阿克拉霉素A、维甲酸对人原代白血病细胞体外诱导分化作用研究
摘要
本试验采用悬浮培养法研究了阿克拉霉素A、全反式维甲酸对人急性非淋巴细胞白血病原代细胞的体外诱导分化作用。培养一周，ACMA60nM组21例中有13例成熟细胞百分数此对照组提高20.0％以上。与对照组相此，13例病人活细胞数、幼稚细胞数降低非常显著(P＜0.01)，成熟细胞数变化不明显。其中8例成熟细胞绝对值有所增加，5例减少。药物处理后的13例细胞NBT还原率、释放活性氧能力较对照组增强(P＜0.05)，细胞膜C_3受体阳性率及硷性磷酸酶染色无明显改变。RA10~(-6)M组24例中有5例成熟细胞百分数此对照组提高20.0％以上。与对照组相比这5例病人活细胞数变化不明显而幼稚细胞数减少(P＜0.01)成熟细胞数增加显著(P＜0.05)。NBT还原率、释放活性氧能力及细胞膜C-3受体出现率均显著高于对照组(P＜0.05)，硷磷酶变化不明显。
上述结果提示，小剂量ACMA体外可能对某些白血病细胞有诱导分化作用，但其使白血病细胞减少主要是细胞毒作用所致，ACMA诱导分化后的细胞氧化功能增强。RA体外可使早幼粒白血病细胞分化成熟，也可使极少数M2白血病细胞分化。经RA诱导成熟的细胞氧化能力及细胞膜C_3受体阳性率均明显提高。
In this study,the differentiation-induction effects of Aclacinomycin-A and All-trans retinoic acid on fresh human ANLL cells in liquid suspension cultures were investigated. On the 7th day of cultivation,samples of 13 out of 21 patients in the flasks containing 60 nM of ACMA showed an increase of mature cells percentage>20.0% as compared with control flasks. In this 13 cases,the decreases of viable and immature cell counts were both significant(p<0.01),but the increase of mature cell counts were not obvious. Eight of the 13 cases showed increase while 5 of the 13 cases showed decrease in mature cell counts.As compared with control,the percentage of NBT positive cells was higher(P<0.05)and the generation of reactive oxygen enhanced(P<0.05)in these 13 patients,but the percentages of cells with C_3 recepter and with alkaline phosphatase did not increase. Increase of percentage of mature cell(20.0% higher than control)was found in 5 from 24 cases treated with RA (10~(-6)M).Numbers of viable cell counts were not altered,while immature cell counts decreased(P<0.01) and mature cell counts increased as compared with control.In t his 5 cases, the percentage of NBT positive,C_3 receptor positive cells and the amount of generation of reactive oxygen were increased significantly (P<0.05). The percentage of ALP positive cells did not change.
The above results suggest that:in vitro,low dose ACMA in this study was able to induce differentiation of leukemia cells in some patients,but its main effect was suppression of leukemia cells due to cytotoxity.The oxidative function of induced mature cells increased.RA can induce differentiation not only in M_3 but in a few M_2 cases,The oxidative function and percentage of C_3 positive cell percentage increased significancly.
上述结果提示，小剂量ACMA体外可能对某些白血病细胞有诱导分化作用，但其使白血病细胞减少主要是细胞毒作用所致，ACMA诱导分化后的细胞氧化功能增强。RA体外可使早幼粒白血病细胞分化成熟，也可使极少数M2白血病细胞分化。经RA诱导成熟的细胞氧化能力及细胞膜C_3受体阳性率均明显提高。
In this study,the differentiation-induction effects of Aclacinomycin-A and All-trans retinoic acid on fresh human ANLL cells in liquid suspension cultures were investigated. On the 7th day of cultivation,samples of 13 out of 21 patients in the flasks containing 60 nM of ACMA showed an increase of mature cells percentage>20.0% as compared with control flasks. In this 13 cases,the decreases of viable and immature cell counts were both significant(p<0.01),but the increase of mature cell counts were not obvious. Eight of the 13 cases showed increase while 5 of the 13 cases showed decrease in mature cell counts.As compared with control,the percentage of NBT positive cells was higher(P<0.05)and the generation of reactive oxygen enhanced(P<0.05)in these 13 patients,but the percentages of cells with C_3 recepter and with alkaline phosphatase did not increase. Increase of percentage of mature cell(20.0% higher than control)was found in 5 from 24 cases treated with RA (10~(-6)M).Numbers of viable cell counts were not altered,while immature cell counts decreased(P<0.01) and mature cell counts increased as compared with control.In t his 5 cases, the percentage of NBT positive,C_3 receptor positive cells and the amount of generation of reactive oxygen were increased significantly (P<0.05). The percentage of ALP positive cells did not change.
