摘要
第一部分Wnt信号途径在衰老造血干细胞中的变化研究
【目的】研究衰老造血干细胞中Wnt信号途径的变化情况。
【方法】以端粒酶功能缺陷小鼠(TERC-/-)为研究对象,分别分离TERC-/-小鼠及野生型(wide type,WT)小鼠全骨髓细胞,以普通PCR方法对Wnt信号途径的相关分子的表达差异进行初步筛查,并用western blot检测感兴趣分子的蛋白表达。进一步通过磁珠分选及流式细胞仪分别分选TERC-/-小鼠及WT小鼠造血干细胞,对Wnt信号通路中差异表达的相关基因进一步行实时定量PCR检测验证。
【结果】Wnt5b转录本在TERC-/-小鼠全骨髓细胞中表达显著升高;Fzd1、Lef1转录本在TERC-/-小鼠全骨髓细胞及造血干细胞中表达均显著减低。Lef1蛋白表达水平在TERC-/-小鼠全骨髓细胞中显著降低。
【结论】衰老造血干细胞及骨髓细胞中Wnt经典信号途径表达水平显著下调,衰老骨髓细胞Wnt非经典信号途径表达水平显著上调,可能与衰老造血干细胞再生能力下降有关。
第二部分造血干细胞联合AGM基质细胞移植对骨髓移植小鼠造血重建影响
【目的】探讨造血干细胞与主动脉—性腺—中肾(Aorta-gonad-mesonephros,AGM)区来源的基质细胞联合移植对同基因骨髓移植(bone marrow transplantation,BMT)小鼠骨髓造血重建的影响。
【方法】建立同基因骨髓移植小鼠模型,随机分成3组:空白对照组、单纯BMT组、BMT联合AGM基质细胞移植组(联合移植组),另设正常组小鼠6只。分别于BMT后第7、14、21、28天检测外周血白细胞及血小板、骨髓单个核细胞(bone marrowmono-nuclear cells,BMMNC)的变化,并同时于BMT后第7、10、21天检测骨髓组织学变化。
【结果】联合移植组外周血白细胞及血小板计数、骨髓单个核细胞及骨髓造血组织恢复均较单纯BMT组快,有显著性差异(p<0.05)。
【结论】BMT联合AGM基质细胞移植对骨髓移植小鼠造血重建具有促进作用。
第三部分三氧化二砷联合全反式维甲酸治疗急性早幼粒细胞白血病的意义研究
【目的】探讨三氧化二砷(As_2O_3)与全反式维甲酸(ATRA)联合治疗急性早幼粒细胞白血病的临床意义。
【方法】对80例急性早幼粒细胞白血病患者回顾性分析,将患者分为单用ATRA组和ATRA与As_2O_3联用组,比较两组间完全缓解(CR)、早期死亡、血象恢复及不良反应发生率等的差异。
【结果】联用组与单用组CR率分别为91.7%和88.2%,无统计学差异;联用组达CR时间、血红蛋白及血小板恢复时间分别为(28±7.8)天、(22.36±8.72)天和(19.38±9.52)天,而单用组分别为(47.7±10.9)天、(28.40±8.95)天和(28.03±7.29)天,联用组与单用组相比均明显缩短:联用组早期死亡率11.1%较单用组20.8%有降低趋势;两组不良反应发生率无显著性差异。
【结论】ATRA与As_2O_3联用治疗初治APL患者较单用ATRA有优势,有望降低早期死亡率,且联用不加重不良反应。
Purpose: To analyze gene expression changes of components of the Wnt signaling pathwayin aging hematopoietic stem cells.
Methods: Use ordinary PCR, real time PCR and western blot to analyze Wnt componentsexpression in bone marrow cells and hematopoietic stem cells isolated from TERC-/- mice(telomerase-deficient mice null for the telomerase RNA component)and wide type mice bymagnetic bead sorting (MACS) and fluorescence activated cell sorting (FACS).
Results: Wnt5b transcripts were significantly upregulated in total bone marrow cells ofTERC -/- mice, while Fzdl and Lefl transcripts were significantly downregulated in totalbone marrow cells as well as hematopoietic stem cells of TERC -/- mice. Lefl was alsodownregulated at protein level in total bone marrow of TERC -/- mice.
