IFN-α联合IL-2体外逆转白血病细胞多药耐药的研究
摘要
目的:探讨干扰素(IFN-α)和白细胞介素-2(IL-2 )对人类髓性白血病多药耐药细胞株HL-60/VCR的作用及作用机制,为IFN-α和IL-2在难治性急性白血病中的应用提供实验依据。
方法:采用甲基四氮唑盐(MTT)法检测IFN-α和IL-2对多药耐药细胞株HL-60/VCR细胞生长的抑制作用;采用流式细胞术检测IFN-α、IL-2、IFN-α联合IL-2处理前后细胞中的P-gp表达水平的变化,进一步探讨其逆转耐药的机制。
结果:1.HL-60细胞及其多药耐药株HL-60/VCR细胞对VCR药物的敏感性分别IC50=3.49ng/ml、IC50=926.12 ng /ml。其HL-60/VCR细胞对VCR的耐药倍数是HL-60细胞的265.57倍,耐药倍数较高,符合实验要求。
2.IFN--α浓度在0-500U/ml之间时对HL-60/VCR细胞未见明显的抑制作用,当细胞因子浓度>500U/ml其抑制作用明显加强,并随剂量加大作用加强。
3.IL-2浓度为0-1000U/ml范围内对HL-60/VCR细胞未见明显的抑制作用。
4.IL-2、IFN-α及IL-2联合IFN-α对HL-60/VCR细胞均有一定的逆转耐药作用,逆转倍数分别为1.53、1.90、3.62倍,且VCR浓度在0.1-2.0范围内IFN-α联合IL-2的逆转作用较细胞因子单独使用时作用明显增强,具有显著性差异,P<0.05。
5.HL-60/VCR细胞在IFN-α、IL-2及IFN-α联合IL-2作用前后的细胞表面P-gp表达水平分别为33.41±4.63,23.07±5.48,21.82±3.87,16.62±1.27,IFN-α组和IL-2+IFN-α组明显下降,P<0.05;细胞内总P-gp的表达水平分别为37.19±5.16、35.3±4.77、37.45±5.19、34.98±3.50,各组间无显著差异,P>0.05。
结论:1.HL-60/VCR细胞为人类髓细胞性白血病多药耐药株,其对VCR有较高耐药性。
2.IFN-α在终浓度均为0-500U/ml时对HL-60/VCR细胞的增殖无明显的抑制作用,但IFN-α终浓度>500U/ml时出现了明显的生长抑制作用,说明高浓度IFN -α对HL-60/VCR具有一定的杀伤作用。
3.在0-1000U/ml终浓度范围内的IL-2对HL-60/VCR细胞无明显的杀伤作用。4.IFN-α和IL-2与VCR同共作用于HL-60/VCR细胞,其对VCR的敏感性增高,说明IFN-α和IL-2具有部分逆转白血病细胞MDR作用。
5.IFN-α联合IL-2(终浓度均为500U/ml)作用HL-60/VCR细胞后,其逆转作用增强。
6.IFN-α联合IL-2应用逆转MDR作用的机制一部分可能是通过影响细胞质和细胞膜之间的P-gp的交换,减少细胞膜上P-gp表达水平,提高药物在细胞内的聚集,增强药物对肿瘤细胞的敏感性从而发挥杀死肿瘤细胞的作用。
Objectives: To investigate the effect of IFN-a plus IL-2 on multidrug resistance of myelogenous leukemia cell line HL-60/VCR and the underlying mechanisms.
Methods: The inhibitory effect of IFN-a plus IL-2 on HL-60/VCR growth was detected by MTT . The expression levels of P-gp in HL-60/VCR cells treated in the presence or absence of IFN-a, IL-2, IFN-a plus IL-2 respectively were determined by Flow Cytometry ,To research machine of resistance retroconversion of leukemia cell
Results: 1. IC50 of VCR to HL-60 and HL-60/VCR are 3.49ng/ml and 0.92μg/ml respectively. Multidrug resistance of HL-60/VCR is 265.57times than that of HL-60, which accords with the requirement of the study.
2.IFN-a shows no significant inhibitory effect on HL-60/VCR at the concentration varies from 0U/ml to 500U/ml, but shows significant effect in the dose of more than 500U/ml. The inhibitory effect was in a dose dependent manner.
3. IL-2 shows no significant inhibitory effect on HL-60/VCR at the concentration varies from 0U/ml to 1000U/ml.
4.All the IFN-a, IL-2, IFN-a plus IL-2 can induce drug resistance retroconversion, and the retroconversion index are1.53,1.90,3.62times respectively. When the concentration of VCR varies from 0.1 to 2.0, the inhibitory effect of IFN-a plus IL-2 is significantly higher than that of the cytokine alone (P<0.05) ).