The above results suggest that:in vitro,low dose ACMA in this study was able to induce differentiation of leukemia cells in some patients,but its main effect was suppression of leukemia cells due to cytotoxity.The oxidative function of induced mature cells increased.RA can induce differentiation not only in M_3 but in a few M_2 cases,The oxidative function and percentage of C_3 positive cell percentage increased significancly.
引文
1. Koeffler HP Induction of differentiation of human acute myelogenous leukemia cclls : therapeutic implications. Blood 1983;62:709
2. Sachs LsCell differentiation and bypassing of genetic defects in the suppression of malignancy .Cancer Research 1987; 47:1981
3. Sachs L.Control of normal cell differentiation and the phenotypic reversion of malignancy in myeloid leukemia.Nature(Lond)1978; 174:535
4. Griffin JD et al Induction of differentiation of human myeloid leukemia cells by inhibitors of DNA synthesis.Exp Hematol 1982; 10 : 774
5. Archimbaud E et al Differentiation of myeloid cells in liquid culture.2.acute myelocytic leukemia cells.Cell Biochemistry And Function 1987 5 : 157
6. Hiroto Ishikura et al :E.ffect of antimetabolites and thymidine blockage on the induction of differentiation of HL-60 cells by retinoic acid or 1a ,25-dihydroxyvitamin D3.Exp Hematol 1985; 13 : 981
7. Koeffler HP et al:Stuty of differentiation of fresh myelogenous leukemic cells by compounds that induce a human promyelocytic leukemic line(HL-60)to differentiate.Leukemia Research 1985; 13 : 981
8. Collins SJ et al:Induction of morphological and functional differentiation of human promyelocytic leukemia cells(HL-60):by compounds which induce defferentiation of murine leukemia cells.Int J Cancer 1980;25 : 213
9. Breitman TR et al Induction of defferentiation of the human prcmyelocytic leukemia cell line(HL-60)by retinoic acid.Proc Natl Acad Sci USA 1980;77:2936
10. Breitman TR et al:Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid. Blood 1981;57 : 1000
11. Honma Y et al:Induction of differentiation of human non-lymphocyte leukemia cells in primary culture by inducers of differentiation of human myeloid leukemia cell line HL-60.Eur J Cancer Clin Oncol 1983; 19;251
12 宋争平等：维胺酯和维胺酸对人早幼粒白血病细胞(HL60)的诱导分化作用。
药学学报 1984；19：576
13. Miyaura C et al: la, 25-dihydroxyvitamin D3 induces differentiation of human myeloid leukemia cells. Biochem Biophys Res Commun 1981; 102: 937
14．孙关林等：急性早幼粒细胞白血病的诱导分化疗法——44例疗效分析。中华血液学杂志 1989；10：119
15. Schwartz EL et al: Evaluation of some anthracycline antibiotics in an in vivo model for studying drug-induced human leukemia cell differentiation. Cancer Research 1983; 43: 2725
16. Schwartz EL et al: Structure activity relationships for the induction of differentiation of HL-60 human acute promyelocytic leukemia cells by anthracyclines. Cancer Research 1982; 42: 2651
17. Gamba-Vitalo C et al: Differentiation of WEHI-3BD~+ monomyelocytic leukemia cells by retinoic acid and aclacinomycin A. Cancer Research 1986; 46: 1189
18．路莹等：阿克拉霉素B对人早幼粒白血病细胞的分化诱导作用。中国医学科学院学报 1986；8：211
19. Schopf RE et al: Measurement of the respiratory burst in human monocytes and polymorphonuclear leukocytes by nitro blue tetrazolium reduction and chemiluminescence. J Immunol Methods 1984; 67: 109
20．刘友华等：抗8—AG和HGPRT缺失的人早幼粒白血病突变株(HL—60—AR)的体外诱导分化潜能。中国医学科学院学报 1986；8：461
21．医学统计学方法 上海第一医学院编 1978
22．严文伟等：急性髓性白血病细胞在液体培养中的自发分化。中华血液学杂志 1988；9：467
23．敖忠芳等：小剂量化疗药物及共与维甲酸合用对白血病细胞的诱导分化。中华血液学杂志 1988；9：29
24. Bear MR et al: Sustained viability of acute myelogenous leukemia cells in liquid suspension culture correlates with occurrence of differentiation. Leukemia Research 1988; 12: 647
25. Hicks DG et al: K_(562) cell erythroid differentiation: requirement for a factor in fetal bovine serum. Exp Hematol 1985; 13: 273
