WAVE1在儿童急性非淋巴细胞白血病中对MDR1、MRP1、BCRP的影响
摘要
研究背景:化疗是目前儿童白血病治疗的主要手段,白血病化疗失败的主要原因是白血病的多药耐药(multidrugresistance,MDR),尤其对于儿童急性非淋巴细胞白血病(acutenonlymphoblastic leukemia,ANLL),多药耐药的发生严重制约着其长期无事件生存率的进一步提高。前期研究已经证实了细胞骨架调节蛋白WASP家族富含脯氨酸同源蛋白1(WASP-family verprolinhomologous protein 1,WAVE1)特异性参与了儿童急淋的发病,与儿童急淋病程呈正相关,表现为活动期(初发和复发患者)WAVE1的表达持续增高,完全缓解期表达恢复到正常水平,并初步发现了WAVE1参与了白血病多药耐药的形成。进一步明确WAVE1对多药耐药相关基因表达的影响,为白血病多药耐药的逆转提供一个新的思路。
目的:探讨儿童ANLL中WAVE1基因参与多药耐药基因(multidrug resistance 1,MDR1)、多药耐药相关蛋白基因(multidrugresistance associated protein 1,MRP)、乳腺癌耐药蛋白基因(Breastcancer resistance protein,BCRP)表达和调控的机制。
方法:应用实时荧光定量PCR(RQ-PCR)法分别检测52例ANLL患儿治疗前及疾病发展过程中骨髓单个核细胞(bone marrowmononuclear cells,BMMCs)中WAVE1,MDR1,MRP1及BCRP mRNA的表达水平。将pCDNA3.1A-WAVE1真核表达质粒转染K562细胞构建WAVE1高表达K562细胞,用RQ-PCR法检测转染前后白血病细胞系WAVE1,MDR1,MRP1及BCRP基因的表达水平。
结果:52例入组患儿中共有21例复发或初次诱导未缓解,31例处于持续缓解状态,复发难治组的WAVE1及耐药相关基因表达水平明显高于缓解组患儿(P＜0.05),同一患儿缓解期WAVE1的表达水平明显低于初治期及复发期(P＜0.05);与K562相比较,K562/A02中WAVE1及MDR1的mRNA表达水平均明显增加;转染WAVE1质粒后的K562中MDR1、MRP1、BCRP的mRNA表达水平均有不同程度的增高。
结论:WAVE1与儿童ANLL的病程及预后相关,WAVE1参与了髓系白血病细胞多药耐药的形成并可影响多个重要的耐药相关基因的表达。
Background: Chemotherapy is one of the main treaments for children with acute leukemia (AL). Multidrug resistance (MDR) is an important reason of treatment failure in children with acute leukemia, especially in acute nonlymphoblastic leukemia (ANLL). The occurrence of multidrug resistance strongly decreases the long-term event-free survival rate.In previous researches, we have confirmed that cytoskeletal regulatory protein WASP-family verprolin homologous protein 1(WAVE1) is involved in the pathogenesis of children with acute lymphoblastic leukemia (ALL), and with positive impact. At the active stage (in patients with primary and recurrent), the expression of WAVE1 continued to increase, while back to normal levels at complete remission stage. WAVE1 was also found involved in MDR. It can be a new way to reverse multidrug resistance if we can confirm WAVE1's impact to multidrug resistance genes.
Objective: To investigate WAVE1's impact to the expression and regulation of multidrug resistance gene 1, multidrug resistance-associated protein gene 1, and breast cancer resistance protein gene.
Methods: WAVE1, MDR1, MRP1, BCRP mRNA expression in bone marrow mononuclear cells (BMMCs) were tested by Real-time fluorescence quantitative PCR (RQ-PCR) in a cohort of fifty-two children with acute myeloblastic leukemia. K562 cell was transient-transfected by PCDNA3. 1A-WAVE1 reconstructed plasmid and the expression of WAVE1, MDR1, MRP1 and BCRP before and after transfection were investigated by real-time PCR.
Results: Twenty-one patients were refractory or relapsed during the follow-up and thirty-one patients were found in continuous remission. Levels of WAVE1, MDR1, MRP1, BCRP's expression in refractory/relapsing group were much higher than in complete continuous remission (CCR) group (P<0.05). Compared with continuous remission group we showed that higher expression of WAVE1 mRNA in newly diagnosed or relapsed ANLL children's BMMCs (P<0.05).WAVE1 and MDR1 mRNA expression in K562/A02 was much higher than that in K562.Levels of WAVE1, MDR1, MRP1, BCRP mRNA expression were increased to varying degrees after transfecting pCDNA3. 1A-WAVE1 reconstructed plasmid in K562 cells.