5.The expression level of P-gp in HL-60/VCR cells treated in the presence or absence of IFN-a plus IL-2 was. 33.41±4.63,23.07±5.48,21.82±3.87,16.62±1.27 respectively,group IFN-a and IL-2+IFN-αare obvious decent, P<0.05; The total expression level of P-gp in cells37.19±5.16、35.3±4.77、37.45±5.19、34.98±3.50 respectively,each interclass no significant deviation P>0.05。
Conclusions:1.HL-60/VCR, a myelogenous leukemia cell line, have multidrug resistance to VCR.2.IFN-αshows no significant inhibitory effect on HL-60/VCR proliferation at the concentration varies from 0U/ml to 500U/ml, but shows significant effect in the dose of more than 500U/ml. the result indicate that high dose of IFN-αable to impair HL-60/VCR proliferation.
3.IL-2 can not impair HL-60/VCR proliferation at the concentration varies from 0U/ml to 1000U/ml.
4.IFN-αand IL-2 can accentuate the effect of VCR on HL-60/VCR, which indicates IFN-αand IL-2 can induce multidrug resistance retroconversion.
5.The inhibitory effect of IFN-αplus IL-2(500U/ml) is significantly higher than that of IFN-αor IL-2 alone.
6.IFN-αplus IL-2 may induce multidrug resistance retroconversion and kill the leukemia via influencing exchange of P-gp between cytoplasm and cytomembrane of HL-60/VCR, attenuating the expression of P-gp on cytomembrane, promoting the aggregation of VCR in cytoplasm and enhancing the effect of medicine on HL-60/VCR..
方法:采用甲基四氮唑盐(MTT)法检测IFN-α和IL-2对多药耐药细胞株HL-60/VCR细胞生长的抑制作用;采用流式细胞术检测IFN-α、IL-2、IFN-α联合IL-2处理前后细胞中的P-gp表达水平的变化,进一步探讨其逆转耐药的机制。
结果:1.HL-60细胞及其多药耐药株HL-60/VCR细胞对VCR药物的敏感性分别IC50=3.49ng/ml、IC50=926.12 ng /ml。其HL-60/VCR细胞对VCR的耐药倍数是HL-60细胞的265.57倍,耐药倍数较高,符合实验要求。
2.IFN--α浓度在0-500U/ml之间时对HL-60/VCR细胞未见明显的抑制作用,当细胞因子浓度>500U/ml其抑制作用明显加强,并随剂量加大作用加强。
3.IL-2浓度为0-1000U/ml范围内对HL-60/VCR细胞未见明显的抑制作用。
4.IL-2、IFN-α及IL-2联合IFN-α对HL-60/VCR细胞均有一定的逆转耐药作用,逆转倍数分别为1.53、1.90、3.62倍,且VCR浓度在0.1-2.0范围内IFN-α联合IL-2的逆转作用较细胞因子单独使用时作用明显增强,具有显著性差异,P<0.05。
5.HL-60/VCR细胞在IFN-α、IL-2及IFN-α联合IL-2作用前后的细胞表面P-gp表达水平分别为33.41±4.63,23.07±5.48,21.82±3.87,16.62±1.27,IFN-α组和IL-2+IFN-α组明显下降,P<0.05;细胞内总P-gp的表达水平分别为37.19±5.16、35.3±4.77、37.45±5.19、34.98±3.50,各组间无显著差异,P>0.05。
结论:1.HL-60/VCR细胞为人类髓细胞性白血病多药耐药株,其对VCR有较高耐药性。
2.IFN-α在终浓度均为0-500U/ml时对HL-60/VCR细胞的增殖无明显的抑制作用,但IFN-α终浓度>500U/ml时出现了明显的生长抑制作用,说明高浓度IFN -α对HL-60/VCR具有一定的杀伤作用。
3.在0-1000U/ml终浓度范围内的IL-2对HL-60/VCR细胞无明显的杀伤作用。4.IFN-α和IL-2与VCR同共作用于HL-60/VCR细胞,其对VCR的敏感性增高,说明IFN-α和IL-2具有部分逆转白血病细胞MDR作用。
5.IFN-α联合IL-2(终浓度均为500U/ml)作用HL-60/VCR细胞后,其逆转作用增强。
6.IFN-α联合IL-2应用逆转MDR作用的机制一部分可能是通过影响细胞质和细胞膜之间的P-gp的交换,减少细胞膜上P-gp表达水平,提高药物在细胞内的聚集,增强药物对肿瘤细胞的敏感性从而发挥杀死肿瘤细胞的作用。
Objectives: To investigate the effect of IFN-a plus IL-2 on multidrug resistance of myelogenous leukemia cell line HL-60/VCR and the underlying mechanisms.
Methods: The inhibitory effect of IFN-a plus IL-2 on HL-60/VCR growth was detected by MTT . The expression levels of P-gp in HL-60/VCR cells treated in the presence or absence of IFN-a, IL-2, IFN-a plus IL-2 respectively were determined by Flow Cytometry ,To research machine of resistance retroconversion of leukemia cell
Results: 1. IC50 of VCR to HL-60 and HL-60/VCR are 3.49ng/ml and 0.92μg/ml respectively. Multidrug resistance of HL-60/VCR is 265.57times than that of HL-60, which accords with the requirement of the study.