26. Hodges RE et al: Hematopietic study in vitamin A deficiency. Am J Clin Nutr 1978; 31: 876
27. Ferrero D et al: Induct ion of differentiation of human myeloid leukemias: surface changes probed with monoclonal antibodies. Blood 1983; 61: 171
28. Olsson IL et al: Induction of differentiation of the human histocytic lymphoma cell line U_(937) by retinoic acid and cyclic adenosine 3',??5'-monophosphate-inducing agents.Cancer Research 1982;42:3924
29. Oki ct al:New antitumor ant ibiotics,aclacinomycins Aand B.J Antibiot 1975,28.830
30. Sakurai M et al.Possible differentiation of human acute myeloblastic leukemia cells by daily and intermittent administration of aclaci- nomycin A.Leukemia Research 1983;7: 139
31. Frank DA et al Alterations in tyrosine phosphorylation during the granulocytic maturation of HL-60 leukemia cells.Cancer Research 1988;48 : 52
32. Flynn PJ et al:Retinoic acid treatment of acute promyelocytic leukemia: in vitro and in vivo observations.Blood 1983;62:1211
33. Reilly IAG et al:Hypoplastic acute leukemia:cytogenetic evidence for differentiation in vivo response to low dose Ara-C. Bri J Hematol 1987,65:384
34. Paran M et al In vitro induction of granulccyte differentiation in hematopoietic cells from leukemic and non-leukemic patients. Proc Natl Acad Sci USA 1970,-67; 1542
35. Friend C et al .Hemoglobin synthesis in murine virus-induced leukemic cells in vitro:stimulation of erythroid differentiation by dimethyl Sulfoxide. Proc Natl Acad Sci USA 1971;68:378
36. Lozzio BB et al:A multipotential leukemia cell line(K562)of human origin. Proc Soc Exp Biol Med 1981; 166 J 546
37. Pegoruro L et at:Different iation of human leukemias in response to TPA in vitro. Blood 1980;55:859
38. Palu G et al:Patients of maturation in short time culture of human AML cells.Br J Cancer 1979540: 719
39. Palu G et al.Spontaneous regression of human AML xenografts and phenotypic evidence for maturation. Br J Cancer 1979;40 : 731
40. Bainton DF.:Abnormal neutrophils in acute myelogeneous leukemia; identification of subpopulations based on analysis ofazurophil and specific granules. Blood Cells 1975; 1 : 191
41. Rausch PG et al;Immunocytochemical identification of abnormal Polymorphonuclear neutrophils in patients with leukemia.Blood cells 1978;4:369
42. Suda T et al :Studies on abnormal polymorphonuclear neutrophils in acute myelogeneous leukemia:clinical significance and changes after chemotherapy.Am J Hematol 1983; 15 : 45
43. Mittermuller J et al In vivo differentiation of leukemic blasts and??effect of low-dose Ara-C in a marrow grafted patient with leukemic relapse.Br J Hematol 1986;62 : 757
44. Campbell AK et al.Chemiluminescence as an analytical tool in cell biology and medicine.Methods Biochem Analysis 1985;31:317
45. Kubo A et al:Generation of oxygen radicals by human polymorphonu- clear leukocytes in response to non-phagocytosable stimuli.Acta Hematol JPN 1988;51 : 36
46. Babior BM.Oxidants from phagocytes:agents of defense and destruction. Blood 1984;64-959
47．田洁等：维生素A酸诱导人早幼粒白血病细胞系HL-60的吞噬发光测定。上海免疫学杂志1988；8：42
48. Bachner RL et al :The biochemical basis of nitroblue-tetrazolium reduction in normal and chronic granulomatous disease polymorpho- nuclear leukocytes.Blood 1976;48: 309
49. Lozzio CB et al:Human chronic myelogenous leukemia cell line with positive Philadelphia chromosome.Blood 1975;45:321
50. Sundatrom C et al. Establishment and characterization of a human his-tiocytic lymphoma cell line(U937).Int J Cancer 1976; 17: 565
51. Koeffler HP et ah Acute myelogenous leukemia: a human cell line responsive to colony-stimulating activity. Science 1978; 200: 1153
