沙利度胺联合三氧化二砷对急性髓系白血病细胞表达VEGF和P-gp的影响
摘要
目的:观察沙利度胺(TLD)和三氧化二砷(As_2O_3 )对急性髓系白血病(AML)细胞分泌血管内皮生长因子(VEGF)和表达P-糖蛋白(P-gP)的影响。
方法:收集AML患者和健康体检者的血液,肝素抗凝并离心后,吸取上层血浆置-20℃冰箱内冷冻保存。收集AML患者的骨髓液,用Ficoll淋巴细胞分离液分离出骨髓单个核细胞(BMMNC)。37℃、5%CO2、饱和湿度条件下培养细胞于RPMI l64O培养液中。HL-60/VCR细胞株的培养基中加入VCR以维持耐药性。TLD和As_2O_3以不同浓度加入培养体系中,同时设空白对照。用双抗体夹心酶联免疫法(ELISA)法检测血浆和细胞培养上清液中VEGF的浓度,用流式细胞术(FCM)检测细胞膜上MDR1/p-gp的表达率。
结果:(1)AML患者血浆中VEGF浓度明显高于正常对照组(P<0.01)。(2)加入TLD和As_2O_3后,AML细胞和HL-60/VCR细胞株培养上清中VEGF浓度明显降低。(3)加入TLD和As_2O_3前后,AML细胞和HL-60/VCR细胞株的细胞膜上P-gP的表达率未见明显改变。(4)加入TLD和As_2O_3前后,AML细胞培养上清中VEGF的升高和细胞膜表面PgP的表达具有一定的正相关性。
结论:(1)白血病细胞可以通过自分泌途径分泌VEGF。(2)TLD和AS2O3均可抑制HL-60/VCR和AML细胞分泌VEGF。(3)TLD和AS2O3均未能影响HL-60/VCR和AML细胞膜上P-gP的表达。(4)AML患者BMMNC培养上清中VEGF的升高和细胞膜表面PgP的表达具有一定的正相关性,二者联合检测可作为监测病情和判断预后的指标。
Objective: To investigate the effect of thalidomide and As203 on the secretion of vascular endothelial growth factor(VEGF) and Pgp expression of the cell of AML.
Methods:The patients with AML and healthy people in contrast group were analyzed. Heparin- anticoagulated blood were centrifuged to obtain plasma then conserved in -20℃fridge. The patients with AML were analyzed. Heparinized marrow was taken, and putted into Ficoll-isopaque solution to purified BMMNC.BMMNC and HL-60/VCR were both cultured in the RPMI 1640 medium, placed in 5% CO2 saturation and 37℃to proliferation.Added VCR to the medium of HL-60/VCR to sustain drug resistance. Thalidomide and As_2O_3 was added to substrate respectively. At the same time, a contrast group was set up. The concentration of VEGF in upper liquid and plasma was examined with enzyme-linked immunosorbent assay (ELISA)and Pgp expression on cell membranes was analyzed by flow cytometry (FCM).
Results : The plasma VEGF concentrations in the patients with AML were significantly higher than the levels of the control (P<0.01).After added thalidomide and As_2O_3 to substrate, the concentration of VEGF in upper liquid and plasma is significantly lower than the contrast group.After added thalidomide and As_2O_3 to substrate, Pgp expression of the cell of AML and HL60/VCR was not significantly changed.Singnificant correlation was observed between P-gp and VEGF in newly diagnosed AML cases.
Conclusions:Leukemia cell can secrete VEGF self;Both thalidomide and As_2O_3 can inhibit the secretion of VEGF of AML and HL-60/VCR;Both thalidomide and As_2O_3 can not affect the Pgp expression on the cell membranes of AML and HL-60/VCR.Test of the two targets together is more effective to the judgment of prognosis in AML.
方法:收集AML患者和健康体检者的血液,肝素抗凝并离心后,吸取上层血浆置-20℃冰箱内冷冻保存。收集AML患者的骨髓液,用Ficoll淋巴细胞分离液分离出骨髓单个核细胞(BMMNC)。37℃、5%CO2、饱和湿度条件下培养细胞于RPMI l64O培养液中。HL-60/VCR细胞株的培养基中加入VCR以维持耐药性。TLD和As_2O_3以不同浓度加入培养体系中,同时设空白对照。用双抗体夹心酶联免疫法(ELISA)法检测血浆和细胞培养上清液中VEGF的浓度,用流式细胞术(FCM)检测细胞膜上MDR1/p-gp的表达率。
结果:(1)AML患者血浆中VEGF浓度明显高于正常对照组(P<0.01)。(2)加入TLD和As_2O_3后,AML细胞和HL-60/VCR细胞株培养上清中VEGF浓度明显降低。(3)加入TLD和As_2O_3前后,AML细胞和HL-60/VCR细胞株的细胞膜上P-gP的表达率未见明显改变。(4)加入TLD和As_2O_3前后,AML细胞培养上清中VEGF的升高和细胞膜表面PgP的表达具有一定的正相关性。
结论:(1)白血病细胞可以通过自分泌途径分泌VEGF。(2)TLD和AS2O3均可抑制HL-60/VCR和AML细胞分泌VEGF。(3)TLD和AS2O3均未能影响HL-60/VCR和AML细胞膜上P-gP的表达。(4)AML患者BMMNC培养上清中VEGF的升高和细胞膜表面PgP的表达具有一定的正相关性,二者联合检测可作为监测病情和判断预后的指标。
Objective: To investigate the effect of thalidomide and As203 on the secretion of vascular endothelial growth factor(VEGF) and Pgp expression of the cell of AML.