2.IFN-a shows no significant inhibitory effect on HL-60/VCR at the concentration varies from 0U/ml to 500U/ml, but shows significant effect in the dose of more than 500U/ml. The inhibitory effect was in a dose dependent manner.
3. IL-2 shows no significant inhibitory effect on HL-60/VCR at the concentration varies from 0U/ml to 1000U/ml.
4.All the IFN-a, IL-2, IFN-a plus IL-2 can induce drug resistance retroconversion, and the retroconversion index are1.53,1.90,3.62times respectively. When the concentration of VCR varies from 0.1 to 2.0, the inhibitory effect of IFN-a plus IL-2 is significantly higher than that of the cytokine alone (P<0.05) ).
5.The expression level of P-gp in HL-60/VCR cells treated in the presence or absence of IFN-a plus IL-2 was. 33.41±4.63,23.07±5.48,21.82±3.87,16.62±1.27 respectively,group IFN-a and IL-2+IFN-αare obvious decent, P<0.05; The total expression level of P-gp in cells37.19±5.16、35.3±4.77、37.45±5.19、34.98±3.50 respectively,each interclass no significant deviation P>0.05。
Conclusions:1.HL-60/VCR, a myelogenous leukemia cell line, have multidrug resistance to VCR.2.IFN-αshows no significant inhibitory effect on HL-60/VCR proliferation at the concentration varies from 0U/ml to 500U/ml, but shows significant effect in the dose of more than 500U/ml. the result indicate that high dose of IFN-αable to impair HL-60/VCR proliferation.
3.IL-2 can not impair HL-60/VCR proliferation at the concentration varies from 0U/ml to 1000U/ml.
4.IFN-αand IL-2 can accentuate the effect of VCR on HL-60/VCR, which indicates IFN-αand IL-2 can induce multidrug resistance retroconversion.
5.The inhibitory effect of IFN-αplus IL-2(500U/ml) is significantly higher than that of IFN-αor IL-2 alone.
6.IFN-αplus IL-2 may induce multidrug resistance retroconversion and kill the leukemia via influencing exchange of P-gp between cytoplasm and cytomembrane of HL-60/VCR, attenuating the expression of P-gp on cytomembrane, promoting the aggregation of VCR in cytoplasm and enhancing the effect of medicine on HL-60/VCR..
引文
1.Ross DD .Novel mechanisms of drug resistance in leukemia [J]. Leukemia 2000;14:467-473.
2.Volm M.Multidrug resistance and its reversa[J].Anticancer Res.1998, 18:2905一2917
3. Abbazadegan MR,Cress AE,Futscher BW,et al.Evidence for a cytoplasmic p-glycopmtein location associated with increased multidrug resistance and resistance to chemosensitzers[J].Cancer Res,1996,54:5435一5442
4.Lehnert M.Chemotherapy resistance in breast cancer.Anticancer Res.1998, 18(3c): 2225-2226
5.Sonneveld P.Drug resistance in multiple myeloma.Pathol Biol.1999, 47(2): 182- 187
6. 童杰,赵志平.干扰素与再生障碍性贫血[J]. 国外医学,免疫学分册,1987; 10(5):189
7.曾云,杨凌,李惠民,等.白细胞介素-2联合干扰素-α对与K562细胞互培养的白血病缓解期外周血淋巴细胞免疫表型的影响[J]. 白血病淋巴瘤,2004,13(5):287-289.
8. 李成文,严文伟,郝玉书,等. IFN-α 联合IL-2激活的骨髓净K562细胞的实验研究[J].中华血液学杂志,1996,17(10):518-520
9.朱兴虎,李建勇,夏学鸣等.HL-60/VCR 多药耐药细胞株耐药机制的研究[J].癌症,2002,21:1310-1313.
10.IsaacsA, Lindermann J. Virus interference[J].Theinterference ,1957,147:258-267.
11.孙亚萍,王英明,乔守怡. 干扰素及最新研究进展[J]中国免疫学杂志, 2006, 22:676-679.
12.Abbazadegan MR,Cress AE,Futscher BW,et al.Evidence for a cytoplasmic p-glycopmtein location associated with increased multidrug resistance and resistance to chemosensitzers [J]. Cancer Res,1996,54:5435一5442
13.童杰,赵志平.干扰素与再生障碍性贫血 [J]. 国外医学·免疫学分册,1987, :189
14.杨吉成,李丽娥,盛伟华等.基因工程 IFNα2a 和 IFNα2b 对肿瘤细胞生长的抑制作用[J].实用癌症杂志,1999,14:164-166.