52. Collins SJ et al: Continuous growth and differentiation of human myeloid leukemic cells in suspension culture. Nature 1977; 270: 347
53. Koeffler HP et al: An undifferentiated strain derived from the human acute myelogenous leukemia cell line KG-1. Blood 1980; 56:265
54. Takeda K et al: Kinetics of appearance of differentiaton associated characteristics in ML-1 a line of human myeloblastic leukemia cells after treament with 12-o-tetradecanoylphorbol-13-acetate, dimethyl sulfoxide, 1-beta-D-arabinofuranosylcytosine. Cancer Research 1981; 42: 5152
55. Martin P et al: HEL cells: a new human erythroleukemia cell line with spontaneous and induced globin expression. Science 1982; 216: 1233
56. Tsuchiya S et al: Establishment and characterization of human acute monocytic leukemia cell line (THP-1). Int J Cancer 1980; 26: 171
57. Lotem H et al: Regulation of normal differentiation in mouse and human myeloid leukemic cells by phorbol esters and the mechanism of tumor promotion. Proc Natl Acad Sci USA 1979; 76: 5158
58. Rovera G et al; Induction of differentiation in human promyelocytic??leukemia cells by tumor promotors. Science 1979; 204: 868
59. Koeffler HP et al: Phorbol ester effect on differentiation of human myeloid leukemia cell lines blocked at different stages of maturation. Cancer Research 1981; 41: 919
60. Fibach E et al: Modulation of the maturation of human leukemic promyelocytes (HL—60) to granulocytes or macrophages. Leukemia Research 1982; 6: 781
61 Tomonoge M et al: Establisment of eosinophilic sublines from human promyelocytic leukemic cells(HL—60): demonstration of multipotentia-lity and single—lineage commitment of HL—60 stem cells. Blood 1986; 67: 1433
62. Fischkoff SA: Graded increase in probability of eosinophilic differentiation of HL—60 promyelocytic leukemia cells induced by culture under alkaline conditions. Leukemia Research 1988; 12: 679
63．刘友华等：抗8—AG和HGPRT缺乏的人早幼粒细胞白血病细胞突变株(HL—60—AR)的建立。中国医学科学院学报 1986；8：454
64．刘友华等：七种癌基因在HL—60—AR细胞中的表达及药物诱导分化后的变化。中国医学科学院学报 1987；9：407
65. Forsoz D et al: Variant cell lines from the human promyelocytic line HL—60. Leukemia Research 1982; 6: 491
66. Eric F et al: Expression of myeloid—specific antigens on two human erythroleukemia cell lines HEL and K562. Leukemia Research 1984; 8: 207
67. Dean A et al: Induction of hemoglobin accumulation in human K562 cells by heroin is reversible. Science 1981; 212: 459
68. Vainchenker W et al: Heterogeneity in the cellular commitment of a human leukemic cell line K562. Blood Cells 1981; 7: 357
69. Andersson IC et al: Induction of erythroid differentiation in the human leukemia cell line K562. Nature 1979; 278: 364
70. Tetteroo PAT et al: Megakaryoblastic differentiaton of proerythroblastic K562 cell—line cells. Leukemia Research 1984; 8: 197
71. Sakagami H et al: Differentiation—associated changes in human nor—T, non—B leukemia cell lines after treatment with 12—0—tetradecanoylphorbol—13—acetate (TPA). Leukemia Rcsearch 1984; 8: 187
72．严文伟等：TPA对50例急性白血病细胞的诱导分化作用。中华血液学杂志??1986；7：449
73. Yamaki H et al: Mechanism of action of aclacinomycin—A1. the effect on macromolecular syntheses. J Antibiot 1978; 31: 1149
74. Long BH et al; Effect of anthracycline analogues on the appearance of newly synthesized total RNA and messenger RNA in the cytoplasm of erythroleukemia cells. Mol pharmacol 1982; 22: 152
75. Fink FM et al: Aclacinomycin—A in the induction treatment of childhood AML. Onkologie Jun 1986; 9: 154
76. Orbach—Arbouys S et al: Aclacinomycin—A inhibits suppressor cells in vivo and in vitro. Behring Inst Mitt 1984; 74: 258
77. Orbach—Arbouys S et al: Reversal of immunological tolerance by aclacinomycin through inhibiton of suppressor cell activity. Cell Immunol 1983; 81: 384
78. Ishizuka M: Immunomodulation by antitumor antibiotics. Gan To Kagaku Ryobo 1986; 13: 697
