中药复方干预AML白血病干细胞NF-κB及FLT3蛋白表达的研究
摘要
目的:本研究旨在通过研究中药复方干预白血病细胞FLT3和NF-κB的蛋白表达情况,以探讨中医药治疗白血病的作用机制。方法:运用中药对45例AML患者白血病干细胞进行干预,通过免疫印迹法(Western Bloting,WB)观察干预前后白血病干细胞内NF-κB和FLT3的表达情况;同时观察患者的性别、年龄、治疗前外周血白细胞数及骨髓原始细胞比例,以探讨其相关性。结果:AML患者(M1、M2、M4、M5)FLT3阳性率为62.2%;FLT3的阳性率与患者的FAB分型、性别、年龄无差异(P>0.05),与患者的外周血白细胞总数、骨髓原始细胞比例存在差异(P<0.01);中药可下调白血病干细胞FLT3和NF-κB基因的蛋白表达水平(P<0.01);其中中药原方组与其拆方扶正组、祛邪组及生理盐水组(空白对照组)相比,能够显著降低白血病干细胞FLT3和NF-κB基因的蛋白表达水平(P<0.01),而扶正组与祛邪组对白血病干细胞FLT3和NF-κB基因表达水平的影响无显著性差异(P>0.05)。结论:AML患者中存在FLT3的阳性表达;其阳性表达率与患者的年龄、性别、FAB分型无关,与患者初发或复发时外周血白细胞计数及骨髓原始细胞数成正相关;中药复方可以下调FLT3及NF-κB在AML患者中的表达,其中原方组较祛邪组、扶正组下调作用明显;揭示了扶正组与祛邪组之间存在协同作用。
Objective:To research changes of proteinic expression in NF-κB (Nuclear Factor- Kappa B)and FLT3(Fms-like tyrosine kinase 3),and the mechanism of herbs to acute myelocytic leukemia cell(AML).Methods: BM(bone marrow)of forty-five AML patients were extracted to get monocytes .After that, by magneton selecting we can get leukemia stem cells.The third step is cultivating the LSC by four different drugs:Yuanfang group,Fuzheng group,Quxie group and 0.9% NaCl.Then we can obtain protein of LSC. The last is getting the protein expressions by western blotting(WB)and analyzing the changes to summarize the mechanisms of NF-κB and FLT3 by herbs.And observe sex,ages,the WBC and aboriginal cells of BM of AML patients to research the relativity. Results: The expression of FLT3 is not existing differents in different ages and sex of AML patents(P>0.05).But you can get the result that there exists differents in different WBC and aboriginal cells of BM of AML patients(P<0.01). The proportion of FLT3 expression is 62.2 %. The proteinic expressions of NF-κB and FLT3 after different drugs treatment are have dissimilarity between random two groups(P<0.01)except Fuzheng group and Quxie groups(P>0.05). Conclusion: Positive expression of FLT3 in AML patients which are not existing relativity in ages and sex ,but has relativities with WBC and aboriginal cells of BM. Formula Herbs can reduce the exoression of FLT3 and NF-κB. And Yuanfang group can obviously resuce the expression comparing with Fuzheng group and Quxie group. Fuzheng group and Quxie group treatment effect are better when using together.
Objective:To research changes of proteinic expression in NF-κB (Nuclear Factor- Kappa B)and FLT3(Fms-like tyrosine kinase 3),and the mechanism of herbs to acute myelocytic leukemia cell(AML).Methods: BM(bone marrow)of forty-five AML patients were extracted to get monocytes .After that, by magneton selecting we can get leukemia stem cells.The third step is cultivating the LSC by four different drugs:Yuanfang group,Fuzheng group,Quxie group and 0.9% NaCl.Then we can obtain protein of LSC. The last is getting the protein expressions by western blotting(WB)and analyzing the changes to summarize the mechanisms of NF-κB and FLT3 by herbs.And observe sex,ages,the WBC and aboriginal cells of BM of AML patients to research the relativity. Results: The expression of FLT3 is not existing differents in different ages and sex of AML patents(P>0.05).But you can get the result that there exists differents in different WBC and aboriginal cells of BM of AML patients(P<0.01). The proportion of FLT3 expression is 62.2 %. The proteinic expressions of NF-κB and FLT3 after different drugs treatment are have dissimilarity between random two groups(P<0.01)except Fuzheng group and Quxie groups(P>0.05). Conclusion: Positive expression of FLT3 in AML patients which are not existing relativity in ages and sex ,but has relativities with WBC and aboriginal cells of BM. Formula Herbs can reduce the exoression of FLT3 and NF-κB. And Yuanfang group can obviously resuce the expression comparing with Fuzheng group and Quxie group. Fuzheng group and Quxie group treatment effect are better when using together.