Methods:The patients with AML and healthy people in contrast group were analyzed. Heparin- anticoagulated blood were centrifuged to obtain plasma then conserved in -20℃fridge. The patients with AML were analyzed. Heparinized marrow was taken, and putted into Ficoll-isopaque solution to purified BMMNC.BMMNC and HL-60/VCR were both cultured in the RPMI 1640 medium, placed in 5% CO2 saturation and 37℃to proliferation.Added VCR to the medium of HL-60/VCR to sustain drug resistance. Thalidomide and As_2O_3 was added to substrate respectively. At the same time, a contrast group was set up. The concentration of VEGF in upper liquid and plasma was examined with enzyme-linked immunosorbent assay (ELISA)and Pgp expression on cell membranes was analyzed by flow cytometry (FCM).
Results : The plasma VEGF concentrations in the patients with AML were significantly higher than the levels of the control (P<0.01).After added thalidomide and As_2O_3 to substrate, the concentration of VEGF in upper liquid and plasma is significantly lower than the contrast group.After added thalidomide and As_2O_3 to substrate, Pgp expression of the cell of AML and HL60/VCR was not significantly changed.Singnificant correlation was observed between P-gp and VEGF in newly diagnosed AML cases.
Conclusions:Leukemia cell can secrete VEGF self;Both thalidomide and As_2O_3 can inhibit the secretion of VEGF of AML and HL-60/VCR;Both thalidomide and As_2O_3 can not affect the Pgp expression on the cell membranes of AML and HL-60/VCR.Test of the two targets together is more effective to the judgment of prognosis in AML.
引文
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[7] Dredge K,Falgleish AG,Marriott JB.Thalidomide analogs as emerging anti cancer drugs[J].Anicancer Drugs,2003,14(5):331.
[8] 耿冬梅,张良明.沙利度胺抗肿瘤作用研究进展[J].国外医学-肿瘤学分册,2004,31(10):763.
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[10] Roboz GJ, Dias S,Lam G, et al.Arsenictrioxide induces dose and time dependent apoptosis of endothelium and may exert santileukemic effect via inhibition of angiogenesis [J ]. Blood ,2000,96(4) :1525-1530.
[11]Tafuri A, Gregorj C, Petrucci MT, et al. MDR1 protein expression is an independent predictor of complete remission in newly diagnosed adult acute lymphoblastic leukemia [J]. Blood,2002,100(3):974-981.
[12] 艾辉胜,罗荣城,乐晓锋.现代白血病学[M].北京:人民军医出版社,1997:95-115.
[13] Kuramoto K,Uesaka T,Kimura A,et al.ZK7,a novel zinc finger gene,is induced by vascular endothelial growth factor and inhibits apoptotic death in hematopoietic cells[J].Cancer Res, 2000,60(2):425-430.
[14]祝焱,谢兆霞,谭达人,等.急性白血病患者单个核细胞内一氧化氮含量、一氧化氮合酶活性的变化与多药耐药的关系[J].中华血液学杂志,2002,23(12):651-652.
[15]张之南主编.血液病诊断标准及疗效标准[M].第 2 版.北京:科学出版社,1998:168.
[16] 李君君,颜家远,余海仁,等.恶性髓系血液病患者血管内皮生长因子表达的检测及分析[J]. 中国实用内科杂志,2005,25 (6):539-540.
[17] Claffey K,Robinson G.Regulation of VEGF/VPF expression in tumor cells:consequencesfor tumor growth and metastasis[J].Cancer Metastasis Rev,1996,15:165.
[18] Hiroyuki K,Manabu O,Megumi B,et a1.The role of circulating 1L-8 and VEGF protein in the progression of gastric cancer[J].Cancer Sci.2003, 94:735.
[19] Sannishtha D,Olga R,Noel M,et a1.VEGF-integrin interplay controls tumor growth and vascularization [J].PNAS,2005,l02(2):7589.
[20] Kini AR,Peterson LA,Tallman MS,et a1.Angiogenesis in acute promyelocytic leukemia:induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid[J].Blood,2001, 97(12):3919-3924.
[21] Aguayo A,Kantarjian H,Manshouri T,et a1.Angiogenesis in acute and chronic leukemias and myelodysplastic syndromes[J]. Blood,2000,96(6):2240-2245.
[22] D’AMATO RJ,LOUGHMAN MS,FLYMN E,et a1. Thalidomide is an inhibitor of angiogenesis[J].Proc Natl Acad Sci USA,1994,91(9):4082-4085.
[23] Davison K, Mann KK, Miller W H.Arsenic trioxide:mechanisms of action [J].Semin Hematol,2002,39(2):3.
[24] 李莉,谢晓恬,梁爱斌,等.血管内皮生长因子在急性白血病细胞株的表达[J].中国小儿血液,2004,9 (4):170-174.
[25] Scott PA,Gleadle JM,Bicknell R,et a1.Role of the hypoxia sensing system,acidity and reproductive hormones in the variability of vascular endothelial growth factor induction in human breast carcinoma cell lines[J].1nt J Cancer,1998,75(5):706-712.
[26] Takahashi Y,Bucana CD,Cleary KR,et a1.P53,vessel count, and vascular endothelial growth factor expression in human colon cancer[J].1nt J Cancer,1998,79(1):34-38.
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