15.于宏,孙立荣,庞秀荣等.干扰素α2b 对 HL-60 细胞抑制增殖与促调亡的影响 [J].中国实验血液学杂志,2007,15:56-58.
16.Minami R,Muta K,Ilesung C,et al.Interleukin-6 sensitizes multiple myeloma cell lines for apoptosis inducedy by interferon-α [J].Exp Hematol,2000,28:244-255.
17.Stark G ,Kerret I, Williams B,et al.How cells respond to interferons. [J].Annu RevBiochem,1998,67:227-264.
18.Pfeffer L ,Dinarello C,Herberman R, et al .Bioligic properties of recombinant interferons:40th anniversary of the disscovery of interferons [J].Cancer Res, 1998, 58:2489-2499.
19.Kaser A,Nagata S,Tiget H,et al.Interferon-αaugments activation induced T cell death by upregulation of Fas (CD95/APO-1) and Fas ligand expression[J]. Cytokine, 1999,11:736-743.
20.Mamta C ,Douglas W,Ernest C,et al.Preferential induction of apoptosis by interferon(IFN)βcomparedwith IFN-α2:correlation with TRAIL/Apo2L induction in melanoma cell lines [J].Clin Cancer Res,2001,7:1821-1831.
21.Finkenxeller G,Sparacio A, Technau A,et al.Sp1 recognition sites in the proximal promoter of the human vascular endothelial growth factor gene are essential for platelet-derived growth factorin-duced gene cspression [J].Oncogene,1997, 15: 669-676.
22.张继红,张锦华,佟海侠.γ-IFN 诱导神经母细胞瘤细胞分化及 TrKA 表达的实验研究 [J].中国小儿血液,2001,6:121-125.
23.李放,王秋娟,高文青. 家蚕细胞基因工程 人α-IFN 对小鼠的免疫调节作用[J].中国现代应用药学杂志,1999,16:31-34.
24.Rosenberg SA ,Spiess PJ ,Schwarz S. Cell Immunol ,1980 ;54 (2) :293～306
25.牛青霞,靖志安.白细胞介素-2 抗癌原理与临床使用方法[J].中国肿瘤临床,1998,25:685-687.
26.曹雪涛.白细胞介素-2 的基础与临床 [M].北京科学技术出版社,1990,144.
27.Ross DD .Novel mechanisms of drug resistance in leukemia [J]. .Leukemia 2000;14:467-473.
28.陈艳,张荣艳.ABC 转运蛋白及其介导的白血病多药耐药研究进展 [J].江西医学院学报,2003,43:96-98.
29.李颖,徐建.谷胱甘肽-S-转移酶与白血病耐药[J].国内医学肿瘤学分册,1999,26:184-185.
30.冯建航,许丽李恩民.核基质成分拓扑异酶Ⅱ与肿瘤耐药[J].肿瘤防治杂志,2001,8:675-677.
31.Laredo J,Huynh A,Muller C,et al.Effect of the protein Kinase Cinhibitor saturosprine on chemosensitivity to claunorubicin of norual and leademic fresh myeloid cells[J].Blood,1994,84:229-237.
32.朱兴虎,李建勇,夏学鸣.白血病细胞耐药与细胞凋亡的研究进展 [J].国外医学,生理、病理科学与临床分册,2002,22:401-403.
33.陈永乐,郭坤元,徐安龙,等.Fas-Fasl 凋亡途径和白血病 [J].国外医学,生理、病理科学与临床分册,2000,20:143-145.
34.薛红漫,李文益.Bcl-2 与白血病耐药 [J].国外医学输血及血液分册,1999,22:79-82
35.Matsuo H,Wakasugi M,Takanaga H,et al.Possibility of the reversal of multidrug resistance and the avoidance of side effects by liposomes modified with MRK-16,a monoclonal antibody to P-glycoprotein [J].J Control Release, 2001,77:77-86.
36.姜国胜,唐天华,张玉花等.干扰素对 HL-60 细胞与维甲酸耐药 HL-60 细胞作用的研究[J].中国免疫学杂志,2000,16:586-588.
37.胡晓梅,邓成册,麻柔.逆转白血病耐药的研究进展 [J].中国中西结合杂志,2000,20:715-718.
38.浦津,楼方定,周绮等.环孢素 A 与细胞因子联合逆转白血病多药耐药的体外研究[J].中华医学杂志,1999,79:224-226
39.陈莉,许小平,王健民等.环孢菌素、他莫西芬及α-干扰素对白血病细胞多药耐药的逆转作用 [J].白血病淋巴瘤. 2003,12:135-138.
40.刘竹珍,赵洪国,李广伦等.IL-2 并 IFN-α对老年急性白血病化疗效果的影响 [J].青鸟大学医学院学报,2003,39:433-435.
41.Arancia G,Malinani A,Calcabnini A,et al.Intracelluar P-glycoprotein in multidrug resistance tumor cells [J].Ital J Anat Embryol,2001,106:59-68.