Conclusion: Our results suggested that higher levels of WAVE1 in BM indicates an unfavorable prognosis in children with ANLL. WAVE1 is involved in the MDR mechanisms and regulates the level of MRP1 and BCRP expression.
目的:探讨儿童ANLL中WAVE1基因参与多药耐药基因(multidrug resistance 1,MDR1)、多药耐药相关蛋白基因(multidrugresistance associated protein 1,MRP)、乳腺癌耐药蛋白基因(Breastcancer resistance protein,BCRP)表达和调控的机制。
方法:应用实时荧光定量PCR(RQ-PCR)法分别检测52例ANLL患儿治疗前及疾病发展过程中骨髓单个核细胞(bone marrowmononuclear cells,BMMCs)中WAVE1,MDR1,MRP1及BCRP mRNA的表达水平。将pCDNA3.1A-WAVE1真核表达质粒转染K562细胞构建WAVE1高表达K562细胞,用RQ-PCR法检测转染前后白血病细胞系WAVE1,MDR1,MRP1及BCRP基因的表达水平。
结果:52例入组患儿中共有21例复发或初次诱导未缓解,31例处于持续缓解状态,复发难治组的WAVE1及耐药相关基因表达水平明显高于缓解组患儿(P＜0.05),同一患儿缓解期WAVE1的表达水平明显低于初治期及复发期(P＜0.05);与K562相比较,K562/A02中WAVE1及MDR1的mRNA表达水平均明显增加;转染WAVE1质粒后的K562中MDR1、MRP1、BCRP的mRNA表达水平均有不同程度的增高。
结论:WAVE1与儿童ANLL的病程及预后相关,WAVE1参与了髓系白血病细胞多药耐药的形成并可影响多个重要的耐药相关基因的表达。
Background: Chemotherapy is one of the main treaments for children with acute leukemia (AL). Multidrug resistance (MDR) is an important reason of treatment failure in children with acute leukemia, especially in acute nonlymphoblastic leukemia (ANLL). The occurrence of multidrug resistance strongly decreases the long-term event-free survival rate.In previous researches, we have confirmed that cytoskeletal regulatory protein WASP-family verprolin homologous protein 1(WAVE1) is involved in the pathogenesis of children with acute lymphoblastic leukemia (ALL), and with positive impact. At the active stage (in patients with primary and recurrent), the expression of WAVE1 continued to increase, while back to normal levels at complete remission stage. WAVE1 was also found involved in MDR. It can be a new way to reverse multidrug resistance if we can confirm WAVE1's impact to multidrug resistance genes.
Objective: To investigate WAVE1's impact to the expression and regulation of multidrug resistance gene 1, multidrug resistance-associated protein gene 1, and breast cancer resistance protein gene.
Methods: WAVE1, MDR1, MRP1, BCRP mRNA expression in bone marrow mononuclear cells (BMMCs) were tested by Real-time fluorescence quantitative PCR (RQ-PCR) in a cohort of fifty-two children with acute myeloblastic leukemia. K562 cell was transient-transfected by PCDNA3. 1A-WAVE1 reconstructed plasmid and the expression of WAVE1, MDR1, MRP1 and BCRP before and after transfection were investigated by real-time PCR.
Results: Twenty-one patients were refractory or relapsed during the follow-up and thirty-one patients were found in continuous remission. Levels of WAVE1, MDR1, MRP1, BCRP's expression in refractory/relapsing group were much higher than in complete continuous remission (CCR) group (P<0.05). Compared with continuous remission group we showed that higher expression of WAVE1 mRNA in newly diagnosed or relapsed ANLL children's BMMCs (P<0.05).WAVE1 and MDR1 mRNA expression in K562/A02 was much higher than that in K562.Levels of WAVE1, MDR1, MRP1, BCRP mRNA expression were increased to varying degrees after transfecting pCDNA3. 1A-WAVE1 reconstructed plasmid in K562 cells.
Conclusion: Our results suggested that higher levels of WAVE1 in BM indicates an unfavorable prognosis in children with ANLL. WAVE1 is involved in the MDR mechanisms and regulates the level of MRP1 and BCRP expression.