Conclusion: The canonical Wnt signaling pathway was downregulated in total bonemarrow cells as well as in hematopoietic stem cells of TERC -/- mice, while thenoncanonical Wnt signaling pathway was upregulated in total bone marrow cells in TERC-/- mice, which might contribute to the impaired regenaration ability of stem cells of theaccelerated aging mice.
Objective: To explore the effects of cotransplantation of hematopoietic stem cells (HSC)and stromal cells derived from aorta-gonad-mesonephros (AGM) region on hematopoieticreconstitution in mice after bone marrow transplantation.
Methods: The typical model of syngeneic BMT was established and the model mice wererandomly divided into 3 groups: the control group, the BMT group, and the group ofcotransplantation of HSC with AGM stromal cells (the cotransplantation group). Thefollowing factors were measured on day 7, 10, 14, 21 and 28 after BMT: peripheral whiteblood cells(WBC) and platelets(PLT), bone marrow mononuclear cells (BMMNC), andhistology changes of bone marrow.
Results: The levels of peripheral WBC, PLT and BMMNC in the contransplantation groupwere higher than those of the single BMT group and the control group.
Conclusion: Cotransplantation with AGM stromal cells could significantly promotehematopoietic reconstruction in mice after BMT. Cotransplantation may represent apromising means of achieving higher engraftment rate after BMT.
Purpose: This study moves towards this goal in understanding the significance ofcombined therapy of arsenic trioxide (As_2O_3) and all-trans retinoic acid (ATRA) in acutepromyelocytic leukemia (APL).
Methods: Retrospective study of 80 APL patients was performed and the completeremission (CR), the recovery of the hemogram, the early mortality, and the adverse effectrates were analyzed between the ATRA group and the combined group.
Results: CR rates of the two groups were 91.7% and 88.2% respectively, which showsno significant difference; time of reaching CR, hemoglobin recovery, and platelet recoveryfor the combined group were (28±7.8)days, (22.36±8.72)days and (19.38±9.52) daysrespectively, while those were (47.7±10.9) days,(28.40±8.95) days and (28.03±7.29) daysfor the ATRA group, which suggested a significantly shorter period of the combined groupof achieving recovery. With 11.1% compared to 20.8%, the mortality of the combinedgroup seemed lower than that of the ATRA group but no significance was observed. Theadverse effect rates of the two groups also lacked of significant difference.
Conclusions: Compared to using ATRA alone, combined therapy of As_2O_3 and ATRAwas dominant in achieving CR and recovery for APL. Besides, the combined therapycarries the promise of reducing the early mortality with no aggravation of the adverseeffects.
引文
[1] Manuel Collado, Maria A. Blasco, Manuel Serrano, et al. Cellular Senescence in Cancer and Aging. Cell, 2007, 130(2), 223-233
[2] S. Chan, J. Chang, J. Prescott, et al. Altering telomere structure allows telomerase to act in yeast lacking ATM kinases. Curr Biol., 2001, 11(16): 1240-1250
[3] Lange T. Sheltering: the protein complex that shapes and safeguards human telomeres. Genes Dev., 2005, 19(18): 2100-2110
[4] Blasco M.A. Telomeres and human disease: ageing, cancer and beyond. Nat. Rev. Genet, 2005, 6(8): 611-622
[5] Wulandari Djojosubroto, Yoon Sik Choi, Han-Woong Lee, et al. Telomeres and Telomerase in Aging, Regeneration and Cancer. Mol. Cells, 15(2): 164-175
[6] Collins K, and Mitchell J.R. Telomerase in the human organism. Oncogene, 2002, 21(4): 564-579
[7] Ande Satyanarayana, Michael P. Manns, K. Lenhard Rudolph. Telomeres, Telomerase and Cancer. Cell Cycle, 2004, 3(9): 1138-1150
