大白鼠急性再生障碍性贫血模型的建立及褪黑素早期干预的初步研究
摘要
目的 建立大白鼠急性再生障碍性贫血模型，研究褪黑素(MT)对急性再生障碍
性贫血的可能的治疗作用。方法Wistar大鼠54只随机分为8组进行以下各项实
验。苯组皮下注射苯0． 5ml／kg·次，每周3次，共5周；白消安组每周1次白消安
15mg／kg灌胃，共5周；苯白5周组皮下注射苯0． 5ml／kg·次，每周3次，同期白
消安15mg／kg灌胃，每周1次，均应用5周；苯白3周组、MT1mg组、MT5mg
组、HDMP组四组前3周实验内容同苯白5周组，后2周苯白3周组不予特殊处
理，MT1mg组予MT1mg／kg灌胃，每日1次，共2周。MT5mg组予MT5mg／kg
灌胃，每日1次，共2周。HDMP组予甲基强的松龙尾静脉注射，每日1次，共2
周。空白对照组不予特殊处理。实验过程中观察大白鼠一般情况的变化，患病率
和死亡率，检测血细胞数，骨髓有核细胞(BMNC)计数和造血器官的病理形态。
结果 苯白5周组急性再生障碍性贫血的患病率为100%，死亡率为100％，平均
存活时间为(43． 5±6． 9) d。各项血液学参数呈渐进性减低，停药后1-3周降至最
低，只至死亡。病理形态学观察：骨髓脂肪化，脾脏、淋巴结等淋巴器官组织明
显萎缩，肝、脾无髓外造血灶。苯组、白消安组血细胞数计数有不同程度减低，
但未达再生障碍性贫血标准。MT1mg组、MT5mg组WBC、PLT、BMNC于用药
2周后明显回升，与HDMP组、苯白3周组比较差异有显著性，而HDMP组与苯
白3周组比较差异无显著性。结论 白消安与苯联合应用可建立较理想的造血干
细胞衰竭型急性再生障碍性贫血模型，早期应用褪黑素有促进骨髓有核细胞数上
升，提高外周血白细胞和血小板的作用。
Objective To develop an acute aplastic anemia model with hematopoietic stem cell falLure in rats and study the effect of melatonin used in the early stage of the model. Methods 12 rats were i.h with benzene three times a week and p.o by busulfan once a week, both benzene and busulfan were used for 5 weeks. A benzene alone group and a busalfan alone group were as control. In the second part of the study, 24 rats were i.h with benzene three times a week and p.o by basulfan once a week, both benzene and busulfan were used for 3 weeks. Then they were randomly divided into four groups. The rats of MTlmg group were p.O by melatonin Img/kg.d, MTSmg group was 5mg/kg.d. The rats of third group were i.v with high dose of methylprednisolone every day. Both MT and HDMP were used for 2 weeks. The fouth group were as control. Incidence and mortality of aplastic anemia rats, RBC, WBC, PLT, BMNC and histology of hematopioetic organs were observed
or tested. Results In the group of benzene and busulfan used for 5 weeks, the incidence of acute aplastic anemia was 100%, the mortality was 100% too. The average survival time was (43.5?.9)days. RBC,WBC, PLT and BMNC decreased gradually, and the patho-morphological examination showed that the bone marrow was replaced by fat cells, and the lymphoid tissue of spleen and lymph-nodes were remarkably atrophied without extra-medullary hematopoiesis. After treated with melatonin for 2 weeks, WRC, PLT and BMNC of the rats of both MTlmg group and MTSmg group increased more remarkably compared with those of the HDMP group, and the myologram of MTlmg group and MT 5mg group improved better. Conclusion Benzene combined with busulfan could make a rat aplastic aremia model with acute hematopoietic stem cell falLure. Using melatonin early could increase BMNC,WBC and PLT of aplastic anemia rats.
