表面P-gP、MRP表达上调，分别为78．3％和58．3％（P〈0．01）。鲎素无论对HL-60／VCR细胞还是对HL-60细胞均有抑制作用，作用呈剂量依赖性。HL-60／VCR细胞和HL-60细胞对鲎素具有相似的敏感性。鲎素能增强HL-60／VCR细胞对VCR的敏感性，但不影响HL-60／VCR细胞表达P-gP和MRP。结论：鲎素具有抗HL-60／VCR细胞耐药性并增加其对VCR敏感性的作用。     

耐药相关基因在非小细胞肺癌组织中的表达及其意义

目的:探讨耐药相关基因在非小细胞肺癌(NSCLC)组织中的表达及其临床意义.方法:应用免疫组化技术检测治疗前肺癌组织标本中P-gp、MRP、LRP、GST-π和TopoⅡ表达.结果:58例治疗前NSCLC中P-gp、MRP、LRP、GST-π和TopoⅡ阳性率分别为96.55%,67.24%,75.86%,65.52%,98.28%,并有部分共表达.癌旁正常肺组织呈阴性或弱阳性表达.性别、有无吸烟史、有无淋巴结转移及在TNM各分期中P-gp、MRP、LRP、GST-π和TopoⅡ阳性表达无明显差异(P＞0.05).比较腺癌组与鳞癌组,MRP、LRP、GST-π阳性表达有显著性差异(P＜0.05),而P-gp、TopoⅡ阳性表达无明显差异(P＞0.05);MRP、LRP、P-gp、GST-π共表达有显著性差异(χ2=21.662,P＜0.001);低分化腺癌、鳞癌与中、高分化腺癌、鳞癌P-gp、MRP、LRP、GST-π和TopoⅡ阳性表达无明显差异(P＞0.05).结论:肺癌耐药为一多途径多基因参与的过程,肺腺癌原发的多药耐药机率较肺鳞癌高,联合检测肺癌组织中耐药相关基因的表达有助于判断化疗疗效及预后.     

乳腺癌组织耐药相关蛋白的表达及其临床意义

目的:探讨乳腺癌组织耐药相关基因表达及其与临床病理学因素之间的关系。方法:应用流式细胞术检测多药耐药蛋白P-糖蛋白(P-gP)、谷胱苷肽-S-转移酶(GST-π)、肺耐药蛋白(LRP)、多药耐药相关蛋白(MRP)和O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)在64例乳腺癌组织中的表达情况,分析其与患者临床分期、年龄、肿瘤大小、腋窝淋巴结转移、雌孕激素受体(ER、PR)表达状态等因素的关系及5种耐药基因间的相关性。结果:P-gp、GST-π、LRP、MGMT和MRP在原发性乳腺癌组织中均有一定水平表达,P-gp和GST-π的表达与腋窝淋巴结转移有关(P值分别为0.007和0.031),MG-MT的表达在年龄<50岁组明显升高,P=0.018。GST-π、MRP和MGMT的表达在肿瘤体积较大组中明显升高(P值分别为0.042、0.000和0.015),5种耐药基因的表达与ER、PR表达相关差异均无统计学意义,P>0.05。乳腺癌组织中各耐药基因之间存在共表达现象,P-gp和GST-π的表达及LRP与MRP的表达均存在正相关性(r=0.66,P=0.000;r=0.434,P=0.004)。结论:乳腺癌组织中耐药蛋白的表达与患者肿瘤体积、年龄、淋巴结转移状况有关,耐药蛋白高表达,均提示为乳腺癌的不良预后指标。乳腺癌组织中各耐药蛋白之间存在共表达现象。     

P-gp、bcl-2蛋白表达在人红白血病多药耐药现象中的意义

目的：探讨P-gp、bcl-2蛋白在人红白血病多药耐药中的作用。方法：用MTT法、原位末端转移酶标记法、流式细胞术等分别对蝎毒诱导人红白血病耐药细胞株(K562／ADM)及敏感细胞株(K562)凋亡及其P-gp、bcl-2蛋白表达进行研究。结果：蝎毒可明显抑制K562及K562／ADM细胞生长和诱导细胞凋亡(P＜0.05，P＜0.01)，其作用强度在一定范围内呈现对浓度的依赖性；耐药细胞株中P-gp、bcl-2蛋白表达明显强于敏感细胞株；蝎毒可抑制K562／ADM细胞中P-gp、bcl-2蛋白表达。结论：凋亡抑制基因bcl-2编码蛋白的过度表达可能是人红白血病多药耐药细胞凋亡耐受的分子基础，细胞凋亡与肿瘤细胞的耐药密切相关。     