引文
[1]吴勇,陈景龙,骆社丹,等.FLT3基因突变与IL-3受体α在急性髓系白血病的表达意义[J].福建医科大学学报,2008;42(3):199-202.
[2]徐勇,霍梅.免疫磁珠分离及流式细胞仪分选纯化外周血CD34+/CD90+干细胞.临床检验杂志,2004;22(4):246-248.
[3] Vaux DL,Cory s,Adams JM.Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells[J].Nature,1988;335:440.
[4]赵卫红,寿好长,闰福岭.细胞凋亡[M].河南:河南医科大学出版社,1997;4.
[5] Reed JC.Bcl-2 and regulation of progranuned cell death[J].Cell Biol, 1994;124(l-2):21.
[6] Camps L,Rouault JP,Sabido O,et al.High expression of bcl-2 protein in acute myeloid leukemia cell is associated with poor response to chemotherapy[J].Blood, 1993;81(11):3091-3096.
[7] Ichikawa A,Hotta T,Saito H.Mutations of the P53 gene in B-cell lymPhoma [J].leuk lymphoma,1993;11(l-2):21-25.
[8] Evan Gl,et al.Cell[M],1992;69:119.
[9] Chen Z,Brand NJ,Chen A,et al.Fusion between anovl Kruppel-like zine finger gene and the retinoic acid recaptor-alphalocus due to a variant t(11;17)transloeation assoeiated with acute promyeloeytic leukemia[J]. EMBOJ,1993;12:1161.
[10] Hitoshi Kiyoi,Tomoki Naoe,Yasuyuki Nakano,et al.Prognostic Implieation of Flt3 and N-RAS Gene Mutations in Acute Myeloid Lukemia[J].Blood, 1999;93(9):3074-3080.
[11]肖志坚,郝玉书.急性白血病治疗现况与未来[J].白血病·淋巴瘤,2006;15(1): 78-80.
[12] Smith M,Barnett M,Bassan R,et al.Adult acute myeloid leukemia[J].Cri Rev Oncol/Hematol,2004;50:197-222.
[13] Tallman MS,Gilliland DG,Rowe JM.Drug therapy for acute myeloid leukemia [J].Blood,2005;106(4):1154-1163.
[14] Ferrara F.Unanswered questions in acute myeloid leukaemai[J].The Lancet Oncol,2004;5(7):443-450.
[15] Sanz M A,Tallman M S,Lo-Coco F.Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia[J].Blood, 2005;105(8):3019-3025.
[16] Craddock C,Tauro S,Moss P,et al.Biology and management of relapsed acute myeloid leukaemia[J].Br J Haematol,2005;129(1):18-34.
[17] Larson RA.Acute lymphoblastic leukemia:older patients and newer drugs[M]. Hematology Am Soc Hematol Educ Program,2005:131-136.
[18]吴翰香,张亭栋,顾振东,等.白血病证治[J].中医杂志,1985;10:13-16.
[19]张亭栋.急性非淋巴细胞性白血病证治[J].中国中西医结合杂志,1985;12:713.
[20]王泽民,杜艳林,王婧.孙一民应用中药鲜药治疗急性白血病经验[J].北京中医药,2008;27(1):51-52.