引文
[1]Varma M V,Ashokraj Y,Dey C S,et al.P-glycoprotein inhibitors and their screening:a perspective from bioavailability enhancement[J].Pharmacol Res,2003,48(4):347- 359
[2]M.L.den Boer,R.Pieters,K.M.Kazemier,et al.Relationship between Major Vault Protein/Lung Resistance Protein,Multidrug Resistance-Associated Protein,P-Glycoprotein Expression,and Drug Resistance in Childhood Leukemia[J].BLOOD,1998,91:2092-2098
[3]P.J.Ancliff,M.P.Blundell,G.O.Cory,et al.Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia[J].Blood,2006,108(7):2182-2189
[4]Y.Kim,J.Y.Sung,I.Ceglia,et al.Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology[J].Nature,2006,442(7104):814-817
[5]S.Eden,R.Rohatgi,A.V.Podtelejnikov,et al.Mechanism of regulation of WAVE1 induced actin nucleation by Racl and Nck[J].Nature,2002,418(6899):790-793
[6]D.Yamazaki,T.Oikawa,T.Takenawa,et al.Rac-WAVE-mediated actin reorganization is required for organization and maintenance of cell-cell adhesion[J].Cell Sci,2007,120(1):86-100
[7]P.A.Zipfel,S.C.Bunnell,D.S.Witherow,et al.Role for the Abi/wave protein complex in T cell receptor-mediated proliferation and cytoskeletal remodeling [J].Curr Biol,2006,16(1):35-36
[8]C.W.Gourlay,K.R.Ayscough.The actin cytoskeleton:a key regulator of apoptosis and aging[J].Nat Rev Mol Cell Biol,2005,6(7):583-589
[9]C.W.Gourlay,L.N.Carpp,P.Timpson,et al.A role for the actin cytoskeleton in cell death and aging in yeast[J].Cell Biol,2004,164(6):803-809
[10]贺钰磊,曹励之,杨静,等.急性淋巴细胞白血病患儿WAVE1和p22phox 的表达及WAVE1与氧化应激的关系[J].中国当代儿科杂志,2009, 11,(2):88-92
[11]康睿,曹励之,俞燕,等.WAVE1基因在K562/A02白血病细胞多药耐药中的作用[J].中华血液学杂志,2007,28,(6):379-382
[12]康睿,曹励之,俞燕,等.中国儿童急性淋巴细胞白血病染色体6q16.3-21区域候选肿瘤抑制基因的定位[J].生物化学与生物物理进展,2006,33(1):65-71
[13]高娜,茆俊卿,张育,等.白血病多药耐药机制研究进展[J].实用医学志,2007,23(1 8):2809-2811.
[14]A.T.Fojo,M.Menefee.Microtubule targeting agents:basic mechanisms of multidrug resistance(MDR)[J].Semin Oncol,2005,32(6 Suppl):S3-8
[15]Chin K-V,Pastan I,Gottesman M M,et al.Function and regulation of the human multidrug resistance gene[J].Adv Cancer Res,1993,60:157-180
[16]Gottesman M M,Fojo T,Bates S E,et al.Multidrug resistance in cancer:role of ATP-dependent transporters[J].Nature Rev Cancer,2002,2:48-58
[17]van der Kolk DM,de Vries EG,M(u|¨)ller M,et al.The role of drug effiux pumps in acute myeloid leukemia[J].Leuk Lymphoma.2002 Apr:43(4):685-701
[18]张蕊、 裴秋玲.人类MRP1和MRP2基因多态性与功能的研究进展[J].毒理学杂志,2008,22(5);395-398
[19]Mao Q,Unadkat JD.Role of the breast cancer resistance protein(ABCG2)in drug transport[J].AAPS Journal,2005,7(1):118-133.
[20]Abbott BL,Colapietro AM,Barmes Y,et al.Low levels of ABCG2 expression in adult AML blast samples[J].Blood,2004,100.- 4594-4601.
[21]Fazlina N,Maha A,Jarnal R,et al.Expression of multidrug resistance(MDR)proteins and in vitro drug resistance in acute leukemias[J].Hematology,2007,12(1):33-7
[22]de Figueiredo-Pontes LL,Pintao MC,Oliveira LC,et al.Determination of P-glycoprotein,MDR-related protein 1,breast cancer resistance protein,and lung-resistance protein expression in leukemic stem cells of acute myeloid leukemia[J].Cytometry B clin Cytom,2008,74(3):163-8
[23]Do JH,Oh SH,Song EJ,et al.Treatment outcome of multidrug resistance related mRNA expression and c-jun-N-terminal kinase activity in patients with acute myeloid leukemia[J].Korean J Lab Med,2007,27(4):229-36.
[24]Trnkova Z,Bedrlikova R,Markova J,et al.Semiquantitative RT-PCR evaluation of the MDR1 gene expression in patients with acute myeloid leukemia[J],Neoplasma,2007,54(5):383-90.