[8] Zhenyu Ju, Hong Jiang, Maike Jaworski, et al. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nature Medicine, 2007, 13(6): 742-747
[9] Zhang R, Poustovoitov MV, Ye X, et al. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASFla and HIRA. Dev Cell, 2005, 8(1):19-30
[10] Ashton KJ, Willems L, Holmgren K, et al. Ageassociated shifts in cardiac gene transcription and transcriptional responses to ischemic stress. Exp Gerontol, 2006 41(2): 189-204
[11] Nusse, R. Wnt signaling in disease and in development. Cell Res, 2005, 15(1): 28-32
[12] Staal, F.J., Luis, T.C., and Tiemessen, M.M.. WNT signalling in the immune system: WNT is spreading its wings. Nat. Rev. Immunol., 2008 8(8): 581-593
[13] Sachin Malhotra and Paul W. Kincade, Wnt-Related Molecules and Signaling Pathway Equilibrium in Hematopoiesis, Cell Stem Cell, 2009, 4(1): 27-36
[14] Mulroy, T, McMahon J.A, Burakoff S.J, et al. Wnt-1 and Wnt-4 regulate thymic cellularity. Eur. J. Immunol. 2002, 32(4): 967-971
[15] Willert, K., Brown, J.D., Danenberg, E., et al. Wnt proteins are lipid-modified and canact as stem cell growth factors. Nature, 2003, 423(6938), 448-452
[16] Malhotra, S., and Kincade, P.W. Canonical Wnt pathway signaling suppresses VCAM-1 expression by marrow stromal and hematopoietic cells. Exp. Hematol, 2009, 37(1): 19-30
[17] Luis T.C, Weerkamp F, Naber B.A. Wnt3a deficiency irreversibly impairs hematopoietic stem cell selfrenewal and leads to defects in progenitor cell differentiation. Blood, 2009, 113(3): 546-554
[18] Liang H, Chen Q, Coles AH, et al. Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. Cancer Cell, 2003, 4(5): 349-360
[19] Hongjun Liu, Maria M Fergusson, Rogerio M. Castilho, et al. Augmented Wnt Signaling in a Mammalian Model of Accelerated Aging. Science, 2007, 317(5839): 803-806
[1] M. Collado, M. Blasco, M. Serrano. Cellular Senescence in Cancer and Aging. Cell, 2007, 130(2): 223-233
[2] Feng J, Funk WD, Wang SS, et al. The RNA component of human telomerase. Science, 1995,269(5228): 1236-1241
[3] Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell, 1985, 43(2 Pt l):405-413
[4] Meyerson M, Counter CM, Eaton EN, et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell, 1997, 90(4): 785-795
[5] Nugent CI, Lundblad V. (1998) The telomerase reverse transcriptase: components and regulations. Genes Dev., 1998, 12(8): 1073-1085
[6] Chiu C. P., Dragowska W., Kim N. W. et al. Differential expression of telomerase activity in hematopoietic progenitors from adult human bone marrow. Stem Cells, 1996, 14(2): 239-248
[7] Br(?)mmendorf TH, Rufer N, Holyoake TL, et al. Telomere length dynamics in normal individuals and in patients with hematopoietic stem cellassociated disorders. Ann. NY. Acad. Sci. 2001, 938: 293-303.
[8] Vulliamy T, Marrone A, Dokal I, et al. Association between aplastic anaemia and mutations in telomerase RNA. Lancet, 2002, 359(9324): 2168-2170
[9] Rudolph K L, Chang S, Millard M, et al. Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science, 2000, 287(5456): 1253-1258
[10] Djojosubroto MW, Choi YS, Lee HW, et al. Telomeres and Telomerase in Aging, Regeneration and Cancer. Mol Cells, 2003, 15(2): 164-175
[11] Lee HW, Blasco MA, Gottlieb GJ, et al. Essential role of mouse telomerase in highly proliferative organs. Nature, 1998, 392(6676): 569-574
[12] Rudolph KL, Chang S, Lee HW, et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell, 1999, 96(5): 701-712
[13] Zhenyu Ju, Hong Jiang, Maike Jaworski, et al. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nature medicine, 2007, 13(6): 742-747
[14] Reya T and Clevers H. Wnt signalling in stem cells and cancer. Nature, 2005, 434(7035): 843-850.