[21]许晓峰,张学进,金璐.IA方案合中药治疗急性髓系白血病[J].浙江中西医结合杂志,2007;17(12):733-734.
[22]戴锡孟,于志峰,汪涛,等.中药扶正合剂介导白血病生物治疗的临床及实验研究[J].天津中医药,2003;20(4):29-31.
[23] Abu-Duhier FM,Goodeve AC,Wilson GA,et al.Genomic structure of human FLT3:implications for mutational analysis[J].Br J Haematol,2001;113: 1076-1077.
[24]王莉红,王建祥.FLT3与急性白血病的关系[J].中华血液学杂志,2003;24(5):278-280.
[25]赵敏.flt3激活机理及其检测在白血病中的应用[J].中国优生与遗传杂志,2006;14(5):125-127.
[26] Rosnet O,Marchetto S,deLapeyriere O,et al.Murine Flt3,a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family[J].Oncogene, 1991;6:1641-1650.
[27] Kelly LM,Liu Q,Kutok JL,et al.FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myelo-Prolifer- ative disease in a murine bone marrow transplant model[J].Blood,2002; 99:310-318.
[28] RomboutsWJ,BloklandI,LowenbergB,et al.Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplic- ations in the Flt3 gene[J].Leukemia,2000;14:675-68.
[29] Yokota S,Kiyoi H,Nakao M,et al.Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodys- plastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines[J].Leukemia,1997;11:1605- 1609.
[30] Mizuki M, Fenski R, Halfter H, et al. Flt3 mutations from patientswith acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways[J].Blood,2000;96:3907-3914.
[31] Meshinchi S,Woods WG,Stirewalt DL,et al.Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia[J].Blood,2001;97:89-94.
[32] Rombouts WJ,Lowenberg B,van Putten WL,et al.Improved prognostic significance of cytokine-induced proliferation in vitro in patients with de novo acute myeloid leukemia of intermediate risk: impact of internal tandem duplications in the Flt3 gene[J].Leukemia,2001;15: 1046-1053.
[33] Fenski R,Flesch K,Serve S,et al.Constitutive activation of FLT3 in acute myeloidleukaemia and its consequences for growth of 32D cells[J].BrJ Haematol,2000;108:322-330.
[34]马军,邱琳.急性白血病靶向治疗的新进展[J].中国处方药,2008;71(2):58-61.
[35] Sen R,Baltimore D.Mutiple nuclear factor interact with the immunog- lobulin enhancer sequenes[J].Cell,1986;46:705-716.
[36] VermaI M,Stevenson J K,Sehwarz E M,et al.Rel/NF-κB/IκB family:intomate tale of assoeiation and dissoeiation[J].Genes Dev,1995;9:2723-2735.
[37] Chen F,Castranova V,Shi X,et al.New insights into the role of Nuclear factor-κB,a ubiquitous transcription factor in the initiation of diseases[J].Clin Chem,1999;45:7-17.
[38] Baldwin AS Jr.The NF-κB and IκB proteins:new discoveries and insights[J].Annu Rev Immunol,1996;14:649-683.
[39] Ghosh S,May M J.Kopp EB:NF-κB and Relproteins: evolutionarilyconserved mediators of immune responses[J].Annu Rev Immunol,1998;16:225-260.
[40] Spiecker M,Darius H,Liao.A functional role of I kappaB-epsilon inendothelial cell activation[J].Immunol,2000;164:6184-6190。
[41] Zandi E,Chen Y, Karin M. Direct phosphorylation of IkappaB by IKKalpha and IKKbeta:discrimination between free and NF-kappaB-bound substrate [J].Science,1998,281:1360-1363.
[42] Yamaoka,S.et al.Complementation cloning of NEMO,a component of the IkappaB kinase complex essential for NF-kappaB activation[J].Cell,1998; 93:1231-1240.
[43] Shimada T,Kawai T,Takeda K,et al.IKK-i,a novel lipopolysac charide- inducible kinase that is related to IkappaB kinases[J].Int Immunol, 1999;11:1357-1362.