[25]Fazlina N,Maha A,Zarina AL,et al.Asseessment of P-gp and MDR1activities using MultiDrugQuant Assay Kit:a preliminary study of correlation between protion expression and its function activities in newly diagnosed acute leukemia patients[J].Malays J Pathol,2008,Dec,30(2):87-93
[26]Steinbach D,Sell W,Voigt A,et al.BCRP gene expression is asaociated with a poor response to re mission induction therapy in childhood acute myeloid leukemial[J].Leukemia,2002,16(8):1443-1447.
[27]Benderra Z,Faussat AM,Sayada L,et al.Breast cancer resistance protein and P - glycoprotein in 149 adult with acute myeloid leukemia[J].Clin Cancer Res,2004,10(23):7896 - 7902.
[28]Galimberti S,Guerrini F,Palumbo GA,et al.Evaluation of BCRP and MDR1coexpression by quantitative molecular assessment in AML patients[J].Leuk Res,2004,28(4):367 - 372
[29]Y.M.Zhang,L.S.Zhang,Y.F.Zhang,et al.Comparison of antileukemic immunity mediated by dendritic cell derived from multidrug resistance leukemia K562/A02 cell and sensitive K562 cells[J].Chin Med J(Engl),2005,118(7):595-597
[30]Pauwels EK,Erba P,Mariani G;et al.Multidrug resistance in cancer:its mechanism and its modulation[J].Drug News Perspect.2007,20:371-377.
[31]常宏宇,潘凯丽.白血病多药耐药逆转研究进展[J].细胞与分子免疫学杂志,2005,21(2):101-102
[1]Varma M V,Ashokraj Y,Dey C S,et al.P-glycoprotein inhibitors and their screening:a perspective from bioavailability enhancement[J].Pharmacol Res,2003,48(4):347- 359.
[2]Kohji T,Toshiyuki S,Katsuhiko O,et al.An update on overcoming MDR1-mediated multidrug resistance in cancer chemotherapy[J].Current Pharmaceutical Design,2006,12(3):273 - 286.
[3]RittierodtM,Tschernig T,Harada K,et al.Modulation of multidrug resistanceassociated P - glycoprotein in human U -87MG and HUV - ECC cells with antisense oligodeoxy nucleotides to MDR1 mRNA[J].Pathobiology,2004,71(3):123- 128.
[4]Hsia TC,L in CC,Wang J J,et al.Relationship between chemotherapy response of small cell lung cancer and P -glycop rotein or multidrug resistance - related protein expression[J].Lung,2002,180(3):173 - 179.
[5]Shman T V,Savitskii V P,Potapnev M P,et al.Study of expression and functional activity of P-GP membrane glycoprotein in children with acute leukemia[J].Bull Exp Biol Med,2006,41(6):727- 730.
[6]Cole S,Bhardwaj G,Gerlach JH,et al.Overexpression of a transporter gene in a multidrug resistant human lung cancer cell line[J].Science,1992,258:1650-1654.
[7]Valera E T,Scrideli C A,Queiroz R G,et al.Multidrug resistance protein (MDR-1),multidrug resistance-related protein(MRP) and lung resistance protein(LRP) gene expression in childhood acute lymphoblastic leukemia[J].Sao Paulo Med J,2004,122(4):166-171.
[8]Margaretha R,Martin F,Susanne T,et al.Expression of MRP1,LRP and Pgp in breast carcinoma patients treated with preoperative chemotherapy [J]. Breast Cancer Research and Treatment, 2003, 81 (2): 149 -157.
[9] Walter B, Ulrike S, Peter H, et al. Multidrug resistance markers P -glycoprotein, multidrug resistance protein 1 ,and lung resistance protein in non -small cell lung cancer: prognostic implications [J]. Journal of Cancer Research Clinical Oncology, 2005,131 (6): 355 - 363.
[10] Chen YN, Mickley LA, Schwartz Am, et al. Characterization of adriamycin resistant human breast cancer cells which display overexpression of a novel resistance related membrance protein [J].Biol chem, 1990,265(10) :73-80.
[11] Ross DD, Karp J, Chen T ,et al .Expression of breast cancer resistance protein in blast cells from patients with acute leukemia [J]. Blood, 2000, 96 :365-368.
[12] IzquierdoM A, Scheffer GL, FlensM J, et al. Broad distribution of the multidrug resistence related vault lung resistence protein in normal human tissue and tumors [J]. Am J Pathol, 1996 148 (3):877-887.
[13] Benderra Z, Faussat AM. Breast cancer resistance protein and P - glycoprotein in 149 adult acute myeloid leukemia [J]. J Clin Cancer Res, 2004, 10 (23):7896 - 7902.
