人肺腺癌细胞耐顺铂系A549/CDDP的比较蛋白组学研究
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摘要
背景：肺癌已经成为我国发病率和死亡率最高的恶性肿瘤,大约70%的患者在诊断时已发展至晚期,无法通过手术治愈,化疗成为肺癌综合治疗中的重要部分,但是肿瘤细胞对化疗药物发生耐药常导致化疗失败。近年来,人们对肿瘤细胞的耐药机制进行了深入的研究。
一直以来,顺铂被认为是肺癌化疗的基石,含铂方案是晚期NSCLC化疗的标准方案,几乎所有一线NSCLC化疗方案都是与顺铂联合应用的方案。顺铂的作用机理是进入肺癌细胞后,与DNA交叉联结,形成稳定的顺铂-DNA复合物,阻断DNA复制,引起肺癌细胞死亡。近年来国内外研究表明,肺癌细胞对顺铂发生耐药的机制,除了早先认为的肿瘤细胞内药物浓度降低、药物在细胞内代谢降解外,更是与DNA损伤修复增强密切相关,是一个多基因参与的复杂事件,涉及了多种蛋白质与数条途径,如已发现由跨膜转运蛋白、多药耐药相关蛋白和肺耐药相关蛋白介导的典型耐药途径,和由其它非跨膜机制如凋亡、酶活性、细胞内pH等变化介导的非典型耐药途径。但肺癌耐药的机制至今仍未完全阐明。因此不断寻找新的耐药相关基因并进行深入研究,对阐明肺癌细胞的耐药机制,进而寻找逆转耐药的途径,具有重要意义。
目的：诱导人肺腺癌细胞A549对顺铂耐药,研究A549细胞产生耐药性前后的蛋白表达差异,明确这些差异蛋白与肺癌耐药的关系,以期为肺癌的治疗发现新的靶点,为揭示肺癌的耐药机制提供线索,并为寻找逆转耐药途径提供基础。
方法：以顺铂为诱导药物,人肺腺癌细胞系A549为诱导对象,采用逐步增加剂量与大剂量冲击相结合的方法,诱导建立耐顺铂细胞株A549/CDDP。对A549与A549/CDDP进行蛋白组学研究,即利用双向凝胶电泳(two-dimensional polyacrylamide electrophoresis,2D-PAGE)分离两组总蛋白后,通过图像分析寻找表达差异的蛋白点,对其进行MALDI-TOF质谱分析。对经质谱鉴定的蛋白质,通过慢病毒介导的RNA干扰技术沉默A549和A549/CDDP细胞内目标蛋白基因的表达,应用蛋白印迹法(western blot)和四甲基偶氮唑蓝比色法(MTT)探讨沉默该基因表达对肺癌细胞生物学行为的影响,阐明其功能。
结果：建立了稳定的耐顺铂细胞系A549/CDDP。比较A549和A549/CDDP两者的2D-PAGE图谱,得到差异蛋白点82个。对其中6个差异蛋白点进行肽质量指纹图分析,鉴定出葡萄糖调节蛋白75、核糖体蛋白S4、线粒体F1-ATP合酶p亚单位、免疫球蛋白重链可变区。以上差异蛋白均在耐药株中过表达,而在对照组细胞中低表达或不表达。A549和A549/CDDP细胞成功转染GRP75 siRNA,转染后A549/CDDP细胞GRP75蛋白明显下调,bcl-2蛋白下调,p53蛋白上调,转染后A549/CDDP细胞对顺铂敏感性有所增强。
结论：成功地通过逐步增加剂量与大剂量冲击相结合的诱导方法建立肺癌耐药株。运用蛋白组学技术鉴定的差异蛋白为阐明肺癌细胞对顺铂耐药性产生的机制提供线索,也为筛选具体潜在价值的肺癌化疗靶位提供理论依据。证实了GRP75高表达与肺癌细胞耐药性的产生相关,为克服肺癌化疗耐药提供了新的突破口。
Background:Lung cancer has highest incidence rate and mortality rate of all malignancy cancers in China. About 70% of the patients have been developed to advanced stage at their diagnosis, and have lost the opportunity of surgical resection. Chemotherapy has become a very important part in the comprehensive treatment of lung cancer, but the resistance of tumor cells to chemotherapy drug often fails the chemotherapy. In recent years, many research has been done to reveal the drug-resistant mechanism of tumor cells.