乳腺癌组织中多药耐药相关蛋白的表达及其临床意义

目的：探讨P-gp、LRP、GST-π和Topo-Ⅱ在乳腺癌组织中的表达及术前化疗对乳腺癌多药耐药的影响和临床意义.方法：采用免疫组织化学SP法,对18例术前曾用化疗和70例术前未用化疗的88例乳腺癌组织检测P-gp、LRP、GST-π和Topo-Ⅱ的表达.结果：88例乳腺癌中P-gp、LRP、GST-π和Topo-Ⅱ的阳性率分别为42.0%、53.4%、48.9%和40.9%.术前应用化疗的的患者癌组织P-gp、LRP和GST-π三者阳性表达率均较未用化疗的患者高,P-gp和LRP差异有统计学意义（P＜0.05）,而GST-π差异无统计学意义,P＞0.05.Topo-Ⅱ有化疗史的患者比无化疗史的患者低,但差异无统计学意义,P＞0.05.结论：P-gp、LRP、GST-π和Topo-Ⅱ的耐药机制各不相同,同时检测P-gp、LRP、GST-π和Topo-Ⅱ等多种导致多药耐药的因素,对乳腺癌化疗有重要的指导意义.     

非小细胞肺癌P-gp、LRP、MRP和GST-π表达及其临床意义

目的:探讨P-糖蛋白(P-gp)、肺耐药蛋白(LRP)、多药耐药相关蛋白(MRP)和谷光甘肽转移酶(GST-π)在非小细胞肺癌(NSCLC)中的表达及其临床意义.方法:应用免疫组织化学S-P技术对86例治疗前非小细胞肺癌组织标本进行P-gp、LRP、MRP和GST-π表达的检测.结果: LRP和MRP在肺腺癌、鳞癌中的表达阳性率分别为77.78%、51.22%和80.00%、53.66%;LRP和MRP在不同组织类型中的表达有显著性差异(均P<0.05).P-gp和GST-π在肺腺癌和鳞癌中的表达阳性率分别为73.33% 、60.98%和80.00%、70.73%;P-gp和GST-π在不同组织类型中的表达无显著性差异(均P>0.05).所测4种耐药基因除P-gp外其余3种在中高分化和低分化组间表达阳性率有显著性差异(均P<0.01);4种耐药基因在TNM各分期中表达阳性率无显著性差异(均P>0.05).在肺腺癌和肺鳞癌中同时有2种、3种或4种耐药基因协同表达的阳性率分别为46.67%和34.15%、31.11%和24.39%、20.00%和17.07%,在肺腺癌和肺鳞癌中耐药基因共表达在各类型间无显著性差异(均P>0.05).结论:在非小细胞肺癌组织中存在不同程度的耐药,肺腺癌原发耐药高于肺鳞癌,其耐药是多途径多基因参与的过程.联合检测P-gp、LRP、MRP和GST-π耐药相关基因的表达,对化疗药物的选择及预后的评价具有重要的临床意义.     

肺癌组织细胞凋亡相关基因与多药耐药基因表达的相关性及其临床意义

背景与目的肺癌耐药机制复杂,除多种耐药基因参与形成外,细胞凋亡相关基因的表达异常与肺癌耐药的产生也存在密切联系。本研究旨在探讨肺癌组织中细胞凋亡相关基因产物P53、Bcl-2表达与患者临床病理特征的关系,以及与多药耐药因子肺耐药蛋白（LRP）、P-糖蛋白（P-gp）、谷胱甘肽-S转移酶π（GST-π）、拓扑异构酶Ⅱ（TopoⅡ）、多药耐药相关蛋白（MRP）表达的相关性及其临床意义。方法采用微波Envision免疫组化法检测68例（Bcl-2为51例）肺癌患者癌组织中两种细胞凋亡相关基因产物突变型P53、Bcl-2及5种多药耐药因子LRP、P-gp、GST-π、Topo Ⅱ、MRP的表达水平。结果P53、Bcl-2在肺癌组织中的阳性表达率分别为75.0%、33.3%。非小细胞肺癌与小细胞肺癌间及不同细胞分化程度间P53表达的差异有统计学意义（P=0.001,P=0.003）。鳞癌与腺癌间Bcl-2表达差异有统计学意义（P=0.002）。P53与Bcl-2间表达无相关性（P〉0.05）。P53与P-gp、P53与GST-π的表达均呈正相关（P=0.002,P=0.017）,共表达率分别为70.6%、47.1%。Bcl-2与各多药耐药因子间的表达均无相关性（P〉0.05）。结论细胞凋亡相关基因与多药耐药基因在肺癌多药耐药的形成中可能有明显协同作用。联合检测细胞凋亡相关基因及多药耐药基因对肺癌耐药的预测和预后判断可能具有一定的临床意义。     