[14] IzquierdoM A, Scheffer GL, FlensM J, et al. Broad distribution of the multidrug resistence-related vault lung resistence protein in normal human tissue and tumors [J]. Am J Pathol, 1996,148 (3):877-887.
[15] 高娜,茆俊卿,张育,等.白血病多药耐药机制研究进展[J].实用医学杂志,2007,23(18):2809-2811.
[16] Yu DQ, Yi YF. Expression and significance of MRP, GST-pi, Topo II alpha,and LRP in gastric carcinoma [J]. Cancer, 2003, 22 (5): 496 - 499.
[17] Guido S, StevenWW, Christian OV, et al. Effects of standard chemotherapy on tumor growth and regulation of multidrug resistance genes and proteins in childhood rhabdomyosarcoma [J]. Pediatric Surgery International, 2007,23 (5):431 -440.
[18] Yeh JJ, Hsu NY, HsuWH, et al. Comparison of chemotherapy response with P -glycoprotein, multidrug resistance related protein - 1, and lung resistance related protein expression in untreated small cell lung cancer [J]. Lung, 2005, 183(3):177-183.
[19]魏玲,宋现让,王兴武,等.MDRl和GST-π在骨软组织肉瘤中的表达及其与化疗耐药的关系[J].中华肿瘤杂志,2006,28(6):445-448.
[20]Chikamori K,Hill J E,Grabowski D R,et al.Downregulation of topoisomerase IIbeta in myeloid leukemia cell lines leads to activation of apoptosis following all-trans retinoic acid-induced differentiation /growth arrest[J].Leukemia,2006,20(10):1809-1818.
[21]Doyle L A,RossD D,Ordonez J V,et al.An etoposide resistant lung cancer subline overexpresses the multidrug resistence associated protein[J].Br J Cancer,1995,72(3):535-542.
[22]Bertino J R,Goker E,Gorlick R,et al.Resistence mechanisms to methotrexate in tumor[J].Stem Cell,1996,14(1):529.
[23]Basu A,Weixel K,Sajjo N,et al.Characterization of the protein kinase C singal transduction pathway in cisp latin sensitive and resistance human small cell lung carcinomer cells[J].Cell Growth Differ,1996,7(11):1507-1512.
[24]陈波,金锋,卢香兰,等.PKC抑制剂对MGC803细胞中P-gp表达及耐药性的影响[J].癌症,2004,23(4):396-400.
[25]沃兴德,俞颖.细胞凋亡抑制与肿瘤多药耐药的研究进展[J].浙江中医药大学学报,2006,30(5):578-580.
[26]Galimberti S,Marchetti A,Buttita F,et al.Multidrug resistance related genes and p53 expression in human non small cell lung cancer[J].Anticancer Res,1998,18(4):2973-2976.
[27]盖晓东,李国利,黄京子,等.野生型p53基因对肝癌细胞多药耐药的逆转作用及其相关机制[J].癌症,2006,25(8):954-959.
[28]张锦海,陈幸华.血液肿瘤多药耐药的研究进展[J].中国实验血液学杂志,2005,13(6):1151-1154.
[29]Mahoney B P,Raghunand N,Baggett B,et al.Tumor acidity,iontrapping and chemotherapeutics.I.Acid pH affects the distribution of chemotherapeutic agents in vitro[J].Biochem Pharmacol,2003,66(7):1207- 1218.
[30]Grandgirard N,Ly-Sunnaram B,Ferrant D,et al.Impact of Topoisomerase Ⅱalpha and spermine on the clinical outcome of children with acute lymphoblastic leukemia[J].Leuk Res,2004,28(5):479- 486.
[31]HazlehurstLA,Landowski TH,Dalton WS,et al.Role of the tumor micro-environment in mediating denovo resistance to drugs and physiological mediators of cell death[J].Oncogene,2003;22:7396 - 7402
[32]Ruiz-Godoy R L,Garcia-Cuellar C M,Herrera Gonzalez N E,et al.Mutational analysis of K-ras and Ras protein expression in larynx squamous cell carcinoma[J].J Exp Clin Cancer Res,2006,25(1):73- 78.
[33]Bentires-Alj M,Barbu V,Fillet M,et al.NF-kappaB transcription factor induces drug resistance through MDR1 expression in cancer cells[J].Oncogene,2003,22(1):90- 97.
[34]Wang Y,Minko T A.Novel cancer therapy:combined liposomal hypoxia inducible factod alpha antisense oligonucleotides and an anticancer drug[J].Biochem Pharm,2004,68(10):2031- 2042.