[15] Topol L., Jiang X., Choi H. et al. (2003). Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3-independent b-catenin degradation. J. Cell Biol., 2003, 162(5): 899-908
[16] Nemeth MJ, Bodine DM. Regulation of hematopoiesis and thehematopoietic stem cell niche by Wnt signaling pathways. Cell Res. 2007, 17(9): 746-758
[17] Malhotra S, Kincade PW. Wnt-Related Molecules and Signaling Pathway Equilibrium in Hematopoiesis. Cell Stem Cell, 2009, 4(1): 27-36
[18] Konstantin Petropoulos, Natalia Arseni, Christina Schessl, et al. A novel role for Lef-l,a central transcription mediator of Wnt signaling, in leukemogenesis. J Exp Mod.. 2008. 205(3) 515-522
[19] Wu QL, Zierold C, and Ranheim EA. Dysregulation of frizzled 6 is a critical component of B cell leukemogenesis in a mouse model of chronic lymphocytic leukemia. Blood, 2009, 113(13): 3031-3039
[1] 高汉林,谢蜀生,杨四旬等。胸腺基质细胞促进骨髓移植小鼠免疫功能重建。中华血液学杂志,1995 Feb;16(2):81-83
[2] Devine SM, Hoffman R. Role of mesenchymal stem cells in hematopoietic stem cell transplantation. Curr Opin Hematol. 2000 Nov;7(6):358
[3] Gurevitch O, Prigozhina TB, Pugatsch T, et al. Transplantation of allogeneic or xenogeneic bone marrow within the donor stromal microenvironment.Transplantation. 1999 Nov 15;68(9):1362
[4] Lutzko C, Meertens L, Li L, et al. Human hematopoietic progenitors engraft in fetal canine recipients and expand with neonatal injection of fibroblasts expressing human hematopoietic cytokines(J). Exp Hematol,2002,30(7):801-8
[5] Janczewska S, Wisniewski M, Stepkowski SM, et al. Fast hematopoietic recovery after bone marrow engraftment needs physiological proximity of stromal and stem cells(J). Cell Transplant,2003,12(4):399-406
[6] Graca Almeida-Porada, Christopher D. Porada, Nam Tran,et al. Cotransplantation of human stromal cell progenitors into preimmune fetal sheep results in early appearance of human donor cells in circulation and boosts cell levels in bone marrow at later time points after transplantation.Blood.2000;95(11):3620-3627
[7] Nobuhisa I,Kato R, Inoue H,et al.Spred-2 suppresses aorta-gonad-mesonephros hematopoiesis by inhibiting MAP kinase activation.J Exp Med,2004,199(5):737
[8] Xu MJ,Tsuji K,Ueda T,et al.Stimulation of mouse and human primitive hematopoiesis by murine embryonic aorta-gonad-mesonephros-derived stromal cell lines.Blood, 1998, 92(6):2032
1 秘营昌,王建祥。我国急性白血病的诊断治疗现状。国际输血及血液学杂志,2006,29(4):290-291
2 Hu J, Shen ZX, Sun GL, et al. Long-term survival and prognostic study in acute promyelocytic leukemia treated with all-trans retinoic acid, chemotherapy, and As_2O_3: an experience of 120 patients at a single institution. Int J Hematol, 1999,70:248-260
3 National Comprehensive Cancer Network.Clinical Practice Guidelines in Oncology-Acute Myeloid Leukemia. Version 1.2006
4 Gianni M, Koken M H, Chelbi A M K, et al. Combined arsenic and retino ic acid treatment enhances differentiation and apoptosis in arsenic2resistant NB4 cells [J]. Blood, 1998, 91: 4300-4310
5 Shao W L, Fanelli M, Ferrara F F, et al. Arsenic trioxide as an inducer of apoptosis and loss of PML/RARalpha protein in acute promyelocytic leukemia [J]. J Natl Cancer Inst, 1998, 90: 124-133
6 刘元日方,沈志祥,陈晓等。全反式维甲酸联合三氧化二砷治疗初发急性早幼粒细胞白血病的近期疗效观察。中华血液学杂志,2003,24(1):25-27
7 王冠军,李薇,崔久嵬等。三氧化二砷联合小剂量全反式维甲酸诱导急性早幼粒细胞白血病缓解的疗效分析。中华医学杂志,2005,85(16):1093-1096
8 任金海,林凤茹,郭晓楠。全反式维甲酸、三氧化二砷及联合化疗治疗急性早幼粒细胞白血病临床观察。中华血液学杂志。2004,25(7):437-438
9 孙关林,黄永光,常晓芬,等.全反式维甲酸治疗544例急性早幼粒细胞白血病的临床研究.中华血液学杂志,1992,12:1352137.