79. Morin MJ: Inhibition of glycoprotein biosynthesis by the inducers of HL—60 cell differentiation, aclacinomycin—A and marcellomycin. Cancer Research 1984; 44: 2807
80. Leydem M et al: Low dose cytosine arabinoside: partial remission of acute myeloid leukemia without evidence of differentiation induction. Br J Hematol 1984; 57: 301
81. Ye Jing—Song et al: Low—dose Ara—C can cause complete remission of acute non—lymphocytic leukemia: differentiation induction? Leukemia Research 1986; 10: 1221
82. Franchi F et al: Cytosine arabinoside—induced differentiation and killing: unresolved question. Folia Haematol, Leipzig 1986; 113: 358
83. Lotem J et al: In vivo control of differentiation of myeloid leukemic cells by cyclosporine A and recombinant interleukin—la. Blood 1988; 72: 1595
84．杜德林等：茯芩素对人早幼粒白血病细胞系HL—60细胞的诱导分化作用。军事医学科学院院刊 1988；12：132
85 Feuerstein M. et al: Rapid phosphorylation—dephosphorylation of specific proteins induced by phorbol ester in HL—60 cells. J Biol Chem 1984; 259: 2782
86. Cooper RA et al: Inhibition of sterol and phospholipid synthesis in HL—60 promyelocytic leukemia cells by inducers of myeloid differentiation, Cancer Research 1981; 41: 184787. Favera RD et al: The human oncogene c—myc: structure, expression and amplification in the human promyelocytic leukemia cell line HL—60. Hematol Bluttransfus 1983; 28: 247
88. Craig RW et al: Early decline in c—myb oncogen expression in the differentiation of human myeloblastic leukemia (ML—1) cells induced with TPA. Cancer Research 1984; 44: 442
89. Dallegri F et al: Expression of cytolytic functions in HL—60 leukemic cells after induction of polymorphonuclear leukocyte differentiation. Blur 1986; 52: 243
90．沈柏均：人早幼粒白血病细胞株HL—60被DMSO诱导分化的可逆性。山东医科大学学报 1988；2：85
91. Ross DW et al: Differentiation versus cytoreduction during remission induction in acute nonlymphblastic leukemia treated with sequential high dose Ara—C and asparaginase. Cancer 1984; 53: 1651
92. Ye Jing—song et al.. Small—dose harringtonine induces complete remission in patients with acute promyelocytic leukemia. Leukemia 1988; 2: 427
93．血液病实验诊断 中国医学科学院血液学研究所主编，1983年
2. Sachs LsCell differentiation and bypassing of genetic defects in the suppression of malignancy .Cancer Research 1987; 47:1981
3. Sachs L.Control of normal cell differentiation and the phenotypic reversion of malignancy in myeloid leukemia.Nature(Lond)1978; 174:535
4. Griffin JD et al Induction of differentiation of human myeloid leukemia cells by inhibitors of DNA synthesis.Exp Hematol 1982; 10 : 774
5. Archimbaud E et al Differentiation of myeloid cells in liquid culture.2.acute myelocytic leukemia cells.Cell Biochemistry And Function 1987 5 : 157
6. Hiroto Ishikura et al :E.ffect of antimetabolites and thymidine blockage on the induction of differentiation of HL-60 cells by retinoic acid or 1a ,25-dihydroxyvitamin D3.Exp Hematol 1985; 13 : 981
7. Koeffler HP et al:Stuty of differentiation of fresh myelogenous leukemic cells by compounds that induce a human promyelocytic leukemic line(HL-60)to differentiate.Leukemia Research 1985; 13 : 981
8. Collins SJ et al:Induction of morphological and functional differentiation of human promyelocytic leukemia cells(HL-60):by compounds which induce defferentiation of murine leukemia cells.Int J Cancer 1980;25 : 213
9. Breitman TR et al Induction of defferentiation of the human prcmyelocytic leukemia cell line(HL-60)by retinoic acid.Proc Natl Acad Sci USA 1980;77:2936
10. Breitman TR et al:Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid. Blood 1981;57 : 1000
11. Honma Y et al:Induction of differentiation of human non-lymphocyte leukemia cells in primary culture by inducers of differentiation of human myeloid leukemia cell line HL-60.Eur J Cancer Clin Oncol 1983; 19;251