42.Ruiz Comez MJ,Souviron Rodriguez A,Martinez Morillo M. P-glycoprotein ,a membrane pump that represents a barrier to chemotherapy in cancer patients[J].An Med Interna,2002,19:477-485.
43.刘丽英,刘复强,杨纯正等.白细胞介素-2 和α-干扰素逆转白血病细胞多药耐药的研究 [J].中华血液学杂志,1997,18:646-648.
44.Stein U,Walther W,Shoemaker R H.Modulation of mdr1 exepression by cytokines in human colon carcinoma cells:an approach for reversal of multidrug resistance[J].Cancer,1996,74:1384-1388.
1. 曾学清,段功香,蒋香莲等.干扰素在抗肿瘤方面的应用[J].中国生化药物杂志,2003,24(4):512.
2. 梁彦,魏熙胤,李凯,等.IFN 及三氧化二砷诱导淋巴瘤细胞凋亡及细胞周期阻滞的研究[J].肿瘤防治杂志,2002,9(2):127 130.
3. 姜国盛,唐天华,张玉昆等.干扰素对 HL60 细胞与维甲酸耐药 HL-60 细胞作用的研究[J]中国免疫学杂志,2000,16:586.
4. Testa U,Ferbus d,Gabbianelli M,et al.Effects of endogenous interferons on th differentiation of human monocyte cell line U937. Caner Res,1988,48:82-87.
5. 陈惠仁,孙关林,韩锐等. 新维甲类联合γ干扰素对急性单核细胞白血病细胞增殖分化作用的体外研究[J].中华血液学杂志, 1999,20(1):10
6. 钱绩虎,邵荣标,丁昌慧,等.IFNα对人体液免疫功能调节作用的实验研究[J].南通医学院学报,1999,19(2):164 165.
7. Saily M,Koistenen P,Soppi E,et al.Effect of interferon-alpha on immunoglobin production by peripheral blood mononuclear cells in multiple milkman[J].Eur J Heamatol,1996,57(2):171-173.
8. 吴敏媛.儿童急性淋巴细胞白血病治疗现状[J]中国肿瘤,2001,10(10):566.
9. 孙黎明,原弛.小儿急性淋巴细胞白血病的诊疗浅谈[J].中国小儿血液, 2001,6(5):532.
10.Nooter K,Sonneveld P.Clinical relevance of p-glycoprotein expression in haematological malignancies.Leuk Res,1994,18(4):233.
11.薛红漫,李文益,侯玲玉等.多药耐药细胞系 HL60/HHT 的建立及耐药机理的初步探讨[J].中国小儿 2000,5(1):13.
12.赵毅,李玲,温丙昭等.复发/难治急性白血病 bcl-2、pl70 的检测研究[J].白血病·淋巴瘤,2002,11(1):
13.付劲蓉,李成荣,杨锡强,等.重组人白细胞介素 4 对白血病细胞 HL-60/VCR多药耐药逆转研究[J].中华血液学杂志, 2000,21(2):94-95.
14.Bassan R,Lerede T,BorleriG,et al.Phase I trial with escalating doses of idarubicin and multidrug resistance reversal by shore-course cyclosporine A,sequential high-dose cytosine arabinoside,and granulocyte colony-stimulating factor for adult patients with refractory acute leukemia [J] Haematologica,2002,87(3):257-263.
15.Sdzuka Y,Sugiyama T,Sonobe T,Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance[J]Toxicol Lett,2000,114(1-3):155-162.
16.Li J,Xu L Z,Yao J J ,et al.Reversal effects of droloxifene on multidrug resistance in adriamycin-resistance K562 cell line[J]Acta Paarmacol Sin,2001, 22(11): 1023-1027.
17.Sargent J M,Williamson C J,Yardley C,et al.Dexrazoxane significantly impairs the induction of doxorubicin resistance in the human leukemia line,K562[J].Br J Cancer,2001,84(7):959-964.
18.Kang Y,Petty R R.Effect of alpha-interferon on P-glycoprote epression and function and on verapamil modulation of doxorubicin resistance[J].Cancer Res,1994,54(11):2952-2958.
19.刘丽辉,刘复强,杨纯正等.白细胞介素 2 和α干扰素逆转白血病细胞多药耐药的研究[J].中国血液,1997,118(12):646.
20.浦津,楼方定,周绮等.环孢菌素 A 与细胞因子联合逆转白血病多药耐药性的体外研究[J].中华医学杂志,1999,179(3):422.
21.Stein U,Walther W,Shoemaker R H.Modulation of mdrl expression by cytokines in human colon carcinoma cells:an approach for reversal of multidrug resistance [J].Cancer,1996,74(9):1384-1391.
22.陈惠仁,孙关林,韩锐,等.新维甲类化合物对早幼粒细胞白血病和正常造血增殖分化作用的体外研究.中华血液学杂志,1997,18:65 68.