性贫血的可能的治疗作用。方法Wistar大鼠54只随机分为8组进行以下各项实
验。苯组皮下注射苯0． 5ml／kg·次，每周3次，共5周；白消安组每周1次白消安
15mg／kg灌胃，共5周；苯白5周组皮下注射苯0． 5ml／kg·次，每周3次，同期白
消安15mg／kg灌胃，每周1次，均应用5周；苯白3周组、MT1mg组、MT5mg
组、HDMP组四组前3周实验内容同苯白5周组，后2周苯白3周组不予特殊处
理，MT1mg组予MT1mg／kg灌胃，每日1次，共2周。MT5mg组予MT5mg／kg
灌胃，每日1次，共2周。HDMP组予甲基强的松龙尾静脉注射，每日1次，共2
周。空白对照组不予特殊处理。实验过程中观察大白鼠一般情况的变化，患病率
和死亡率，检测血细胞数，骨髓有核细胞(BMNC)计数和造血器官的病理形态。
结果 苯白5周组急性再生障碍性贫血的患病率为100%，死亡率为100％，平均
存活时间为(43． 5±6． 9) d。各项血液学参数呈渐进性减低，停药后1-3周降至最
低，只至死亡。病理形态学观察：骨髓脂肪化，脾脏、淋巴结等淋巴器官组织明
显萎缩，肝、脾无髓外造血灶。苯组、白消安组血细胞数计数有不同程度减低，
但未达再生障碍性贫血标准。MT1mg组、MT5mg组WBC、PLT、BMNC于用药
2周后明显回升，与HDMP组、苯白3周组比较差异有显著性，而HDMP组与苯
白3周组比较差异无显著性。结论 白消安与苯联合应用可建立较理想的造血干
细胞衰竭型急性再生障碍性贫血模型，早期应用褪黑素有促进骨髓有核细胞数上
升，提高外周血白细胞和血小板的作用。
Objective To develop an acute aplastic anemia model with hematopoietic stem cell falLure in rats and study the effect of melatonin used in the early stage of the model. Methods 12 rats were i.h with benzene three times a week and p.o by busulfan once a week, both benzene and busulfan were used for 5 weeks. A benzene alone group and a busalfan alone group were as control. In the second part of the study, 24 rats were i.h with benzene three times a week and p.o by basulfan once a week, both benzene and busulfan were used for 3 weeks. Then they were randomly divided into four groups. The rats of MTlmg group were p.O by melatonin Img/kg.d, MTSmg group was 5mg/kg.d. The rats of third group were i.v with high dose of methylprednisolone every day. Both MT and HDMP were used for 2 weeks. The fouth group were as control. Incidence and mortality of aplastic anemia rats, RBC, WBC, PLT, BMNC and histology of hematopioetic organs were observed
or tested. Results In the group of benzene and busulfan used for 5 weeks, the incidence of acute aplastic anemia was 100%, the mortality was 100% too. The average survival time was (43.5?.9)days. RBC,WBC, PLT and BMNC decreased gradually, and the patho-morphological examination showed that the bone marrow was replaced by fat cells, and the lymphoid tissue of spleen and lymph-nodes were remarkably atrophied without extra-medullary hematopoiesis. After treated with melatonin for 2 weeks, WRC, PLT and BMNC of the rats of both MTlmg group and MTSmg group increased more remarkably compared with those of the HDMP group, and the myologram of MTlmg group and MT 5mg group improved better. Conclusion Benzene combined with busulfan could make a rat aplastic aremia model with acute hematopoietic stem cell falLure. Using melatonin early could increase BMNC,WBC and PLT of aplastic anemia rats.