水杨酸钠对HL—60／VCR细胞多药耐药的部分逆转

目的：研究水杨酸钠(Na-Sal对HL-60／VCR细胞多药耐药的部分逆转作用。方法：采用噻唑蓝(MTT)法、流式细胞术等方法，观察非甾体抗炎药Na-Sal对HL-60／VCR细胞多药耐药的部分逆转作用。结果：Na-Sal对HL-60／VCR细胞的生长具有抑制作用并表现出剂量依赖性，1mmol/L的非细胞毒剂量的Na-Sal和化疗药物联合应用可以提高多种化疗药物的细胞毒性作用，逆转倍数为1．01-3．26，相对逆转效率为0．52％-73．62％。流式细胞仪测定细胞内柔红霉素(DNR)浓度发现，Na-Sal并不增加HL-60／VCR细胞内DNR浓度。结论：Na-Sal能有效地部分逆转HL-60／VCR细胞的多药耐药性。     

Bcl-2, bax and bcl-xL expression in human sensitive and resistant leukemia cell lines.

With the growing understanding of cytostatic drug-induced programmed cell death new drug-resistance mechanisms based on the altered ability of cells to die by apoptosis have been defined. At first, the sensitive and P-glycoprotein (P-gp)-related resistant cell lines were tested to induce apoptosis by a non-P-gp transported drug, such as cytosine arabinoside (ara-C). It was demonstrated that ara-C induces apoptosis in sensitive as well as in P-gp-related resistant cell lines, as expected. Furthermore, the role of bcl-2 and bcl-xL apoptosis inhibitors as well as bax expression (apoptosis inducer) in human sensitive leukemic cell lines (CCRF-CEM and HL-60) as compared to their resistant variants such as CCRF-CEM/ACT400, CCRF-CEM/VCR1000, HL-60/IDA40, HL-60/DNR250 was evaluated. In addition to the P-gp-related resistance, a possible multidrug resistance-associated protein (MRP) and the lung resistance protein (LRP)-related resistance were assessed by flow cytometry using the monoclonal antibodies 4E3.16, MRPr1 and LRP56. Furthermore, the function of P-gp was determined with the rhodamine-123 (R-123) accumulation test. Bcl-2 and bax were analyzed by both flow cytometry and ECL Western blot, bcl-xL by ECL-Western blot alone. Comparison of the two sensitive cell lines demonstrated different bcl-2, bax and bcl-xL patterns. The common characteristic was the increased expression of one of the apoptosis inhibitor proteins, such as bcl-2 or bcl-xL. The sensitive CCRF-CEM showed a high bax level, where a decrease of about 75% in resistant variants was measured. Compared to their sensitive counterpart HL-60, a low bax expression was analyzed, which increased in the resistant variant. The common characteristic of all resistant cell lines was the decreased expression of bax compared to bcl-2 or bcl-xL. In the P-gp-related resistant HL-60/DNR250 only an increase in bcl-xL was seen, whereas in the LRP-expressing as well as P-gp and MRP negative resistant HL-60/IDA40 both apoptotic inhibitor proteins bcl-2 and bcL-xL showed maximum increase, compared to the other resistant cell lines. The P-gp-related resistant cell lines CCRF-CEM/ACT400 and CCRF-CEM/VCR1000 also showed an increased expression of both bcl-2 and bcl-xL. Summarizing these results, it was shown that the examined sensitive human leukemic cell lines and their resistant variants demonstrated a different pattern of markers for preventing and promoting apoptosis. An association between P-gp and possible LRP-expressing leukemic cells as well as apoptosis-preventing markers (bcl-2, bcl-xL) seems to exist. The clinical relevance of the coexpression of various resistance mechanisms remains to be confirmed in large leukemia patient groups.     