12 宋争平等：维胺酯和维胺酸对人早幼粒白血病细胞(HL60)的诱导分化作用。
药学学报 1984；19：576
13. Miyaura C et al: la, 25-dihydroxyvitamin D3 induces differentiation of human myeloid leukemia cells. Biochem Biophys Res Commun 1981; 102: 937
14．孙关林等：急性早幼粒细胞白血病的诱导分化疗法——44例疗效分析。中华血液学杂志 1989；10：119
15. Schwartz EL et al: Evaluation of some anthracycline antibiotics in an in vivo model for studying drug-induced human leukemia cell differentiation. Cancer Research 1983; 43: 2725
16. Schwartz EL et al: Structure activity relationships for the induction of differentiation of HL-60 human acute promyelocytic leukemia cells by anthracyclines. Cancer Research 1982; 42: 2651
17. Gamba-Vitalo C et al: Differentiation of WEHI-3BD~+ monomyelocytic leukemia cells by retinoic acid and aclacinomycin A. Cancer Research 1986; 46: 1189
18．路莹等：阿克拉霉素B对人早幼粒白血病细胞的分化诱导作用。中国医学科学院学报 1986；8：211
19. Schopf RE et al: Measurement of the respiratory burst in human monocytes and polymorphonuclear leukocytes by nitro blue tetrazolium reduction and chemiluminescence. J Immunol Methods 1984; 67: 109
20．刘友华等：抗8—AG和HGPRT缺失的人早幼粒白血病突变株(HL—60—AR)的体外诱导分化潜能。中国医学科学院学报 1986；8：461
21．医学统计学方法 上海第一医学院编 1978
22．严文伟等：急性髓性白血病细胞在液体培养中的自发分化。中华血液学杂志 1988；9：467
23．敖忠芳等：小剂量化疗药物及共与维甲酸合用对白血病细胞的诱导分化。中华血液学杂志 1988；9：29
24. Bear MR et al: Sustained viability of acute myelogenous leukemia cells in liquid suspension culture correlates with occurrence of differentiation. Leukemia Research 1988; 12: 647
25. Hicks DG et al: K_(562) cell erythroid differentiation: requirement for a factor in fetal bovine serum. Exp Hematol 1985; 13: 273
26. Hodges RE et al: Hematopietic study in vitamin A deficiency. Am J Clin Nutr 1978; 31: 876
27. Ferrero D et al: Induct ion of differentiation of human myeloid leukemias: surface changes probed with monoclonal antibodies. Blood 1983; 61: 171
28. Olsson IL et al: Induction of differentiation of the human histocytic lymphoma cell line U_(937) by retinoic acid and cyclic adenosine 3',??5'-monophosphate-inducing agents.Cancer Research 1982;42:3924
29. Oki ct al:New antitumor ant ibiotics,aclacinomycins Aand B.J Antibiot 1975,28.830
30. Sakurai M et al.Possible differentiation of human acute myeloblastic leukemia cells by daily and intermittent administration of aclaci- nomycin A.Leukemia Research 1983;7: 139
31. Frank DA et al Alterations in tyrosine phosphorylation during the granulocytic maturation of HL-60 leukemia cells.Cancer Research 1988;48 : 52
32. Flynn PJ et al:Retinoic acid treatment of acute promyelocytic leukemia: in vitro and in vivo observations.Blood 1983;62:1211
33. Reilly IAG et al:Hypoplastic acute leukemia:cytogenetic evidence for differentiation in vivo response to low dose Ara-C. Bri J Hematol 1987,65:384
34. Paran M et al In vitro induction of granulccyte differentiation in hematopoietic cells from leukemic and non-leukemic patients. Proc Natl Acad Sci USA 1970,-67; 1542
35. Friend C et al .Hemoglobin synthesis in murine virus-induced leukemic cells in vitro:stimulation of erythroid differentiation by dimethyl Sulfoxide. Proc Natl Acad Sci USA 1971;68:378
36. Lozzio BB et al:A multipotential leukemia cell line(K562)of human origin. Proc Soc Exp Biol Med 1981; 166 J 546
37. Pegoruro L et at:Different iation of human leukemias in response to TPA in vitro. Blood 1980;55:859
38. Palu G et al:Patients of maturation in short time culture of human AML cells.Br J Cancer 1979540: 719
39. Palu G et al.Spontaneous regression of human AML xenografts and phenotypic evidence for maturation. Br J Cancer 1979;40 : 731
40. Bainton DF.:Abnormal neutrophils in acute myelogeneous leukemia; identification of subpopulations based on analysis ofazurophil and specific granules. Blood Cells 1975; 1 : 191