[44] SandorV,Senderowicz A,Mertins S,et al.P21-dependent g(1) arrestwith downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228[J].BrJ Cancer,2000;83:817-825.
[45] Hutchins JR,Hughes M,Clarke PR.Substrate specificity determinants of the checkpoint protein kinase Chk1[J].FEBS Lett,2000;466:91-95.
[46] Baidwin AS,Jr,Azizkhan JC,Jensen DE,et al.Induction of NF-κB DNA- binding activity during the G0-to-G1transition in mouse fibroblasts [J].Mol Cell Biol,1991;11(10):4943-4951.
[47] Bureau F,Vanderplasschen A,Jaspar F.Constitutive nuclear factor-κBactivity preserves homeostasis of quiescent mature lymphocytes and granulocytes by controlling the exprssion of distinet Bcl-2 familly proteins[J].Blood,2002;99(10):3683-3691.
[48] Guzman ML,Neering SJ,Upchurch D,et al.Nuclear factor-κB is constituti- vely activated in primitive human acute myelogenous leukemia cells[J]. Blood,2001;98(8):2301-2307.
[49] Zaninoni A,Imperiali FG,Pasquini C, et al. Cytokine modulation of nuclear factor-kappaB activity in B-chronic lymphocytic leukemia[J].Exp Hematol, 2003;31(3):185-190.
[50] Bureau F,Vanderplasschen A,Jaspar F.Constitutive nuclear factor-κB activity preserves homeostasis of quiescent mature lymphocytes and granulocytes by controlling the exprssion of distinet Bcl-2 familly proteins[J].Blood,2002;99(10):3683-3691.
[51] Munzert G, Kirchner D,Stobbe H.Tumor necrosis factor receptor-associated factor 1 gene overexpression in B-cell chronic lymphocytic leukemia: analysis of NF-kappaB/Rel-regulated inhibitors of apoptosis[J].Blood, 2002;100(10):3749-3756.
[52] Carow CE,Levenstein M,Kaufmann S H,et al. Expression of the hematopoietic growth factor receptor FLT3(STK-1/Flk2)in human leukemias[J].Blood, 1996;87(3):1089-1096.
[53] Ozeki K, Kiyoi H, Hirose Y,et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia[J].Blood,2004;103 (5):1901-1908.
[54] Kottaridis PD, Gale RE, Frew ME,et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia(AML)adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials[J]. Blood, 2001;98(6):1752-1759.
[55] Steudel C, Wermke M, Schaich M, et al. Comparative analysis of MLL partial tandem duplication and FLT3 internal tandem duplication mutations in 956 adult patients with acute myeloid leukemia[J]. Genes Chromosomes Cancer, 2003;37(3):237-51.
[1]陈敏章,邵丙扬.中华内科学[M].北京:人民卫生出版社,99:2772-2785.
[2]路瑾,黄晓军,单福香,等.左旋门冬酰胺酶不同用法副作用的观察[J].中国综合临床,2004;21(7):605-606.
[3]林凤茄,姚尔固,徐世荣,等.VAD方案治疗成人急性淋巴细胞白血病[J].山西白血病,1993;2(1):57-58.
[4]李娟,刘柯,张志彪.VDAP方案治疗急性淋巴细胞白血病疗效观察[J].实用诊断与治疗杂志,2008;22(2):151-152.
[5]蔡益鹏,方复海.VCAP方案治疗成人难治性急性淋巴细胞白血病22例疗效观察[J].临床医学,2002;22(1):15-16.
[6]罗鸣.米托蒽醌治疗急性淋巴细胞白血病临床16例分析[J].镇江医学院学报,1994;4(3):204-206.
[7] Thomas DA,Faderl S,Cortes J,et al.Treatment of Philadelphia chromosome- positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate[J].Blood,2004;103(12):4396-4407.
[8]赵朴,陈瑜,王爱华.FLAG方案治疗复发/难治的急性髓系白血病患者的临床研究[J].癌症进展杂志,2007;5(6):585-588.