引文
1 Morley A, Blake J. An animal model of chronic aplastic marrow failure.I.Late marrow failure after busulfan. Blood,1974;44:49-56
2 Gordan-Smith EC. Management of aplastic anemia. Brit J Haemat,1983;53:185-188
3 Moeschlin S. Experimental studies of the mechanism of action of benzene on the bone marrow. Acta haemat,1967;38;104-108
4 赵均铭，褚建新，丁顺利，等．5-氟尿嘧啶与白消安合用建立大鼠再生障碍性贫血模 型．中华血液学杂志，2001；22：202-204
5 储榆林，张茂宏，吴梓梁，等．再生障碍性贫血的药物治疗．中华血液学杂 志,1999；20：208-210
6 Tan DX, Manchester LC, Reiter RJ,et al.Identification of highly elevated levels of melatonin in bone marrow: its origin and significance. Biochim Biophys Acta, 1999;1472:206-214
7 Conti A, Conconi S, Hertens E,et al. Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res,2000; 28(4) : 193-202
8 Maestroni GJ. Is hematopoiesis under the influence of neural and neuroendocrine mechanisms? Histol Histopathol,1998; 13(1) : 271-274
9 Maestroni GJ, Covacci V, Conti A. Hematopoietic rescue via T-cell-dependent, endogenous granulocyte-macrophage colony-stimulating factor induced by the pineal neurohormone melatonin in tumor-bearing mice. Cancer Res,1994;54(9) :2429-2432
10 Maestroni GJ, Conti A, Lissoni P. Colony-stimulating activity and hematopoietic rescue from cancer chemotherapy compounds are induced by melatonin via endogenous interleukin 4． Cancer Res,1994;54(17) :4740-4743
11 Maestroni GJ. T-helper-2 lymphocytes as a peripheral target of melatonin. J Pineal Res. 1995; 18(2) : 84-89
12 Maestroni GJ, Hertens E, Galli P,et al. Melatonin-induced T-helper cell hematopoietic cytokines resembling both interleukin-4 and dynorphin. J Pineal Res. 1996; 21(3) : 131-139
13 Maestroni GJ. kappa-Opioid receptors in marrow stroma mediate the hematopoietic effects of melatonin-induced opioid cytokines. Ann N-Y Acad Sci,1998; 840411-840419
14 Maestroni GJ. The photoperiod transducer melatonin and the immune-hematopoietic system. J Photochem Photobiol B,1998; 43(3) : 186-192
15 Maestroni GJ, Zammaretti F, Pedrinis E. Hematopoietic effect of melatonin interleukin-1． J Pineal Res, 1999; 27(3) : 145-153
16 Boranic M, Krizanac-Bengez L, Gabrilovac J,et al. Enkephalins in hematopoiesis. Biomed Pharmacother, 1997; 51(1) : 29-37
17 Currier NL, Sicotte M, Miller SC. Deleterious effects of Echinacea purpurea and melatonin on myeloid cells in mouse spleen and bone marrow. J Leukoc Biol, 2001; 70(2) : 274-276
18 Lissoni P, Tancini G, Paolorossi F,et al. Chemoneuroendocrine therapy of metastatic breast cancer with persistent thrombocytopenia with weekly low-dose epirubicin plus melatonin: a phase II study. J Pineal Res, 1999; 26(3) : 169-173
19 李家增，王鸿利，韩朝忠主编．血液实验学．上海：上海科学技术出版社. 1997：1-2，8-9，302-303，618
20 全国白血病与再障流行病学调查协作组．全国再障流行病学发病情况调查．中 国医学科学学报，1992，14：6-11
21 Melenhorst JJ, van-Krieken JH, Dreef E.et al. T cells selectively infiltrate bone marrow areas with residual haemopoiesis of patients with acquired aplastic anaemia. Br J Haematol. 1997; 99(3) : 517-519
22 Manz CY, Dietrich PY, Schnuriger V,et al. T-cell receptor beta chain variability in
bone marrow and peripheral blood in severe acquired aplastic anemia. Blood-Cells Mol Dis, 1997; 23(1) : 110-122
23 Nakao S. Immune mechanism of aplastic anemia. Int J Hematol, 1997 ; 66(2) : 127-134
24 Nakao S, Takami A, Takamatsu H,etal. Isolation of a T-cell clone showing HLA-DRB 1*0405-restricted cytotoxicity for hematopoietic cells in a patient with aplastic anemia. Blood,1997; 89(10) : 3691-3699
25 Callera F, Falcao RP. Increased apoptotic cells in bone marrow biopsies from patients with aplastic anaemia. Br J Haematol,1997; 98(1) : 18-20