41. Rausch PG et al;Immunocytochemical identification of abnormal Polymorphonuclear neutrophils in patients with leukemia.Blood cells 1978;4:369
42. Suda T et al :Studies on abnormal polymorphonuclear neutrophils in acute myelogeneous leukemia:clinical significance and changes after chemotherapy.Am J Hematol 1983; 15 : 45
43. Mittermuller J et al In vivo differentiation of leukemic blasts and??effect of low-dose Ara-C in a marrow grafted patient with leukemic relapse.Br J Hematol 1986;62 : 757
44. Campbell AK et al.Chemiluminescence as an analytical tool in cell biology and medicine.Methods Biochem Analysis 1985;31:317
45. Kubo A et al:Generation of oxygen radicals by human polymorphonu- clear leukocytes in response to non-phagocytosable stimuli.Acta Hematol JPN 1988;51 : 36
46. Babior BM.Oxidants from phagocytes:agents of defense and destruction. Blood 1984;64-959
47．田洁等：维生素A酸诱导人早幼粒白血病细胞系HL-60的吞噬发光测定。上海免疫学杂志1988；8：42
48. Bachner RL et al :The biochemical basis of nitroblue-tetrazolium reduction in normal and chronic granulomatous disease polymorpho- nuclear leukocytes.Blood 1976;48: 309
49. Lozzio CB et al:Human chronic myelogenous leukemia cell line with positive Philadelphia chromosome.Blood 1975;45:321
50. Sundatrom C et al. Establishment and characterization of a human his-tiocytic lymphoma cell line(U937).Int J Cancer 1976; 17: 565
51. Koeffler HP et ah Acute myelogenous leukemia: a human cell line responsive to colony-stimulating activity. Science 1978; 200: 1153
52. Collins SJ et al: Continuous growth and differentiation of human myeloid leukemic cells in suspension culture. Nature 1977; 270: 347
53. Koeffler HP et al: An undifferentiated strain derived from the human acute myelogenous leukemia cell line KG-1. Blood 1980; 56:265
54. Takeda K et al: Kinetics of appearance of differentiaton associated characteristics in ML-1 a line of human myeloblastic leukemia cells after treament with 12-o-tetradecanoylphorbol-13-acetate, dimethyl sulfoxide, 1-beta-D-arabinofuranosylcytosine. Cancer Research 1981; 42: 5152
55. Martin P et al: HEL cells: a new human erythroleukemia cell line with spontaneous and induced globin expression. Science 1982; 216: 1233
56. Tsuchiya S et al: Establishment and characterization of human acute monocytic leukemia cell line (THP-1). Int J Cancer 1980; 26: 171
57. Lotem H et al: Regulation of normal differentiation in mouse and human myeloid leukemic cells by phorbol esters and the mechanism of tumor promotion. Proc Natl Acad Sci USA 1979; 76: 5158
58. Rovera G et al; Induction of differentiation in human promyelocytic??leukemia cells by tumor promotors. Science 1979; 204: 868
59. Koeffler HP et al: Phorbol ester effect on differentiation of human myeloid leukemia cell lines blocked at different stages of maturation. Cancer Research 1981; 41: 919
60. Fibach E et al: Modulation of the maturation of human leukemic promyelocytes (HL—60) to granulocytes or macrophages. Leukemia Research 1982; 6: 781
61 Tomonoge M et al: Establisment of eosinophilic sublines from human promyelocytic leukemic cells(HL—60): demonstration of multipotentia-lity and single—lineage commitment of HL—60 stem cells. Blood 1986; 67: 1433
62. Fischkoff SA: Graded increase in probability of eosinophilic differentiation of HL—60 promyelocytic leukemia cells induced by culture under alkaline conditions. Leukemia Research 1988; 12: 679
63．刘友华等：抗8—AG和HGPRT缺乏的人早幼粒细胞白血病细胞突变株(HL—60—AR)的建立。中国医学科学院学报 1986；8：454
64．刘友华等：七种癌基因在HL—60—AR细胞中的表达及药物诱导分化后的变化。中国医学科学院学报 1987；9：407
65. Forsoz D et al: Variant cell lines from the human promyelocytic line HL—60. Leukemia Research 1982; 6: 491
66. Eric F et al: Expression of myeloid—specific antigens on two human erythroleukemia cell lines HEL and K562. Leukemia Research 1984; 8: 207