23.平宝红,周淑芸,刘启发,等.干扰素逆转白血病多药耐药性的研究及机制的初步探讨[J].中华血液学杂志,1996,17(1):13-15.
24.FOgler WE,Parson J W.Volkern K,et al.Enhancement by recombinant human interferon alfa of the reversal of multidrug resistance by MRK-16 monoclonal antibody[J].Natl Cancer Inst, 1995, 87(2):94-104.
25.柴晔,张连生,张玉芳等.环孢素A与干扰素联合逆转复发难治性急性白血病多药耐 药的临床研究[J].临床血液学杂志,2003,16(5):211
26.唐义平,邓承祺,缪世锟等.干扰素逆转复发难治性急性白血病的临床观察[J].JOURNAOL OF LEUKEMIA,2001,10(3):160
27.王薇娜,王丽,施秀荣,张田.α-2b 干扰素联合化疗逆转原发耐药急性白血病 2 例[J].重庆医学,2003,32(7):835.
28.LupH,NegrinRS.Anovel population of expanded human CD3+ /CD56+ cell derived from T cells with potentin vivo antitumor antivity in mice with severe combined immunodeficiency [J]. Immunol,1994,153:1687-1696.
29.周晓宏,童春荣.自体细胞因子诱导的杀伤细胞治疗急性 B 淋巴细胞白血病 22 例临床观察[J].河北医学,2003,9(4):306.`
2.Volm M.Multidrug resistance and its reversa[J].Anticancer Res.1998, 18:2905一2917
3. Abbazadegan MR,Cress AE,Futscher BW,et al.Evidence for a cytoplasmic p-glycopmtein location associated with increased multidrug resistance and resistance to chemosensitzers[J].Cancer Res,1996,54:5435一5442
4.Lehnert M.Chemotherapy resistance in breast cancer.Anticancer Res.1998, 18(3c): 2225-2226
5.Sonneveld P.Drug resistance in multiple myeloma.Pathol Biol.1999, 47(2): 182- 187
6. 童杰,赵志平.干扰素与再生障碍性贫血[J]. 国外医学,免疫学分册,1987; 10(5):189
7.曾云,杨凌,李惠民,等.白细胞介素-2联合干扰素-α对与K562细胞互培养的白血病缓解期外周血淋巴细胞免疫表型的影响[J]. 白血病淋巴瘤,2004,13(5):287-289.
8. 李成文,严文伟,郝玉书,等. IFN-α 联合IL-2激活的骨髓净K562细胞的实验研究[J].中华血液学杂志,1996,17(10):518-520
9.朱兴虎,李建勇,夏学鸣等.HL-60/VCR 多药耐药细胞株耐药机制的研究[J].癌症,2002,21:1310-1313.
10.IsaacsA, Lindermann J. Virus interference[J].Theinterference ,1957,147:258-267.
11.孙亚萍,王英明,乔守怡. 干扰素及最新研究进展[J]中国免疫学杂志, 2006, 22:676-679.
12.Abbazadegan MR,Cress AE,Futscher BW,et al.Evidence for a cytoplasmic p-glycopmtein location associated with increased multidrug resistance and resistance to chemosensitzers [J]. Cancer Res,1996,54:5435一5442
13.童杰,赵志平.干扰素与再生障碍性贫血 [J]. 国外医学·免疫学分册,1987, :189
14.杨吉成,李丽娥,盛伟华等.基因工程 IFNα2a 和 IFNα2b 对肿瘤细胞生长的抑制作用[J].实用癌症杂志,1999,14:164-166.
15.于宏,孙立荣,庞秀荣等.干扰素α2b 对 HL-60 细胞抑制增殖与促调亡的影响 [J].中国实验血液学杂志,2007,15:56-58.
16.Minami R,Muta K,Ilesung C,et al.Interleukin-6 sensitizes multiple myeloma cell lines for apoptosis inducedy by interferon-α [J].Exp Hematol,2000,28:244-255.
17.Stark G ,Kerret I, Williams B,et al.How cells respond to interferons. [J].Annu RevBiochem,1998,67:227-264.
18.Pfeffer L ,Dinarello C,Herberman R, et al .Bioligic properties of recombinant interferons:40th anniversary of the disscovery of interferons [J].Cancer Res, 1998, 58:2489-2499.
19.Kaser A,Nagata S,Tiget H,et al.Interferon-αaugments activation induced T cell death by upregulation of Fas (CD95/APO-1) and Fas ligand expression[J]. Cytokine, 1999,11:736-743.
20.Mamta C ,Douglas W,Ernest C,et al.Preferential induction of apoptosis by interferon(IFN)βcomparedwith IFN-α2:correlation with TRAIL/Apo2L induction in melanoma cell lines [J].Clin Cancer Res,2001,7:1821-1831.
21.Finkenxeller G,Sparacio A, Technau A,et al.Sp1 recognition sites in the proximal promoter of the human vascular endothelial growth factor gene are essential for platelet-derived growth factorin-duced gene cspression [J].Oncogene,1997, 15: 669-676.