26 Bacigalupo A, Piaggio G, Podesta M,et al. In vitro effect of stem cell factor on colony growth from acquired severe aplastic anemia. Stem Cells, 1993 ; 11 Suppl 2175-2179
27 Gibson FM, Scopes J, Daly S,et al. Haemopoietic growth factor production by normal and apiastic anaemia stroma in long-term bone marrow culture. Br J Haematol, 1995 ; 91(3) : 551-561
28 Koike M, Ishiyama T, Tomoyasu S,et al. Spontaneous cytokine overproduction by peripheral blood mononuclear cells from patients with myelodysplastic syndromes and aplastic anemia. Leuk Res, 1995; 19(9) : 639-644
29 邵宗鸿，陈克奇，陈桂彬，等．严重型再生障碍性贫血患者血清水平与免疫抑制 治疗关系的研究.中华血液学杂志，1997；18：180-182
30 Paquette RL, Hsu NC, Koeffler HP. Analysis of c-kit gene integrity in aplastic anemia. Blood Cells Mol Dis, 1996; 22(2) : 159-68
31 Nakao S, Takamatsu H, Chuhjo T,et al. Identification of a specific HLA class II haplotype strongly associated with susceptibility to cyclosporine-dependent aplastic anemia. Blood,1994 15; 84(12) : 4257-61
32 Klassen LW. Experimental medullary aplasia. J Lab Clin Med, 1972,80:8-12
33 Adler SS. Heampopietic stem cell dynamics in 89Sr marrow-ablated mice. J Lab Clin Med,1977,89:592-595
34 Gurney CW. Treatment of strontium-89-induced hypoplastic anemia in mice by intraperitoneal implants of spleen slices. In Experimental Hematology today (Ed) Baum S J p105, New York Springer, 1979
35 Barnes DWH. Aplastic anaemia in sublethally irradiated mice given allogenetic lymphnode cell. Brit J Haemat, 1967; 13:482-486
36 姚军，李树农．淋巴细胞与再生障碍性贫血关系的实验研究．中华血液学杂志， 1991；12：229-231
37 廖继东，汪明春，马秀君，等．组胺H2受体阻制剂对免疫介导再生障碍性贫血小 鼠血清IFN-γ、TNF-α和IL-2水平的影响．中华血液学杂志，2001；22：542-543
38 Rosendaal M, Adam J. Patterns of haematopoietic recovery after stage II. Treatment with fluorouracil. Leuk Res,1988;12:479-485
39 Hodgson GS, Bradley TR. Properties of haematopoietic stem cells surviving 5-fluorouracil treatment:evidence for a pre-CFU-S cell? Nature,1979;281;381-382
40 Botnick LE. Multisystem stem cell failure after apparent recovery from alkylating agents. Cancer Reserch,1978;38:1942-1947
41 McManus PM. Busulfan-induced chronic bone marrow failure changesin cortical bone marrow stromal cells and adherent cell colonies. Blood,1984;64:1036-1042
42 Bacigalupo A, Brand R, Oneto R,et al. Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy-The European Group for Blood and Marrow Transplantation experience. Semin Hematol,2000; 37(1) : 69-80
43 Young NS, Barrett AJ. The treatment of severe acquired aplastic anemia. Blood, 1995; 85(12) : 3367-3377
44 Schwinger W, Urban C, Lackner H,et al. Transplantation of related and unrelated
umbilical cord blood stem cells in Austria. Austrian Working Party for Stem Cell Transplantation. Austrian Society of Hematology and Oncology. Wien Klin Wochenschr, 1999; 111(9) : 348-353
45 Herrera-Garza J, Jaime-Perez J, Montemayor J,et al. High-dose peripheral blood stem cell transplant for multitransfused severe aplastic anaemia patients without antithymocyte globulin in the conditioning regimen. Bone Marrow Transplant, 1999 ; 24(8) : 845-848
46 Tan DX, Chen LD, Poeggeler B,et al. Melatonin:a potent endogenous hydroxyl radical scavenger. Endocrine J,1993;1:57-60
47 Lissoni P, Tancinp G, Barni S,et al. Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Support Care Cancer, 1997; 5(2) : 126-129
48 Reiter RJ, Tan DX, Qi W,et al. Pharmacology and physiology of melatonin in the reduction of oxidative stress in vivo. Biol Signals Recept,2000; 9(3-4) : 160-171
49 Ghielmini M, Pagani O, de-Jong J,et al. Double-blind randomized study on the myeloprotective effect of melatonin in combination with carboplatin and etoposide in advanced lung cancer. Br J Cancer,1999; 80(7) : 1058-1061