[2]M.L.den Boer,R.Pieters,K.M.Kazemier,et al.Relationship between Major Vault Protein/Lung Resistance Protein,Multidrug Resistance-Associated Protein,P-Glycoprotein Expression,and Drug Resistance in Childhood Leukemia[J].BLOOD,1998,91:2092-2098
[3]P.J.Ancliff,M.P.Blundell,G.O.Cory,et al.Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia[J].Blood,2006,108(7):2182-2189
[4]Y.Kim,J.Y.Sung,I.Ceglia,et al.Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology[J].Nature,2006,442(7104):814-817
[5]S.Eden,R.Rohatgi,A.V.Podtelejnikov,et al.Mechanism of regulation of WAVE1 induced actin nucleation by Racl and Nck[J].Nature,2002,418(6899):790-793
[6]D.Yamazaki,T.Oikawa,T.Takenawa,et al.Rac-WAVE-mediated actin reorganization is required for organization and maintenance of cell-cell adhesion[J].Cell Sci,2007,120(1):86-100
[7]P.A.Zipfel,S.C.Bunnell,D.S.Witherow,et al.Role for the Abi/wave protein complex in T cell receptor-mediated proliferation and cytoskeletal remodeling [J].Curr Biol,2006,16(1):35-36
[8]C.W.Gourlay,K.R.Ayscough.The actin cytoskeleton:a key regulator of apoptosis and aging[J].Nat Rev Mol Cell Biol,2005,6(7):583-589
[9]C.W.Gourlay,L.N.Carpp,P.Timpson,et al.A role for the actin cytoskeleton in cell death and aging in yeast[J].Cell Biol,2004,164(6):803-809
[10]贺钰磊,曹励之,杨静,等.急性淋巴细胞白血病患儿WAVE1和p22phox 的表达及WAVE1与氧化应激的关系[J].中国当代儿科杂志,2009, 11,(2):88-92
[11]康睿,曹励之,俞燕,等.WAVE1基因在K562/A02白血病细胞多药耐药中的作用[J].中华血液学杂志,2007,28,(6):379-382
[12]康睿,曹励之,俞燕,等.中国儿童急性淋巴细胞白血病染色体6q16.3-21区域候选肿瘤抑制基因的定位[J].生物化学与生物物理进展,2006,33(1):65-71
[13]高娜,茆俊卿,张育,等.白血病多药耐药机制研究进展[J].实用医学志,2007,23(1 8):2809-2811.
[14]A.T.Fojo,M.Menefee.Microtubule targeting agents:basic mechanisms of multidrug resistance(MDR)[J].Semin Oncol,2005,32(6 Suppl):S3-8
[15]Chin K-V,Pastan I,Gottesman M M,et al.Function and regulation of the human multidrug resistance gene[J].Adv Cancer Res,1993,60:157-180
[16]Gottesman M M,Fojo T,Bates S E,et al.Multidrug resistance in cancer:role of ATP-dependent transporters[J].Nature Rev Cancer,2002,2:48-58
[17]van der Kolk DM,de Vries EG,M(u|¨)ller M,et al.The role of drug effiux pumps in acute myeloid leukemia[J].Leuk Lymphoma.2002 Apr:43(4):685-701
[18]张蕊、 裴秋玲.人类MRP1和MRP2基因多态性与功能的研究进展[J].毒理学杂志,2008,22(5);395-398
[19]Mao Q,Unadkat JD.Role of the breast cancer resistance protein(ABCG2)in drug transport[J].AAPS Journal,2005,7(1):118-133.
[20]Abbott BL,Colapietro AM,Barmes Y,et al.Low levels of ABCG2 expression in adult AML blast samples[J].Blood,2004,100.- 4594-4601.
[21]Fazlina N,Maha A,Jarnal R,et al.Expression of multidrug resistance(MDR)proteins and in vitro drug resistance in acute leukemias[J].Hematology,2007,12(1):33-7
[22]de Figueiredo-Pontes LL,Pintao MC,Oliveira LC,et al.Determination of P-glycoprotein,MDR-related protein 1,breast cancer resistance protein,and lung-resistance protein expression in leukemic stem cells of acute myeloid leukemia[J].Cytometry B clin Cytom,2008,74(3):163-8
[23]Do JH,Oh SH,Song EJ,et al.Treatment outcome of multidrug resistance related mRNA expression and c-jun-N-terminal kinase activity in patients with acute myeloid leukemia[J].Korean J Lab Med,2007,27(4):229-36.
[24]Trnkova Z,Bedrlikova R,Markova J,et al.Semiquantitative RT-PCR evaluation of the MDR1 gene expression in patients with acute myeloid leukemia[J],Neoplasma,2007,54(5):383-90.