[9] Jackson G H. Use of fludarabine in the treatment of acute myeloid leukemia[J].Hematol J,2004;5(l):62-67.
[10]王毓洲,隋雪梅,武永吉.协和医院1983年至1999年急性白血病初治诱导化疗分析[J].北京医学,2001;(23)4:211-212.
[11]吴翰香,张亭栋,顾振东,等.白血病证治[J].中医杂志,1985;10:10-16.
[12]焦中华,顾振东,等.中西医结合治疗高白细胞型急性白血病19例临床分析[J].中西医结合杂志,1989;9(8):582-583.
[13]杨新中.常见恶性肿瘤的中西医治疗[M].第一版.北京:北京医科大中国协和医科大学联合出版社.
[14]李世明.中药治疗急性白血病化疗后白细胞减少40例[J].河南中医,2002;22 (5):50 .
[15]马武开,张惠臣.中药复方防止急性白血病化疗毒副作用探讨[J].江西中医药,2007;1(1):42-43.
[16]张寅,李冬云,田邵丹,等.复方浙贝颗粒配方伍用化疗治疗难治性急性白血病临床研究[J].河北中医药学报,2006;21(4):9-12.
[17]徐瑞成,陈小义,陈莉,等.蟾蜍灵对HL-60细胞的生长抑制及凋亡诱导作用[J].中华血液学杂志,2000;21(7):359-361.
[18]谢新生,张秀丽,赵家军,等.穿山甲煎液诱导HL-60细胞凋亡的研究[J].浙江中西医结合杂志,2001;11(8):477-479.
[19]陈英玉,郑合勇,胡建达,等.大黄素抑制HL-60/ADR耐药细胞增殖和诱导凋亡的作用[J].中国实验血液学杂志,2007;15(5):955-960.
[20]郑敏,王亚平.当归多糖对K562细胞增殖抑制与诱导分化的实验研究[J].中国中西医结合杂志,2002;22(1):54-57.
[21]王来慈,肖肃,张志华,等.中药苦参治疗老年急非淋白血病的疗效观察[J].中医院学报,1993;1:18-19.
[22]李先荣,刘德宽,张燚,等.苦参生物碱抗小鼠移植性肿瘤的实验研究[J].中西医结合杂志,1982;2:42-43.
[23]孙伟正,胡青山.急性白血病的中医中药治疗[J].黑龙江医药,1979;4:32-34.
[2]徐勇,霍梅.免疫磁珠分离及流式细胞仪分选纯化外周血CD34+/CD90+干细胞.临床检验杂志,2004;22(4):246-248.
[3] Vaux DL,Cory s,Adams JM.Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells[J].Nature,1988;335:440.
[4]赵卫红,寿好长,闰福岭.细胞凋亡[M].河南:河南医科大学出版社,1997;4.
[5] Reed JC.Bcl-2 and regulation of progranuned cell death[J].Cell Biol, 1994;124(l-2):21.
[6] Camps L,Rouault JP,Sabido O,et al.High expression of bcl-2 protein in acute myeloid leukemia cell is associated with poor response to chemotherapy[J].Blood, 1993;81(11):3091-3096.
[7] Ichikawa A,Hotta T,Saito H.Mutations of the P53 gene in B-cell lymPhoma [J].leuk lymphoma,1993;11(l-2):21-25.
[8] Evan Gl,et al.Cell[M],1992;69:119.
[9] Chen Z,Brand NJ,Chen A,et al.Fusion between anovl Kruppel-like zine finger gene and the retinoic acid recaptor-alphalocus due to a variant t(11;17)transloeation assoeiated with acute promyeloeytic leukemia[J]. EMBOJ,1993;12:1161.
[10] Hitoshi Kiyoi,Tomoki Naoe,Yasuyuki Nakano,et al.Prognostic Implieation of Flt3 and N-RAS Gene Mutations in Acute Myeloid Lukemia[J].Blood, 1999;93(9):3074-3080.