50 Vijayalaxmi, Meltz ML, Reiter RJ,et al.Melatonin and protection from genetic damage in blood and bone marrow: whole-body irradiation studies in mice. J Pineal Res, 1999; 27(4) : 221-225
51 Badr FM, El-Habit OH, Harraz MM. Radioprotective effect of melatonin assessed by measuring chromosomal damage in mitotic and meiotic cells. Mutat Res, 1999; 444(2) : 367-372
52 Haldar C, Haussler D, Gupta D. Effect of the pineal gland on circadian rhythmicity of colony forming units for granulocytes and macrophages (CFU-GM) from rat bone marrow cell cultures. J Pineal Res, 1992; 12(2) : 79-83
2 Gordan-Smith EC. Management of aplastic anemia. Brit J Haemat,1983;53:185-188
3 Moeschlin S. Experimental studies of the mechanism of action of benzene on the bone marrow. Acta haemat,1967;38;104-108
4 赵均铭，褚建新，丁顺利，等．5-氟尿嘧啶与白消安合用建立大鼠再生障碍性贫血模 型．中华血液学杂志，2001；22：202-204
5 储榆林，张茂宏，吴梓梁，等．再生障碍性贫血的药物治疗．中华血液学杂 志,1999；20：208-210
6 Tan DX, Manchester LC, Reiter RJ,et al.Identification of highly elevated levels of melatonin in bone marrow: its origin and significance. Biochim Biophys Acta, 1999;1472:206-214
7 Conti A, Conconi S, Hertens E,et al. Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res,2000; 28(4) : 193-202
8 Maestroni GJ. Is hematopoiesis under the influence of neural and neuroendocrine mechanisms? Histol Histopathol,1998; 13(1) : 271-274
9 Maestroni GJ, Covacci V, Conti A. Hematopoietic rescue via T-cell-dependent, endogenous granulocyte-macrophage colony-stimulating factor induced by the pineal neurohormone melatonin in tumor-bearing mice. Cancer Res,1994;54(9) :2429-2432
10 Maestroni GJ, Conti A, Lissoni P. Colony-stimulating activity and hematopoietic rescue from cancer chemotherapy compounds are induced by melatonin via endogenous interleukin 4． Cancer Res,1994;54(17) :4740-4743
11 Maestroni GJ. T-helper-2 lymphocytes as a peripheral target of melatonin. J Pineal Res. 1995; 18(2) : 84-89
12 Maestroni GJ, Hertens E, Galli P,et al. Melatonin-induced T-helper cell hematopoietic cytokines resembling both interleukin-4 and dynorphin. J Pineal Res. 1996; 21(3) : 131-139
13 Maestroni GJ. kappa-Opioid receptors in marrow stroma mediate the hematopoietic effects of melatonin-induced opioid cytokines. Ann N-Y Acad Sci,1998; 840411-840419
14 Maestroni GJ. The photoperiod transducer melatonin and the immune-hematopoietic system. J Photochem Photobiol B,1998; 43(3) : 186-192
15 Maestroni GJ, Zammaretti F, Pedrinis E. Hematopoietic effect of melatonin interleukin-1． J Pineal Res, 1999; 27(3) : 145-153
16 Boranic M, Krizanac-Bengez L, Gabrilovac J,et al. Enkephalins in hematopoiesis. Biomed Pharmacother, 1997; 51(1) : 29-37
17 Currier NL, Sicotte M, Miller SC. Deleterious effects of Echinacea purpurea and melatonin on myeloid cells in mouse spleen and bone marrow. J Leukoc Biol, 2001; 70(2) : 274-276
18 Lissoni P, Tancini G, Paolorossi F,et al. Chemoneuroendocrine therapy of metastatic breast cancer with persistent thrombocytopenia with weekly low-dose epirubicin plus melatonin: a phase II study. J Pineal Res, 1999; 26(3) : 169-173
19 李家增，王鸿利，韩朝忠主编．血液实验学．上海：上海科学技术出版社. 1997：1-2，8-9，302-303，618
20 全国白血病与再障流行病学调查协作组．全国再障流行病学发病情况调查．中 国医学科学学报，1992，14：6-11
21 Melenhorst JJ, van-Krieken JH, Dreef E.et al. T cells selectively infiltrate bone marrow areas with residual haemopoiesis of patients with acquired aplastic anaemia. Br J Haematol. 1997; 99(3) : 517-519
22 Manz CY, Dietrich PY, Schnuriger V,et al. T-cell receptor beta chain variability in
bone marrow and peripheral blood in severe acquired aplastic anemia. Blood-Cells Mol Dis, 1997; 23(1) : 110-122