10 姚尔固,徐世荣,董作仁。新编白血病化疗学1天津:天津科学技术出版社,1999,68-73
11 沈志祥,陈国强,陈赛娟等。三氧化二砷单用或联合全反式维甲酸治疗急性早幼粒细胞白血病临床及作用机制研究。上海医学,2004,27(10):731
12 张鹏。关于三氧化二砷与全反式维甲酸联合治疗急性早幼粒细胞白血病的浅见。白血病·淋巴瘤。2002,11 (2):117
[1] Heissig B,Ohki Y, Sato Y,et al.A role for niches in hematopoietic cell development(J). Hematology,2005,10:247-53
[2] Sacchetti B, Funari A, Michienzi S, Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell. 2007 Oct 19;131(2):324-36
[3] Fromigu(?) O, Hamidouche Z, Chateauvieux S, Distinct osteoblastic differentiation potential of murine fetal liver and bone marrow stroma-derived mesenchymal stem cells. J Cell Biochem. 2008 May 15;104(2):620-8
[4] Zhu J,Emerson SG..A new bone to pick: osteoblasts and the haematopoietic stem-cell niche(J).Bioessays,2004,26:595-9
[5] Stier S,Ko Y,Forkert R,et al. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size(J).J Exp Med,2005,201:1781-1791
[6] Arai F,Hirao A,Suda T,et al. Regulation of hematopoietic stem cells by the niche(J).Trends Cardiovasc Med.Trends Cardiovasc Med,2005,15:75-9
[7] Yamaguchi M, Hirayama F, Kanai M, et al. Serum-free coculture system for ex vivo expansion of human cord blood primitive progenitors and SCID mouse-reconstituting cells using human bone marrow primary stromal cells. Exp Hematol. 2001 Feb;29(2): 174
[8] Samokhvalov IM, Samokhvalova NI, Nishikawa S, et al. Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature. 2007 Apr 26;446(7139):996-7.
[9] Weisel KC,Moore MA. Genetic and functional characterization of isolated stromal cell lines from the aorta-gonado-mesonephros region(J).Ann N Y Acad Sci,2005,1044:51-9
[10] 陈惠芹,张绪超,黄绍良等。人胚胎AGM区基质细胞在体外培养中对脐血CD34~+细胞的支持作用。中华血液学杂志。2006,27(6):390-393
[11] Zambidis ET, Sinka L, Tavian M, Emergence of human angiohematopoietic cells in normal development and from cultured embryonic stem cells. Ann N Y Acad Sci. 2007 Jun;1106:223-32
[12] Kusadasi N,Oostendorp RA,Koevoet WJ,et al. Stromal cells from murine embryonic aorta-gonad-mesonephros region, liver and gut mesentery expand human umbilical cord blood-derived CAFC(week6) in extended long-term cultures(J).Leukemia,2002,16:1782-90
[13]Miao Z, Jin J, Chen L. Isolation of mesenchymal stem cells from human placenta: comparison with human bone marrow mesenchymal stem cells. Cell Biol Int. 2006 Sep;30(9):681-7
[14] Gekas C,Dieterlen-Lievre F,Orkin SH,et al. The placenta is a niche for hematopoietic stem cells(J).Dev Cell,2005,8:365-75
[15] Kucia M, Wysoczynski M, Ratajczak J .Identification of very small embryonic like (VSEL) stem cells in bone marrow. Cell Tissue Res. 2008 Jan;331(1): 125-34.
[16] Janczewska S,Wisniewski M,Stepkowski SM,et al. Fast hematopoietic recovery after bone marrow engraftment needs physiological proximity of stromal and stem cells(J). Cell Transplant,2003,12:399-406
[17] Chung NG,Jeong DC,Park SJ,et al. Cotransplantation of marrow stromal cells may prevent lethal graft-versus-host disease in major histocompatibility complex mismatched murine hematopoietic stem cell transplantation(J). Int J Hematol,2004,80:370-6
[18]Sundin M, Remberger M, L(?)nnies H. No increased trapping of multipotent mesenchymal stromal cells in bone marrow filters compared with other bone marrow cells. Cytotherapy. 2008;10(3):238-42
[19] Krupnick AS,Shaaban A,Radu A,et al. Bone marrow tissue engineering(J).Tissue Eng,2002,8:145-55
[20] Zhang Y,Adachi Y,Suzuki Y,et al. Simultaneous injection of bone marrow cells and stromal cells into bone marrow accelerates hematopoiesis in vivo(J).Stem Cells,2004,22:1256-62