正常人骨髓成纤维样基质细胞对HL-60/VCR耐药细胞增殖的影响

目的观察正常人骨髓成纤维样细胞系HFCL对白血病多药耐药细胞HL-60/VCR增殖和分化的影响.方法采用四唑氮蓝(MTT)法进行HL-60/VCR细胞药物敏感实验.建立HL-60/VCR细胞和HFCL细胞共培养体系,苔盼蓝拒染法测定生长曲线;硝基四氮唑蓝(NBT)确定细胞分化;流式细胞仪检测细胞周期和CD11b、CD13、CD14、CD33细胞表面抗原进一步鉴定细胞分化;Western blot检测增殖细胞核抗原(Proliferating Cell Nuclear Antigen,PCNA)和P糖蛋白(P-glycoprotein,P-gp).结果HL-60/VCR细胞对多种药物耐药.与HFCL细胞共培养后,HL-60/VCR细胞生长受抑,且与HFCL细胞直接接触组的抑制作用＞用transwell组.同时发现HL-60/VCR细胞与HFCL细胞共培养后,G1期细胞增多,S期细胞减少;同时CD11b和CD14表达增高,CD13和CD33变化不大;且NBT阳性细胞轻度增多.Western blot检测结果显示,PCNA表达下调,以直接接触组为甚.但是P-gp表达无变化.结论正常人骨髓成纤维样细胞HFCL能抑制白血病MDR细胞HL-60/VCR的增殖,抑制PCNA的表达,出现G1期阻滞,并部分向单核细胞分化.     

P-glycoprotein expression does not change the apoptotic pathway induced by curcumin in HL-60 cells

Purpose One of the mechanisms responsible for the multidrug resistance (MDR) phenotype of cancer cells is overexpression of so-called ATP-dependent drug efflux proteins: the 170-kDa P-glycoprotein (P-gp) encoded by the MDR1 gene and the 190-kDa multidrug resistance-associated protein 1 encoded by the MRP1 gene. The purpose of the present study was to verify the hypothesis postulating that P-gp expression, apart from enabling drug efflux, confers on the cells resistance to apoptosis by inhibiting caspase-8 and caspase-3.Materials and methods Human HL-60 cells, either drug-sensitive or with the MDR phenotype caused by overexpression of P-gp (HL-60/Vinc) or MRP1 (HL-60/Adr), were treated with the natural dye curcumin at 50 M or with UVC to induce apoptosis. Symptoms of cell death were assessed by morphological observation after Hoechst staining, DNA fragmentation was measured by flow cytometry and the TUNEL method, and caspase-8 and caspase-3 activation and cytochrome c release from mitochondria were measured by Western blotting.Results Curcumin induced cell death in HL-60 cells, both sensitive and with the MDR phenotype, which could be classified as caspase-3-dependent apoptosis, together with cytochrome c release, activation of caspase-3 and oligonucleosomal DNA fragmentation. No active caspase-8 was detected. Also UVC caused caspase-3 activation in both the sensitive and the MDR HL-60 cells.Conclusions Our findings show that there was no correlation between P-gp expression and resistance to caspase-3-dependent apoptosis induced by curcumin and UVC, at least in HL-60 cells. However, we cannot exclude the possibility of parallel P-gp expression and caspase-3 inhibition in some other cell lines, as cancer cells can acquire many different apoptosis-resistance mechanisms.     

CD34+ cells from acute myeloid leukemia, myelodysplastic syndromes, and normal bone marrow display different apoptosis and drug resistance-associated phenotypes.

Myelodysplastic syndromes and acute myeloid leukemia (AML) are heterogeneous disorders in which conflicting results in apoptosis and multidrug resistance (MDR) have been reported. We have evaluated by multiparameter flow cytometry the expression of apoptosis- (APO2.7, bcl-2, and bax) and MDR-related proteins [P-glycoprotein (P-gp), multidrug resistance protein (MRP), and lung resistance protein (LRP)] specifically on bone marrow (BM) CD34+ cells, and their major CD32-/dim and CD32+ subsets, in de novo AML (n=90), high-risk myelodysplastic syndrome (n=9), and low-risk myelodysplastic syndrome (n=21) patients at diagnosis, and compared with normal BM CD34+ cells (n=6). CD34+ myeloid cells from AML and high-risk myelodysplastic syndrome patients displayed higher expression of bcl-2 (P <0.0001) and lower reactivity for APO2.7 (P=0.002) compared with low-risk myelodysplastic syndrome and normal controls. Similar results applied to the two predefined CD34+ myeloid cell subsets. No significant differences were found in the expression of P-gp, MRP, and LRP between low-risk myelodysplastic syndrome patients and normal BM, but decreased expression of MRP (P <0.03) in AML and high-risk myelodysplastic syndromes and P-gp (P=0.008) in high-risk myelodysplastic syndromes were detected. Hierarchical clustering analysis showed that low-risk myelodysplastic syndrome patients were clustered next to normal BM samples, whereas high-risk myelodysplastic syndromes were clustered together and mixed with the de novo AML patients. In summary, increased resistance to chemotherapy of CD34+ cells from both AML and high-risk myelodysplastic syndromes would be explained more appropriately in terms of an increased antiapoptotic phenotype rather than a MDR phenotype. In low-risk myelodysplastic syndromes abnormally high apoptotic rates would be restricted to the CD34- cell compartments.     