[11]肖志坚,郝玉书.急性白血病治疗现况与未来[J].白血病·淋巴瘤,2006;15(1): 78-80.
[12] Smith M,Barnett M,Bassan R,et al.Adult acute myeloid leukemia[J].Cri Rev Oncol/Hematol,2004;50:197-222.
[13] Tallman MS,Gilliland DG,Rowe JM.Drug therapy for acute myeloid leukemia [J].Blood,2005;106(4):1154-1163.
[14] Ferrara F.Unanswered questions in acute myeloid leukaemai[J].The Lancet Oncol,2004;5(7):443-450.
[15] Sanz M A,Tallman M S,Lo-Coco F.Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia[J].Blood, 2005;105(8):3019-3025.
[16] Craddock C,Tauro S,Moss P,et al.Biology and management of relapsed acute myeloid leukaemia[J].Br J Haematol,2005;129(1):18-34.
[17] Larson RA.Acute lymphoblastic leukemia:older patients and newer drugs[M]. Hematology Am Soc Hematol Educ Program,2005:131-136.
[18]吴翰香,张亭栋,顾振东,等.白血病证治[J].中医杂志,1985;10:13-16.
[19]张亭栋.急性非淋巴细胞性白血病证治[J].中国中西医结合杂志,1985;12:713.
[20]王泽民,杜艳林,王婧.孙一民应用中药鲜药治疗急性白血病经验[J].北京中医药,2008;27(1):51-52.
[21]许晓峰,张学进,金璐.IA方案合中药治疗急性髓系白血病[J].浙江中西医结合杂志,2007;17(12):733-734.
[22]戴锡孟,于志峰,汪涛,等.中药扶正合剂介导白血病生物治疗的临床及实验研究[J].天津中医药,2003;20(4):29-31.
[23] Abu-Duhier FM,Goodeve AC,Wilson GA,et al.Genomic structure of human FLT3:implications for mutational analysis[J].Br J Haematol,2001;113: 1076-1077.
[24]王莉红,王建祥.FLT3与急性白血病的关系[J].中华血液学杂志,2003;24(5):278-280.
[25]赵敏.flt3激活机理及其检测在白血病中的应用[J].中国优生与遗传杂志,2006;14(5):125-127.
[26] Rosnet O,Marchetto S,deLapeyriere O,et al.Murine Flt3,a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family[J].Oncogene, 1991;6:1641-1650.
[27] Kelly LM,Liu Q,Kutok JL,et al.FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myelo-Prolifer- ative disease in a murine bone marrow transplant model[J].Blood,2002; 99:310-318.
[28] RomboutsWJ,BloklandI,LowenbergB,et al.Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplic- ations in the Flt3 gene[J].Leukemia,2000;14:675-68.
[29] Yokota S,Kiyoi H,Nakao M,et al.Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodys- plastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines[J].Leukemia,1997;11:1605- 1609.
[30] Mizuki M, Fenski R, Halfter H, et al. Flt3 mutations from patientswith acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways[J].Blood,2000;96:3907-3914.
[31] Meshinchi S,Woods WG,Stirewalt DL,et al.Prevalence and prognostic significance of Flt3 internal tandem duplication in pediatric acute myeloid leukemia[J].Blood,2001;97:89-94.
[32] Rombouts WJ,Lowenberg B,van Putten WL,et al.Improved prognostic significance of cytokine-induced proliferation in vitro in patients with de novo acute myeloid leukemia of intermediate risk: impact of internal tandem duplications in the Flt3 gene[J].Leukemia,2001;15: 1046-1053.
[33] Fenski R,Flesch K,Serve S,et al.Constitutive activation of FLT3 in acute myeloidleukaemia and its consequences for growth of 32D cells[J].BrJ Haematol,2000;108:322-330.
[34]马军,邱琳.急性白血病靶向治疗的新进展[J].中国处方药,2008;71(2):58-61.
[35] Sen R,Baltimore D.Mutiple nuclear factor interact with the immunog- lobulin enhancer sequenes[J].Cell,1986;46:705-716.