[25]Fazlina N,Maha A,Zarina AL,et al.Asseessment of P-gp and MDR1activities using MultiDrugQuant Assay Kit:a preliminary study of correlation between protion expression and its function activities in newly diagnosed acute leukemia patients[J].Malays J Pathol,2008,Dec,30(2):87-93
[26]Steinbach D,Sell W,Voigt A,et al.BCRP gene expression is asaociated with a poor response to re mission induction therapy in childhood acute myeloid leukemial[J].Leukemia,2002,16(8):1443-1447.
[27]Benderra Z,Faussat AM,Sayada L,et al.Breast cancer resistance protein and P - glycoprotein in 149 adult with acute myeloid leukemia[J].Clin Cancer Res,2004,10(23):7896 - 7902.
[28]Galimberti S,Guerrini F,Palumbo GA,et al.Evaluation of BCRP and MDR1coexpression by quantitative molecular assessment in AML patients[J].Leuk Res,2004,28(4):367 - 372
[29]Y.M.Zhang,L.S.Zhang,Y.F.Zhang,et al.Comparison of antileukemic immunity mediated by dendritic cell derived from multidrug resistance leukemia K562/A02 cell and sensitive K562 cells[J].Chin Med J(Engl),2005,118(7):595-597
[30]Pauwels EK,Erba P,Mariani G;et al.Multidrug resistance in cancer:its mechanism and its modulation[J].Drug News Perspect.2007,20:371-377.
[31]常宏宇,潘凯丽.白血病多药耐药逆转研究进展[J].细胞与分子免疫学杂志,2005,21(2):101-102
[1]Varma M V,Ashokraj Y,Dey C S,et al.P-glycoprotein inhibitors and their screening:a perspective from bioavailability enhancement[J].Pharmacol Res,2003,48(4):347- 359.
[2]Kohji T,Toshiyuki S,Katsuhiko O,et al.An update on overcoming MDR1-mediated multidrug resistance in cancer chemotherapy[J].Current Pharmaceutical Design,2006,12(3):273 - 286.
[3]RittierodtM,Tschernig T,Harada K,et al.Modulation of multidrug resistanceassociated P - glycoprotein in human U -87MG and HUV - ECC cells with antisense oligodeoxy nucleotides to MDR1 mRNA[J].Pathobiology,2004,71(3):123- 128.
[4]Hsia TC,L in CC,Wang J J,et al.Relationship between chemotherapy response of small cell lung cancer and P -glycop rotein or multidrug resistance - related protein expression[J].Lung,2002,180(3):173 - 179.
[5]Shman T V,Savitskii V P,Potapnev M P,et al.Study of expression and functional activity of P-GP membrane glycoprotein in children with acute leukemia[J].Bull Exp Biol Med,2006,41(6):727- 730.
[6]Cole S,Bhardwaj G,Gerlach JH,et al.Overexpression of a transporter gene in a multidrug resistant human lung cancer cell line[J].Science,1992,258:1650-1654.
[7]Valera E T,Scrideli C A,Queiroz R G,et al.Multidrug resistance protein (MDR-1),multidrug resistance-related protein(MRP) and lung resistance protein(LRP) gene expression in childhood acute lymphoblastic leukemia[J].Sao Paulo Med J,2004,122(4):166-171.
[8]Margaretha R,Martin F,Susanne T,et al.Expression of MRP1,LRP and Pgp in breast carcinoma patients treated with preoperative chemotherapy [J]. Breast Cancer Research and Treatment, 2003, 81 (2): 149 -157.
[9] Walter B, Ulrike S, Peter H, et al. Multidrug resistance markers P -glycoprotein, multidrug resistance protein 1 ,and lung resistance protein in non -small cell lung cancer: prognostic implications [J]. Journal of Cancer Research Clinical Oncology, 2005,131 (6): 355 - 363.
[10] Chen YN, Mickley LA, Schwartz Am, et al. Characterization of adriamycin resistant human breast cancer cells which display overexpression of a novel resistance related membrance protein [J].Biol chem, 1990,265(10) :73-80.
[11] Ross DD, Karp J, Chen T ,et al .Expression of breast cancer resistance protein in blast cells from patients with acute leukemia [J]. Blood, 2000, 96 :365-368.
[12] IzquierdoM A, Scheffer GL, FlensM J, et al. Broad distribution of the multidrug resistence related vault lung resistence protein in normal human tissue and tumors [J]. Am J Pathol, 1996 148 (3):877-887.
[13] Benderra Z, Faussat AM. Breast cancer resistance protein and P - glycoprotein in 149 adult acute myeloid leukemia [J]. J Clin Cancer Res, 2004, 10 (23):7896 - 7902.