[21] Cahill RA,Jones OY,Klemperer M,et al. Replacement of recipient stromal/mesenchymal cells after bone marrow transplantation using bone fragments and cultured osteoblast-like cells(J). Biol Blood Marrow Transplant,2004,10:709-17
[22] Li A,Jiang J,Zhang Q,et al. Cytokines transduced bone marrow stromal cell lines promote immunohematopoietic reconstitution in mice after allogeneic bone marrow transplantation(J). Immunol Lett,2005,98:216-24
[23] Lazarus HM, Koc ON,Devine SM. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients(J). Biol Blood Marrow Transplant,2005,11:389-98
[24] Jones OY,Good RA,Cahill RA,et al. Nonmyeloablative allogeneic bone marrow transplantation for treatment of childhood overlap syndrome and small vessel vasculitis(J).Bone Marrow Transplant,2004,33:1061-3
[25] Almeida-Porada G,Flake AW,Glimp HA,et al. Cotransplantation of stroma results in enhancement of engraftment and early expression of donor hematopoietic stem cells in utero(J). Exp Hematol,1999,27:1569-75
[1] Cross D, Burmester JK. Gene therapy for cancer treatment: past, present and future [J]. Clin Med Res, 2006 , 4(3): 218-27
[2] Butterfield LH. Recent advances in immunotherapy for hepatocellular cancer [J]. Swiss Med Wkly, 2007,137:83-90
[3] V. M. Moiseyenko, A. O, Danilov, I. A. Baldueva,et al. Phase Ⅰ/Ⅱ trial of gene therapy with autologous tumor cells modified with tag7/PGRP-S gene in patients with disseminated solid tumors [J]. Annals of Oncology,2005, 16: 162-168
[4] Mark E. Dudley, John R. Wunderlich, Paul F. Robbins, et al. Cancer Regression and Autoimmunity in Patients After Clonal Repopulation with Antitumor Lymphocytes [J]. Science,2002,298(5594):850-4
[5] Ming Shi, Bing Zhang, Zi-Rong Tang, et al. Autologous cytokine-induced killer cell therapy in clinical trial phase I is safe in patients with primary hepatocellular carcinoma [J]. World J Gastroenterol, 2004,10(8): 1146-1151
[6] Lisa H. Butterfield,Antoni Ribas,Vivian B. Dissette, et al. A Phase I/II TrialTesting Immunization of Hepatocellular Carcinoma Patientswith Dendritic Cells Pulsed with Four A-Fetoprotein Peptides [J]. Clin Cancer Res,2006 ,12(9):2817-25
[7] Jan Wierecky, Martin R. Muller, Stefan Wirths, et al. Immunologic and Clinical Responses after Vaccinations with Peptide-Pulsed Dendritic Cells in Metastatic Renal Cancer Patients [J]. Cancer Res, 2006, 66(11): 5910-8
[8] Chen-Lung Lin, Wei-Feng Lo, Tzong-Hsien Lee, et al. Immunization with Epstein-Barr Virus (EBV) Peptide-pulsed Dendritic Cells Induces Functional CD8+ T-Cell Immunity and May Lead to Tumor Regression in Patients with EBV-positive Nasopharyngeal Carcinoma [J]. CANCER RESEARCH,2002, 62:6952-6958
[9] Scott J. Antonia, NoweedaMirza,Ingo Fricke, et al. Combination of p53 Cancer Vaccinewith Chemotherapy in Patients with Extensive StageSmall Cell LungCancer [J]. Clin Cancer Res, 2006 , 12(3):878-87
[10] Bruce E. Loveland, Anne Zhao, Shane White, et al. Mannan-MUC 1-Pulsed Dendritic Cell Immunotherapy: APhase I Trial in Patientswith Adenocarcinoma [J]. Clin Cancer Res, 2006, 12(3):869-77
[11] Max Schnurr, Christoph Scholz, Simon Rothenfusser, et al. Apoptotic pancreatic tumor cells are superior to cell lysates in promoting cross-priming of cytotoxic T cells and activate NK and gammadelta T cells [J]. CANCER RESEARCH, 2002,62:2347-2352
[12] A. Escobar,M. L(?)pez,A. Serrano, et al. Dendritic cell immunizations alone or combined with low doses of interleukin-2 induce specific immune responses in melanoma patients [J]. Clinical and Experimental Immunology, 2005,142:555-568