Cisplatin has long been the foundation stone of the chemotherapy of lung cancer. Platinum-based regime is the standard of advanced NSCLC chemotherapy. Almost all first-line NSCLC chemotherapy regime is cisplatin application solutions. The mechanism of cisplatin is cross-coupling with DNA after entering lung cancer cells, founding stable cisplatin-DNA complex, blocking DNA duplication, and causing lung cancer cells death. Recent research has shown that the cisplatin-resistant mechanism of lung cancer cells includes lower drug concentration and higher degradation metabolism in tumor cells, and more importantly the enhancement of DNA damage repair. The mechanism is a complex and multi-gene involved event, coming down to several pathways and many proteins. It involves the classical pathways mediated by transmembrane transporters, multidrug resistance associated protein, lung resistance protein, and non-classical pathways mediated by non-transmembrane mechanism such as apoptosis, enzyme activity, intracellular PH. However, the cisplatin-resistant mechanism of lung cancer cells is still not fully understood. It's of great importance to keep looking for new drug resistance related genes and continue in-depth research to elucidate the resistant mechanism of lung cancer cells, and then we shall find ways of reversing the resistance.
Objective:Our study is to identify differently expressed proteins before and after cisplatin resistance of human lung adenocarcinoma cell A549 by using proteome analysis, so as to find new targets for the treatment of lung cancer, reveal drug-resistant mechanism, and provide clues for ways to reverse resistance.
Methods:Cisplatin-resistant cell strain A549/CDDP was established from their parental human lung adenocarcinoma cell line A549 by combining gradually increasing concentration of cisplatin with big dosage impact. Comparative proteome analysis of A549 and A549/CDDP were carried out by means of two-dimensional gel electrophoresis. The differentially expressed proteins were analyzed and identified by MALDI-TOF mass spectrometry. The siRNA for the gene of the identified protein was transfect to A549 and A549/CDDP cells by lentivirus. Western blot and methyl thiazolyl tetrazolium (MTT) assay were applied to explore the influence of silencing the gene expression on lung cancer cell biological behavior, and elucidate the function of the gene.
Results:82 differentially expressed proteins were screened by analyzing the electrophoretic maps of A549 and A549/CDDP.6 differential proteins were analyzed by peptide mass fingerprinting. Glusose regulating protein 75 (GRP75), ribosomal protein S4, mitochondrial ATP synthase Fl complex beta subunit, and immunoglobulin heavy chain variable region were identified. All four differentially expressed proteins were over-expressed in A549/CDDP, whereas low-expressed or no-expressed in A549. GRP75siRNA was successfully transfected to A549 and A549/CDDP. After transfection GRP75 protein in A549/CDDP dramatically decreased, bcl-2 protein decreased, p53 protein increased. And the sensitivity to cisplatin of the transfected cells was increased compared with A549/CDDP.
Conclusion:Our study Successfully established cisplatin-resistant A549/CDDP cell strain by combining gradually increasing concentration of cisplatin with big dosage impact. The differentially expressed proteins give some clues to elucidate the mechanism of lung cancer cell resistant of cisplatin, and provide the basis of searching for potential target of chemotherapy of lung cancer. The fact that cisplatin resistance of lung cancer cells may be associated with the over-expression of GRP75 gene gives priority to overcome the drug resistance of lung cancer cells.