[36] VermaI M,Stevenson J K,Sehwarz E M,et al.Rel/NF-κB/IκB family:intomate tale of assoeiation and dissoeiation[J].Genes Dev,1995;9:2723-2735.
[37] Chen F,Castranova V,Shi X,et al.New insights into the role of Nuclear factor-κB,a ubiquitous transcription factor in the initiation of diseases[J].Clin Chem,1999;45:7-17.
[38] Baldwin AS Jr.The NF-κB and IκB proteins:new discoveries and insights[J].Annu Rev Immunol,1996;14:649-683.
[39] Ghosh S,May M J.Kopp EB:NF-κB and Relproteins: evolutionarilyconserved mediators of immune responses[J].Annu Rev Immunol,1998;16:225-260.
[40] Spiecker M,Darius H,Liao.A functional role of I kappaB-epsilon inendothelial cell activation[J].Immunol,2000;164:6184-6190。
[41] Zandi E,Chen Y, Karin M. Direct phosphorylation of IkappaB by IKKalpha and IKKbeta:discrimination between free and NF-kappaB-bound substrate [J].Science,1998,281:1360-1363.
[42] Yamaoka,S.et al.Complementation cloning of NEMO,a component of the IkappaB kinase complex essential for NF-kappaB activation[J].Cell,1998; 93:1231-1240.
[43] Shimada T,Kawai T,Takeda K,et al.IKK-i,a novel lipopolysac charide- inducible kinase that is related to IkappaB kinases[J].Int Immunol, 1999;11:1357-1362.
[44] SandorV,Senderowicz A,Mertins S,et al.P21-dependent g(1) arrestwith downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228[J].BrJ Cancer,2000;83:817-825.
[45] Hutchins JR,Hughes M,Clarke PR.Substrate specificity determinants of the checkpoint protein kinase Chk1[J].FEBS Lett,2000;466:91-95.
[46] Baidwin AS,Jr,Azizkhan JC,Jensen DE,et al.Induction of NF-κB DNA- binding activity during the G0-to-G1transition in mouse fibroblasts [J].Mol Cell Biol,1991;11(10):4943-4951.
[47] Bureau F,Vanderplasschen A,Jaspar F.Constitutive nuclear factor-κBactivity preserves homeostasis of quiescent mature lymphocytes and granulocytes by controlling the exprssion of distinet Bcl-2 familly proteins[J].Blood,2002;99(10):3683-3691.
[48] Guzman ML,Neering SJ,Upchurch D,et al.Nuclear factor-κB is constituti- vely activated in primitive human acute myelogenous leukemia cells[J]. Blood,2001;98(8):2301-2307.
[49] Zaninoni A,Imperiali FG,Pasquini C, et al. Cytokine modulation of nuclear factor-kappaB activity in B-chronic lymphocytic leukemia[J].Exp Hematol, 2003;31(3):185-190.
[50] Bureau F,Vanderplasschen A,Jaspar F.Constitutive nuclear factor-κB activity preserves homeostasis of quiescent mature lymphocytes and granulocytes by controlling the exprssion of distinet Bcl-2 familly proteins[J].Blood,2002;99(10):3683-3691.
[51] Munzert G, Kirchner D,Stobbe H.Tumor necrosis factor receptor-associated factor 1 gene overexpression in B-cell chronic lymphocytic leukemia: analysis of NF-kappaB/Rel-regulated inhibitors of apoptosis[J].Blood, 2002;100(10):3749-3756.
[52] Carow CE,Levenstein M,Kaufmann S H,et al. Expression of the hematopoietic growth factor receptor FLT3(STK-1/Flk2)in human leukemias[J].Blood, 1996;87(3):1089-1096.
[53] Ozeki K, Kiyoi H, Hirose Y,et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia[J].Blood,2004;103 (5):1901-1908.
[54] Kottaridis PD, Gale RE, Frew ME,et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia(AML)adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials[J]. Blood, 2001;98(6):1752-1759.