[13] Mu LJ, Kyte JA, Kvalheim G, et al. Immunotherapy with allotumour mRNA-transfected dendritic cells in androgen-resistant prostate cancer patients [J]. Br J Cancer, 2005, 93(7):749-56
[14] P. Comolil, R. De Palma, S. Siena3, et al. Adoptive transfer of allogeneic Epstein-Barr virus (EBV)-specific cytotoxic T cells with in vitro antitumor activity boosts LMP2-specific immune response in a patient with EBV-related nasopharyngeal carcinoma [J]. Annals of Oncology,2004, 15: 113-117
[15] Catherine M. Bollard, Laura Aguilar, Karin C. Straathof,et al. Cytotoxic T Lymphocyte Therapy for Epstein-Barr Virus+ Hodgkin's Disease [J]. J Exp Med, 2004 ,200(12): 1623-33
[16] Gabriel Bricard, Hanifa Bouzourene, Olivier Martinet, et al. Naturally Acquired MAGE-A10- and SSX-2-Specific CD8+ T Cell Responses in Patients with Hepatocellular Carcinoma [J]. The Journal of Immunology, 2005, 174: 1709-1716
[17] LoneDuval, Henrik Schmidt, Keld Kaltoft, et al. Adoptive Transfer of Allogeneic Cytotoxic T Lymphocytes Equipped with a HLA-A2 Restricted MART-1 T-Cell Receptor: APhase I Trial in Metastatic Melanoma [J]. Clin Cancer Res, 2006, 12(4): 1229-36
[18] Edward A. Sausville. Genes in the Service of Therapeutic Index: Progress for Virus-Directed Enzyme Prodrug Therapy [J]. J Clin Oncol, 2004 ,22(9): 1535-7
[19] John T. Mullen,Kenneth K. Tanabe. New Approaches to the Treatment of Hepatic Malignancies Viral Oncolysis for Malignant Liver Tumors [J]. Annals of Surgical Oncology, 2002,10(6):596-605
[20] Roland L. Chu, Dawn E. Post,Fadlo R. Khuri, et al. Use of Replicating Oncolytic Adenoviruses in Combination Therapy for Cancer [J]. Clinical Cancer Research, 2004,10:5299-5312
[21] Delia Makower, Alla Rozenblit,Howard Kaufman, et al. Phase II Clinical Trial of Intralesional Administration of the Oncolytic Adenovirus ONYX-015 in Patients with Hepatobiliary Tumors with Correlative p53 Studies [J]. Clinical Cancer Research, 2003, 9:693-702
[22] Tony Reid, Eva Galanis, James Abbruzzese, et al. Hepatic Arterial Infusion of a Replication-selective Oncolytic Adenovirus (dl1520): Phase II Viral, Immunologic, and Clinical Endpoints [J]. CANCER RESEARCH,2002, 62: 607-6079
[23] J. Randolph Hecht, Rudolph Bedford,James L. Abbruzzese, et al. A Phase I/II Trial of Intratumoral Endoscopic ultrasound Injection of ONYX-015 with Intravenous Gemcitabine in Unresectable Pancreatic Carcinoma [J]. Clinical Cancer Research.,2003,9: 555-561
[24] Stephen Morley, Gordon MacDonald,David Kirn, et al. The dl1520 Virus Is Found Preferentially in Tumor Tissue after Direct Intratumoral Injection in Oral Carcinoma [J]. Clinical Cancer Research,2004,10: 4357-4362
[25] Wei Lu, Shu Zheng, Xu-Feng Li, et al. Intra-tumor injection of H101, a recombinant adenovirus, in combination with chemotherapy in patients with advanced cancers: A pilot phase II clinical trial [J]. World J Gastroenterol, 2004,10(24):3634-3638
[26] Habib N, Salama H, Abd El Latif Abu Median A, et al. Clinical trial of ElB-deleted adenovirus (dl1520) gene therapy for hepatocellular carcinoma [J]. Cancer Gene Ther, 2002, 9(3):254-9
[27] Bruno Sangro, Guillermo Mazzolini, Juan Ruiz, et al. Phase I Trial of Intratumoral Injection of an Adenovirus Encoding Interleukin-12 for Advanced Digestive Tumors [J]. JOURNAL OF CLINICAL ONCOLOGY,2004,22:1389-97
[28] Daniel H. Sterman, Adriana Recio, AnilVachani, et al. Long-term Follow-up of PatientswithMalignant Pleural Mesothelioma Receiving High-Dose Adenovirus Herpes Simplex Thymidine Kinase/Ganciclovir Suicide Gene Therapy [J]. Clin Cancer Res, 2005,11(20):7444-53