[14] IzquierdoM A, Scheffer GL, FlensM J, et al. Broad distribution of the multidrug resistence-related vault lung resistence protein in normal human tissue and tumors [J]. Am J Pathol, 1996,148 (3):877-887.
[15] 高娜,茆俊卿,张育,等.白血病多药耐药机制研究进展[J].实用医学杂志,2007,23(18):2809-2811.
[16] Yu DQ, Yi YF. Expression and significance of MRP, GST-pi, Topo II alpha,and LRP in gastric carcinoma [J]. Cancer, 2003, 22 (5): 496 - 499.
[17] Guido S, StevenWW, Christian OV, et al. Effects of standard chemotherapy on tumor growth and regulation of multidrug resistance genes and proteins in childhood rhabdomyosarcoma [J]. Pediatric Surgery International, 2007,23 (5):431 -440.
[18] Yeh JJ, Hsu NY, HsuWH, et al. Comparison of chemotherapy response with P -glycoprotein, multidrug resistance related protein - 1, and lung resistance related protein expression in untreated small cell lung cancer [J]. Lung, 2005, 183(3):177-183.
[19]魏玲,宋现让,王兴武,等.MDRl和GST-π在骨软组织肉瘤中的表达及其与化疗耐药的关系[J].中华肿瘤杂志,2006,28(6):445-448.
[20]Chikamori K,Hill J E,Grabowski D R,et al.Downregulation of topoisomerase IIbeta in myeloid leukemia cell lines leads to activation of apoptosis following all-trans retinoic acid-induced differentiation /growth arrest[J].Leukemia,2006,20(10):1809-1818.
[21]Doyle L A,RossD D,Ordonez J V,et al.An etoposide resistant lung cancer subline overexpresses the multidrug resistence associated protein[J].Br J Cancer,1995,72(3):535-542.
[22]Bertino J R,Goker E,Gorlick R,et al.Resistence mechanisms to methotrexate in tumor[J].Stem Cell,1996,14(1):529.
[23]Basu A,Weixel K,Sajjo N,et al.Characterization of the protein kinase C singal transduction pathway in cisp latin sensitive and resistance human small cell lung carcinomer cells[J].Cell Growth Differ,1996,7(11):1507-1512.
[24]陈波,金锋,卢香兰,等.PKC抑制剂对MGC803细胞中P-gp表达及耐药性的影响[J].癌症,2004,23(4):396-400.
[25]沃兴德,俞颖.细胞凋亡抑制与肿瘤多药耐药的研究进展[J].浙江中医药大学学报,2006,30(5):578-580.
[26]Galimberti S,Marchetti A,Buttita F,et al.Multidrug resistance related genes and p53 expression in human non small cell lung cancer[J].Anticancer Res,1998,18(4):2973-2976.
[27]盖晓东,李国利,黄京子,等.野生型p53基因对肝癌细胞多药耐药的逆转作用及其相关机制[J].癌症,2006,25(8):954-959.
[28]张锦海,陈幸华.血液肿瘤多药耐药的研究进展[J].中国实验血液学杂志,2005,13(6):1151-1154.
[29]Mahoney B P,Raghunand N,Baggett B,et al.Tumor acidity,iontrapping and chemotherapeutics.I.Acid pH affects the distribution of chemotherapeutic agents in vitro[J].Biochem Pharmacol,2003,66(7):1207- 1218.
[30]Grandgirard N,Ly-Sunnaram B,Ferrant D,et al.Impact of Topoisomerase Ⅱalpha and spermine on the clinical outcome of children with acute lymphoblastic leukemia[J].Leuk Res,2004,28(5):479- 486.
[31]HazlehurstLA,Landowski TH,Dalton WS,et al.Role of the tumor micro-environment in mediating denovo resistance to drugs and physiological mediators of cell death[J].Oncogene,2003;22:7396 - 7402
[32]Ruiz-Godoy R L,Garcia-Cuellar C M,Herrera Gonzalez N E,et al.Mutational analysis of K-ras and Ras protein expression in larynx squamous cell carcinoma[J].J Exp Clin Cancer Res,2006,25(1):73- 78.
[33]Bentires-Alj M,Barbu V,Fillet M,et al.NF-kappaB transcription factor induces drug resistance through MDR1 expression in cancer cells[J].Oncogene,2003,22(1):90- 97.
[34]Wang Y,Minko T A.Novel cancer therapy:combined liposomal hypoxia inducible factod alpha antisense oligonucleotides and an anticancer drug[J].Biochem Pharm,2004,68(10):2031- 2042.