22.张继红,张锦华,佟海侠.γ-IFN 诱导神经母细胞瘤细胞分化及 TrKA 表达的实验研究 [J].中国小儿血液,2001,6:121-125.
23.李放,王秋娟,高文青. 家蚕细胞基因工程 人α-IFN 对小鼠的免疫调节作用[J].中国现代应用药学杂志,1999,16:31-34.
24.Rosenberg SA ,Spiess PJ ,Schwarz S. Cell Immunol ,1980 ;54 (2) :293～306
25.牛青霞,靖志安.白细胞介素-2 抗癌原理与临床使用方法[J].中国肿瘤临床,1998,25:685-687.
26.曹雪涛.白细胞介素-2 的基础与临床 [M].北京科学技术出版社,1990,144.
27.Ross DD .Novel mechanisms of drug resistance in leukemia [J]. .Leukemia 2000;14:467-473.
28.陈艳,张荣艳.ABC 转运蛋白及其介导的白血病多药耐药研究进展 [J].江西医学院学报,2003,43:96-98.
29.李颖,徐建.谷胱甘肽-S-转移酶与白血病耐药[J].国内医学肿瘤学分册,1999,26:184-185.
30.冯建航,许丽李恩民.核基质成分拓扑异酶Ⅱ与肿瘤耐药[J].肿瘤防治杂志,2001,8:675-677.
31.Laredo J,Huynh A,Muller C,et al.Effect of the protein Kinase Cinhibitor saturosprine on chemosensitivity to claunorubicin of norual and leademic fresh myeloid cells[J].Blood,1994,84:229-237.
32.朱兴虎,李建勇,夏学鸣.白血病细胞耐药与细胞凋亡的研究进展 [J].国外医学,生理、病理科学与临床分册,2002,22:401-403.
33.陈永乐,郭坤元,徐安龙,等.Fas-Fasl 凋亡途径和白血病 [J].国外医学,生理、病理科学与临床分册,2000,20:143-145.
34.薛红漫,李文益.Bcl-2 与白血病耐药 [J].国外医学输血及血液分册,1999,22:79-82
35.Matsuo H,Wakasugi M,Takanaga H,et al.Possibility of the reversal of multidrug resistance and the avoidance of side effects by liposomes modified with MRK-16,a monoclonal antibody to P-glycoprotein [J].J Control Release, 2001,77:77-86.
36.姜国胜,唐天华,张玉花等.干扰素对 HL-60 细胞与维甲酸耐药 HL-60 细胞作用的研究[J].中国免疫学杂志,2000,16:586-588.
37.胡晓梅,邓成册,麻柔.逆转白血病耐药的研究进展 [J].中国中西结合杂志,2000,20:715-718.
38.浦津,楼方定,周绮等.环孢素 A 与细胞因子联合逆转白血病多药耐药的体外研究[J].中华医学杂志,1999,79:224-226
39.陈莉,许小平,王健民等.环孢菌素、他莫西芬及α-干扰素对白血病细胞多药耐药的逆转作用 [J].白血病淋巴瘤. 2003,12:135-138.
40.刘竹珍,赵洪国,李广伦等.IL-2 并 IFN-α对老年急性白血病化疗效果的影响 [J].青鸟大学医学院学报,2003,39:433-435.
41.Arancia G,Malinani A,Calcabnini A,et al.Intracelluar P-glycoprotein in multidrug resistance tumor cells [J].Ital J Anat Embryol,2001,106:59-68.
42.Ruiz Comez MJ,Souviron Rodriguez A,Martinez Morillo M. P-glycoprotein ,a membrane pump that represents a barrier to chemotherapy in cancer patients[J].An Med Interna,2002,19:477-485.
43.刘丽英,刘复强,杨纯正等.白细胞介素-2 和α-干扰素逆转白血病细胞多药耐药的研究 [J].中华血液学杂志,1997,18:646-648.
44.Stein U,Walther W,Shoemaker R H.Modulation of mdr1 exepression by cytokines in human colon carcinoma cells:an approach for reversal of multidrug resistance[J].Cancer,1996,74:1384-1388.
1. 曾学清,段功香,蒋香莲等.干扰素在抗肿瘤方面的应用[J].中国生化药物杂志,2003,24(4):512.
2. 梁彦,魏熙胤,李凯,等.IFN 及三氧化二砷诱导淋巴瘤细胞凋亡及细胞周期阻滞的研究[J].肿瘤防治杂志,2002,9(2):127 130.
3. 姜国盛,唐天华,张玉昆等.干扰素对 HL60 细胞与维甲酸耐药 HL-60 细胞作用的研究[J]中国免疫学杂志,2000,16:586.
4. Testa U,Ferbus d,Gabbianelli M,et al.Effects of endogenous interferons on th differentiation of human monocyte cell line U937. Caner Res,1988,48:82-87.