[55] Steudel C, Wermke M, Schaich M, et al. Comparative analysis of MLL partial tandem duplication and FLT3 internal tandem duplication mutations in 956 adult patients with acute myeloid leukemia[J]. Genes Chromosomes Cancer, 2003;37(3):237-51.
[1]陈敏章,邵丙扬.中华内科学[M].北京:人民卫生出版社,99:2772-2785.
[2]路瑾,黄晓军,单福香,等.左旋门冬酰胺酶不同用法副作用的观察[J].中国综合临床,2004;21(7):605-606.
[3]林凤茄,姚尔固,徐世荣,等.VAD方案治疗成人急性淋巴细胞白血病[J].山西白血病,1993;2(1):57-58.
[4]李娟,刘柯,张志彪.VDAP方案治疗急性淋巴细胞白血病疗效观察[J].实用诊断与治疗杂志,2008;22(2):151-152.
[5]蔡益鹏,方复海.VCAP方案治疗成人难治性急性淋巴细胞白血病22例疗效观察[J].临床医学,2002;22(1):15-16.
[6]罗鸣.米托蒽醌治疗急性淋巴细胞白血病临床16例分析[J].镇江医学院学报,1994;4(3):204-206.
[7] Thomas DA,Faderl S,Cortes J,et al.Treatment of Philadelphia chromosome- positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate[J].Blood,2004;103(12):4396-4407.
[8]赵朴,陈瑜,王爱华.FLAG方案治疗复发/难治的急性髓系白血病患者的临床研究[J].癌症进展杂志,2007;5(6):585-588.
[9] Jackson G H. Use of fludarabine in the treatment of acute myeloid leukemia[J].Hematol J,2004;5(l):62-67.
[10]王毓洲,隋雪梅,武永吉.协和医院1983年至1999年急性白血病初治诱导化疗分析[J].北京医学,2001;(23)4:211-212.
[11]吴翰香,张亭栋,顾振东,等.白血病证治[J].中医杂志,1985;10:10-16.
[12]焦中华,顾振东,等.中西医结合治疗高白细胞型急性白血病19例临床分析[J].中西医结合杂志,1989;9(8):582-583.
[13]杨新中.常见恶性肿瘤的中西医治疗[M].第一版.北京:北京医科大中国协和医科大学联合出版社.
[14]李世明.中药治疗急性白血病化疗后白细胞减少40例[J].河南中医,2002;22 (5):50 .
[15]马武开,张惠臣.中药复方防止急性白血病化疗毒副作用探讨[J].江西中医药,2007;1(1):42-43.
[16]张寅,李冬云,田邵丹,等.复方浙贝颗粒配方伍用化疗治疗难治性急性白血病临床研究[J].河北中医药学报,2006;21(4):9-12.
[17]徐瑞成,陈小义,陈莉,等.蟾蜍灵对HL-60细胞的生长抑制及凋亡诱导作用[J].中华血液学杂志,2000;21(7):359-361.
[18]谢新生,张秀丽,赵家军,等.穿山甲煎液诱导HL-60细胞凋亡的研究[J].浙江中西医结合杂志,2001;11(8):477-479.
[19]陈英玉,郑合勇,胡建达,等.大黄素抑制HL-60/ADR耐药细胞增殖和诱导凋亡的作用[J].中国实验血液学杂志,2007;15(5):955-960.
[20]郑敏,王亚平.当归多糖对K562细胞增殖抑制与诱导分化的实验研究[J].中国中西医结合杂志,2002;22(1):54-57.
[21]王来慈,肖肃,张志华,等.中药苦参治疗老年急非淋白血病的疗效观察[J].中医院学报,1993;1:18-19.
[22]李先荣,刘德宽,张燚,等.苦参生物碱抗小鼠移植性肿瘤的实验研究[J].中西医结合杂志,1982;2:42-43.
[23]孙伟正,胡青山.急性白血病的中医中药治疗[J].黑龙江医药,1979;4:32-34.