67. Dean A et al: Induction of hemoglobin accumulation in human K562 cells by heroin is reversible. Science 1981; 212: 459
68. Vainchenker W et al: Heterogeneity in the cellular commitment of a human leukemic cell line K562. Blood Cells 1981; 7: 357
69. Andersson IC et al: Induction of erythroid differentiation in the human leukemia cell line K562. Nature 1979; 278: 364
70. Tetteroo PAT et al: Megakaryoblastic differentiaton of proerythroblastic K562 cell—line cells. Leukemia Research 1984; 8: 197
71. Sakagami H et al: Differentiation—associated changes in human nor—T, non—B leukemia cell lines after treatment with 12—0—tetradecanoylphorbol—13—acetate (TPA). Leukemia Rcsearch 1984; 8: 187
72．严文伟等：TPA对50例急性白血病细胞的诱导分化作用。中华血液学杂志??1986；7：449
73. Yamaki H et al: Mechanism of action of aclacinomycin—A1. the effect on macromolecular syntheses. J Antibiot 1978; 31: 1149
74. Long BH et al; Effect of anthracycline analogues on the appearance of newly synthesized total RNA and messenger RNA in the cytoplasm of erythroleukemia cells. Mol pharmacol 1982; 22: 152
75. Fink FM et al: Aclacinomycin—A in the induction treatment of childhood AML. Onkologie Jun 1986; 9: 154
76. Orbach—Arbouys S et al: Aclacinomycin—A inhibits suppressor cells in vivo and in vitro. Behring Inst Mitt 1984; 74: 258
77. Orbach—Arbouys S et al: Reversal of immunological tolerance by aclacinomycin through inhibiton of suppressor cell activity. Cell Immunol 1983; 81: 384
78. Ishizuka M: Immunomodulation by antitumor antibiotics. Gan To Kagaku Ryobo 1986; 13: 697
79. Morin MJ: Inhibition of glycoprotein biosynthesis by the inducers of HL—60 cell differentiation, aclacinomycin—A and marcellomycin. Cancer Research 1984; 44: 2807
80. Leydem M et al: Low dose cytosine arabinoside: partial remission of acute myeloid leukemia without evidence of differentiation induction. Br J Hematol 1984; 57: 301
81. Ye Jing—Song et al: Low—dose Ara—C can cause complete remission of acute non—lymphocytic leukemia: differentiation induction? Leukemia Research 1986; 10: 1221
82. Franchi F et al: Cytosine arabinoside—induced differentiation and killing: unresolved question. Folia Haematol, Leipzig 1986; 113: 358
83. Lotem J et al: In vivo control of differentiation of myeloid leukemic cells by cyclosporine A and recombinant interleukin—la. Blood 1988; 72: 1595
84．杜德林等：茯芩素对人早幼粒白血病细胞系HL—60细胞的诱导分化作用。军事医学科学院院刊 1988；12：132
85 Feuerstein M. et al: Rapid phosphorylation—dephosphorylation of specific proteins induced by phorbol ester in HL—60 cells. J Biol Chem 1984; 259: 2782
86. Cooper RA et al: Inhibition of sterol and phospholipid synthesis in HL—60 promyelocytic leukemia cells by inducers of myeloid differentiation, Cancer Research 1981; 41: 184787. Favera RD et al: The human oncogene c—myc: structure, expression and amplification in the human promyelocytic leukemia cell line HL—60. Hematol Bluttransfus 1983; 28: 247
88. Craig RW et al: Early decline in c—myb oncogen expression in the differentiation of human myeloblastic leukemia (ML—1) cells induced with TPA. Cancer Research 1984; 44: 442
89. Dallegri F et al: Expression of cytolytic functions in HL—60 leukemic cells after induction of polymorphonuclear leukocyte differentiation. Blur 1986; 52: 243
90．沈柏均：人早幼粒白血病细胞株HL—60被DMSO诱导分化的可逆性。山东医科大学学报 1988；2：85
91. Ross DW et al: Differentiation versus cytoreduction during remission induction in acute nonlymphblastic leukemia treated with sequential high dose Ara—C and asparaginase. Cancer 1984; 53: 1651
92. Ye Jing—song et al.. Small—dose harringtonine induces complete remission in patients with acute promyelocytic leukemia. Leukemia 1988; 2: 427
93．血液病实验诊断 中国医学科学院血液学研究所主编，1983年