[29] Svend o. Freytag, Hans Stricker, Jan Pegg, et al. Phase I Study of Replication-Competent Adenovirus-Mediated Double-Suicide Gene Therapy in Combination with Conventional-Dose Three-Dimensional Conformal Radiation Therapy for the Treatment of Newly Diagnosed, Intermediate- to High-Risk Prostate Cancer [J]. CANCER RESEARCH,2003, 63: 7497-7506
[30] Reinhard Dummer, Jessica C. Hassel, Friederike Fellenberg, et al. Adenovirus-mediated intralesional interferon- (?) gene transfer induces tumor regressions in cutaneous lymphomas [J]. Blood, 2004, 104:1631-1638
[31] Daniel T Rein,M Breidenbach,David T Curiel. Current developments in adenovirus-based cancer gene therapy [J]. Future Oncol,2006,2(1): 137-143
[32] Tina Korn,Dirk M. Nettelbeck,Tina V(?)olkel, et al. Recombinant bispecific antibodies for the targeting of adenoviruses to CEA-expressing tumour cells: a comparative analysis of bacterially expressed single-chain diabody and tandem scFv [J]. J Gene Med, 2004, 6: 642-651
[33] Robert M. Sharkey,David M. Goldenberg. Targeted Therapy of Cancer: New Prospects for Antibodies and Immunoconjugates [J]. CA Cancer J Clin, 2006,56:226-243
[34] Andrew M. Scott, Fook-Thean Lee, Niall Tebbutt, et al. A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors [J]. PNAS,2007,104(10) :4071-4076
[35] Sylvain Choquet, Veronique Leblond, Raoul Herbrecht, et al. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study [J]. Blood, 2006, 107:3053-3057
[36] Farhad Ravandi, Jeffrey L. Jorgensen, Susan M. O'Brien, et al. Eradication of minimal residual disease in hairy cell leukemia [J]. Blood, 2006,107:4658-4662
[37] H. Hagberg, C. Gisselbrecht. Randomised phase III study of R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by high-dose therapy and a second randomisation to maintenance treatment with rituximab or not: an update of the CORAL study [J]. Ann Oncol, 2006 ,17 Suppl 4:iv31-2
[38] Laura Orlando, Anna Cardillo, Raffaella Ghisini, et al. Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer [J]. BMC Cancer, 2006, 6:225-32
[39] Vasso Apostolopoulos, Geoffrey A Pietersz, Anastasios Tsibanis, et al. Pilot phase III immunotherapy study in early-stage breast cancer patients using oxidized mannan-MUCl [ISRCTN71711835] [J]. Breast Cancer Res, 2006,8(3):R27-37
[40] Michael J.Morris, Chaitanya R. Divgi, Neeta Pandit-Taskar, et al. Pilot Trial of Unlabeled and Indium-111- Labeled Anti-Prostate-Specific Membrane Antigen Antibody J591 for Castrate Metastatic Prostate Cancer [J]. Clin Cancer Res, 2005, 11(20):7454-61
[41] Geoffrey Chong, FookThean Lee, Wendie Hopkins, et al. Phase I Trial of 131I-huA33 in PatientswithAdvanced Colorectal Carcinoma [J]. Clin Cancer Res, 2005, 11(13):4818-26
[42] Auayporn Nademanee, Stephen Forman, Arturo Molina, et al. Aphase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma [J]. Blood, 2005,106:2896-2902
[43] CarolM. Richman,SallyJ. DeNardo,Robert T. O'Donnell, et al. High-Dose Radioimmunotherapy Combined with Fixed, Low-Dose Paclitaxel in Metastatic Prostate and Breast Cancer by Using a MUC-1 Monoclonal Antibody, ml70, Linked to Indium-lll/Yttrium-90 via a Cathepsin Cleavable Linker with Cyclosporine to Prevent Human Anti-mouse Antibody [J]. Clin Cancer Res, 2005, 11(16):5920-7
[44] Lisa H. Butterfield, Antoni Ribas, Wilson S. Meng, et al. T-Cell Responses to HLA-A*0201 Immunodominant Peptides Derived from gamma-Fetoprotein in Patients with Hepatocellular Cancer [J]. Clinical Cancer Research,2003,9: 5902-5908
[45] Ryungsa Kim,Tetsuya Toge. Changes in Therapy for Solid Tumors: Potential for Overcoming Drug Resistance In Vivo with Molecular Targeting Agents [J]. Surg Today, 2004,34:293-303