Multidrug resistance genes in infant acute lymphoblastic leukemia: Ara-C is not a substrate for the breast cancer resistance protein.

Infants with acute lymphoblastic leukemia (ALL) are more resistant to chemotherapeutic drugs than older children with ALL, except for Ara-C. Drug resistance mechanisms in infant ALL, however, remain unknown. Possibly, multidrug resistance (MDR) proteins like P-glycoprotein, MDR-associated protein (MRP1), lung resistance-related protein (LRP/MVP) and the breast cancer resistance protein (BCRP) play a role. Accordingly, we measured the mRNA levels of these proteins in infants (n=13) and non-infants (n=13) with ALL, using quantitative RT-PCR. Infants expressed 2.4-fold less BCRP mRNA (P=0.009) than non-infants with ALL. MDR1, MRP1 and LRP/MVP expression did not differ between both groups. MDR gene expression levels did not correlate to prednisolone, vincristine, daunorubicin or Ara-C cytotoxicity, except for BCRP expression, which correlated with resistance to Ara-C (Rs=0.53, P=0.012), suggesting that Ara-C might be a BCRP substrate. However, culturing patients ALL cells in the presence of the BCRP inhibitor Ko143 had no effect on Ara-C sensitivity. Inhibiting Bcrp1 in the Mdr1a-, Mdr1b- and Mrp1-deficient and Bcrp1-overexpressing mouse cell line Mef3.8/T6400, also did not modulate Ara-C cytotoxicity. Therefore, we conclude that Ara-C is not a substrate for BCRP and that MDR proteins do not play a significant role in drug resistance in infant ALL.     

Cytotoxicity,apoptosis induction and downregulation of MDR-1 expression by the anti-topoisomerase II agent,salvicine, in multidrug-resistant tumor cells

Salvicine, a novel topoisomerase II inhibitor and a diterpenoid quinone compound, exerts potent in vitro and in vivo antitumor effects. In our study, we show that salvicine effectively kills multidrug-resistant (MDR) sublines, such as K562/A02, KB/VCR and MCF-7/ADR, and parental K562, KB and MCF-7 cell lines to an equivalent degree. These cytotoxic activities of salvicine were much more potent than those of several classical anticancer drugs (average resistance factor: 1.42 for salvicine vs. 344.35, 233.19 and 71.22 for vincristine, doxorubicin and etoposide, respectively). Flow cytometry and DNA agarose gel electrophoresis demonstrated that salvicine induced similar levels of apoptosis in MDR K562/A02 and parental cells. The compound activated caspase-1 and -3 (but not caspase-8) and increased the ratio of bax to bcl-2 mRNA via reduction of bcl-2 mRNA expression in the same cells. Furthermore, salvicine induced the downregulation of mdr-1 gene and P-gp expression but had no effect on MRP and LRP gene expression in MDR K562/A02 cells. These results suggest that the reduction of mdr-1 and bcl-2 expression by salvicine possibly contributes to its cytotoxicity and apoptotic induction in this system. The effectiveness, broad-spectrum activity and possibly novel mechanism of killing MDR tumor cells in vitro of salvicine signify promising in vivo and clinical activity. The novel chemical structure of this compound further implies a role for salvicine in future MDR tumor therapy.     

Prognostic significance of multidrug resistance-related proteins in childhood acute lymphoblastic leukaemia

An important problem in the treatment of children with acute lymphoblastic leukaemia (ALL) is pre-existent or acquired resistance to structurally and functionally unrelated chemotherapeutic compounds. Various cellular mechanisms can give rise to multidrug resistance (MDR). Best studied is the transmembrane protein-mediated efflux of cytotoxic compounds that leads to decreased cellular drug accumulation and toxicity. Several MDR-related efflux pumps have been characterised, including P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), breast cancer resistance protein (BCRP) and lung resistance protein (LRP). P-gp expression and/or activity has been associated with unfavourable outcome in paediatric ALL patients, whereas MRP1 and BCRP do not seem to play a major role. LRP might contribute to drug resistance in B-lineage ALL, but larger studies are needed to confirm these results. The present review summarises the current knowledge concerning multidrug resistance-related proteins and focuses on the clinical relevance and prognostic value of these efflux pumps in childhood ALL.