23 Nakao S. Immune mechanism of aplastic anemia. Int J Hematol, 1997 ; 66(2) : 127-134
24 Nakao S, Takami A, Takamatsu H,etal. Isolation of a T-cell clone showing HLA-DRB 1*0405-restricted cytotoxicity for hematopoietic cells in a patient with aplastic anemia. Blood,1997; 89(10) : 3691-3699
25 Callera F, Falcao RP. Increased apoptotic cells in bone marrow biopsies from patients with aplastic anaemia. Br J Haematol,1997; 98(1) : 18-20
26 Bacigalupo A, Piaggio G, Podesta M,et al. In vitro effect of stem cell factor on colony growth from acquired severe aplastic anemia. Stem Cells, 1993 ; 11 Suppl 2175-2179
27 Gibson FM, Scopes J, Daly S,et al. Haemopoietic growth factor production by normal and apiastic anaemia stroma in long-term bone marrow culture. Br J Haematol, 1995 ; 91(3) : 551-561
28 Koike M, Ishiyama T, Tomoyasu S,et al. Spontaneous cytokine overproduction by peripheral blood mononuclear cells from patients with myelodysplastic syndromes and aplastic anemia. Leuk Res, 1995; 19(9) : 639-644
29 邵宗鸿，陈克奇，陈桂彬，等．严重型再生障碍性贫血患者血清水平与免疫抑制 治疗关系的研究.中华血液学杂志，1997；18：180-182
30 Paquette RL, Hsu NC, Koeffler HP. Analysis of c-kit gene integrity in aplastic anemia. Blood Cells Mol Dis, 1996; 22(2) : 159-68
31 Nakao S, Takamatsu H, Chuhjo T,et al. Identification of a specific HLA class II haplotype strongly associated with susceptibility to cyclosporine-dependent aplastic anemia. Blood,1994 15; 84(12) : 4257-61
32 Klassen LW. Experimental medullary aplasia. J Lab Clin Med, 1972,80:8-12
33 Adler SS. Heampopietic stem cell dynamics in 89Sr marrow-ablated mice. J Lab Clin Med,1977,89:592-595
34 Gurney CW. Treatment of strontium-89-induced hypoplastic anemia in mice by intraperitoneal implants of spleen slices. In Experimental Hematology today (Ed) Baum S J p105, New York Springer, 1979
35 Barnes DWH. Aplastic anaemia in sublethally irradiated mice given allogenetic lymphnode cell. Brit J Haemat, 1967; 13:482-486
36 姚军，李树农．淋巴细胞与再生障碍性贫血关系的实验研究．中华血液学杂志， 1991；12：229-231
37 廖继东，汪明春，马秀君，等．组胺H2受体阻制剂对免疫介导再生障碍性贫血小 鼠血清IFN-γ、TNF-α和IL-2水平的影响．中华血液学杂志，2001；22：542-543
38 Rosendaal M, Adam J. Patterns of haematopoietic recovery after stage II. Treatment with fluorouracil. Leuk Res,1988;12:479-485
39 Hodgson GS, Bradley TR. Properties of haematopoietic stem cells surviving 5-fluorouracil treatment:evidence for a pre-CFU-S cell? Nature,1979;281;381-382
40 Botnick LE. Multisystem stem cell failure after apparent recovery from alkylating agents. Cancer Reserch,1978;38:1942-1947
41 McManus PM. Busulfan-induced chronic bone marrow failure changesin cortical bone marrow stromal cells and adherent cell colonies. Blood,1984;64:1036-1042
42 Bacigalupo A, Brand R, Oneto R,et al. Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy-The European Group for Blood and Marrow Transplantation experience. Semin Hematol,2000; 37(1) : 69-80
43 Young NS, Barrett AJ. The treatment of severe acquired aplastic anemia. Blood, 1995; 85(12) : 3367-3377
44 Schwinger W, Urban C, Lackner H,et al. Transplantation of related and unrelated
umbilical cord blood stem cells in Austria. Austrian Working Party for Stem Cell Transplantation. Austrian Society of Hematology and Oncology. Wien Klin Wochenschr, 1999; 111(9) : 348-353
45 Herrera-Garza J, Jaime-Perez J, Montemayor J,et al. High-dose peripheral blood stem cell transplant for multitransfused severe aplastic anaemia patients without antithymocyte globulin in the conditioning regimen. Bone Marrow Transplant, 1999 ; 24(8) : 845-848
46 Tan DX, Chen LD, Poeggeler B,et al. Melatonin:a potent endogenous hydroxyl radical scavenger. Endocrine J,1993;1:57-60
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