5. 陈惠仁,孙关林,韩锐等. 新维甲类联合γ干扰素对急性单核细胞白血病细胞增殖分化作用的体外研究[J].中华血液学杂志, 1999,20(1):10
6. 钱绩虎,邵荣标,丁昌慧,等.IFNα对人体液免疫功能调节作用的实验研究[J].南通医学院学报,1999,19(2):164 165.
7. Saily M,Koistenen P,Soppi E,et al.Effect of interferon-alpha on immunoglobin production by peripheral blood mononuclear cells in multiple milkman[J].Eur J Heamatol,1996,57(2):171-173.
8. 吴敏媛.儿童急性淋巴细胞白血病治疗现状[J]中国肿瘤,2001,10(10):566.
9. 孙黎明,原弛.小儿急性淋巴细胞白血病的诊疗浅谈[J].中国小儿血液, 2001,6(5):532.
10.Nooter K,Sonneveld P.Clinical relevance of p-glycoprotein expression in haematological malignancies.Leuk Res,1994,18(4):233.
11.薛红漫,李文益,侯玲玉等.多药耐药细胞系 HL60/HHT 的建立及耐药机理的初步探讨[J].中国小儿 2000,5(1):13.
12.赵毅,李玲,温丙昭等.复发/难治急性白血病 bcl-2、pl70 的检测研究[J].白血病·淋巴瘤,2002,11(1):
13.付劲蓉,李成荣,杨锡强,等.重组人白细胞介素 4 对白血病细胞 HL-60/VCR多药耐药逆转研究[J].中华血液学杂志, 2000,21(2):94-95.
14.Bassan R,Lerede T,BorleriG,et al.Phase I trial with escalating doses of idarubicin and multidrug resistance reversal by shore-course cyclosporine A,sequential high-dose cytosine arabinoside,and granulocyte colony-stimulating factor for adult patients with refractory acute leukemia [J] Haematologica,2002,87(3):257-263.
15.Sdzuka Y,Sugiyama T,Sonobe T,Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance[J]Toxicol Lett,2000,114(1-3):155-162.
16.Li J,Xu L Z,Yao J J ,et al.Reversal effects of droloxifene on multidrug resistance in adriamycin-resistance K562 cell line[J]Acta Paarmacol Sin,2001, 22(11): 1023-1027.
17.Sargent J M,Williamson C J,Yardley C,et al.Dexrazoxane significantly impairs the induction of doxorubicin resistance in the human leukemia line,K562[J].Br J Cancer,2001,84(7):959-964.
18.Kang Y,Petty R R.Effect of alpha-interferon on P-glycoprote epression and function and on verapamil modulation of doxorubicin resistance[J].Cancer Res,1994,54(11):2952-2958.
19.刘丽辉,刘复强,杨纯正等.白细胞介素 2 和α干扰素逆转白血病细胞多药耐药的研究[J].中国血液,1997,118(12):646.
20.浦津,楼方定,周绮等.环孢菌素 A 与细胞因子联合逆转白血病多药耐药性的体外研究[J].中华医学杂志,1999,179(3):422.
21.Stein U,Walther W,Shoemaker R H.Modulation of mdrl expression by cytokines in human colon carcinoma cells:an approach for reversal of multidrug resistance [J].Cancer,1996,74(9):1384-1391.
22.陈惠仁,孙关林,韩锐,等.新维甲类化合物对早幼粒细胞白血病和正常造血增殖分化作用的体外研究.中华血液学杂志,1997,18:65 68.
23.平宝红,周淑芸,刘启发,等.干扰素逆转白血病多药耐药性的研究及机制的初步探讨[J].中华血液学杂志,1996,17(1):13-15.
24.FOgler WE,Parson J W.Volkern K,et al.Enhancement by recombinant human interferon alfa of the reversal of multidrug resistance by MRK-16 monoclonal antibody[J].Natl Cancer Inst, 1995, 87(2):94-104.
25.柴晔,张连生,张玉芳等.环孢素A与干扰素联合逆转复发难治性急性白血病多药耐 药的临床研究[J].临床血液学杂志,2003,16(5):211
26.唐义平,邓承祺,缪世锟等.干扰素逆转复发难治性急性白血病的临床观察[J].JOURNAOL OF LEUKEMIA,2001,10(3):160
27.王薇娜,王丽,施秀荣,张田.α-2b 干扰素联合化疗逆转原发耐药急性白血病 2 例[J].重庆医学,2003,32(7):835.
28.LupH,NegrinRS.Anovel population of expanded human CD3+ /CD56+ cell derived from T cells with potentin vivo antitumor antivity in mice with severe combined immunodeficiency [J]. Immunol,1994,153:1687-1696.
29.周晓宏,童春荣.自体细胞因子诱导的杀伤细胞治疗急性 B 淋巴细胞白血病 22 例临床观察[J].河北医学,2003,9(4):306.`