一直以来,顺铂被认为是肺癌化疗的基石,含铂方案是晚期NSCLC化疗的标准方案,几乎所有一线NSCLC化疗方案都是与顺铂联合应用的方案。顺铂的作用机理是进入肺癌细胞后,与DNA交叉联结,形成稳定的顺铂-DNA复合物,阻断DNA复制,引起肺癌细胞死亡。近年来国内外研究表明,肺癌细胞对顺铂发生耐药的机制,除了早先认为的肿瘤细胞内药物浓度降低、药物在细胞内代谢降解外,更是与DNA损伤修复增强密切相关,是一个多基因参与的复杂事件,涉及了多种蛋白质与数条途径,如已发现由跨膜转运蛋白、多药耐药相关蛋白和肺耐药相关蛋白介导的典型耐药途径,和由其它非跨膜机制如凋亡、酶活性、细胞内pH等变化介导的非典型耐药途径。但肺癌耐药的机制至今仍未完全阐明。因此不断寻找新的耐药相关基因并进行深入研究,对阐明肺癌细胞的耐药机制,进而寻找逆转耐药的途径,具有重要意义。
目的：诱导人肺腺癌细胞A549对顺铂耐药,研究A549细胞产生耐药性前后的蛋白表达差异,明确这些差异蛋白与肺癌耐药的关系,以期为肺癌的治疗发现新的靶点,为揭示肺癌的耐药机制提供线索,并为寻找逆转耐药途径提供基础。
方法：以顺铂为诱导药物,人肺腺癌细胞系A549为诱导对象,采用逐步增加剂量与大剂量冲击相结合的方法,诱导建立耐顺铂细胞株A549/CDDP。对A549与A549/CDDP进行蛋白组学研究,即利用双向凝胶电泳(two-dimensional polyacrylamide electrophoresis,2D-PAGE)分离两组总蛋白后,通过图像分析寻找表达差异的蛋白点,对其进行MALDI-TOF质谱分析。对经质谱鉴定的蛋白质,通过慢病毒介导的RNA干扰技术沉默A549和A549/CDDP细胞内目标蛋白基因的表达,应用蛋白印迹法(western blot)和四甲基偶氮唑蓝比色法(MTT)探讨沉默该基因表达对肺癌细胞生物学行为的影响,阐明其功能。
结果：建立了稳定的耐顺铂细胞系A549/CDDP。比较A549和A549/CDDP两者的2D-PAGE图谱,得到差异蛋白点82个。对其中6个差异蛋白点进行肽质量指纹图分析,鉴定出葡萄糖调节蛋白75、核糖体蛋白S4、线粒体F1-ATP合酶p亚单位、免疫球蛋白重链可变区。以上差异蛋白均在耐药株中过表达,而在对照组细胞中低表达或不表达。A549和A549/CDDP细胞成功转染GRP75 siRNA,转染后A549/CDDP细胞GRP75蛋白明显下调,bcl-2蛋白下调,p53蛋白上调,转染后A549/CDDP细胞对顺铂敏感性有所增强。
结论：成功地通过逐步增加剂量与大剂量冲击相结合的诱导方法建立肺癌耐药株。运用蛋白组学技术鉴定的差异蛋白为阐明肺癌细胞对顺铂耐药性产生的机制提供线索,也为筛选具体潜在价值的肺癌化疗靶位提供理论依据。证实了GRP75高表达与肺癌细胞耐药性的产生相关,为克服肺癌化疗耐药提供了新的突破口。
Background:Lung cancer has highest incidence rate and mortality rate of all malignancy cancers in China. About 70% of the patients have been developed to advanced stage at their diagnosis, and have lost the opportunity of surgical resection. Chemotherapy has become a very important part in the comprehensive treatment of lung cancer, but the resistance of tumor cells to chemotherapy drug often fails the chemotherapy. In recent years, many research has been done to reveal the drug-resistant mechanism of tumor cells.
Cisplatin has long been the foundation stone of the chemotherapy of lung cancer. Platinum-based regime is the standard of advanced NSCLC chemotherapy. Almost all first-line NSCLC chemotherapy regime is cisplatin application solutions. The mechanism of cisplatin is cross-coupling with DNA after entering lung cancer cells, founding stable cisplatin-DNA complex, blocking DNA duplication, and causing lung cancer cells death. Recent research has shown that the cisplatin-resistant mechanism of lung cancer cells includes lower drug concentration and higher degradation metabolism in tumor cells, and more importantly the enhancement of DNA damage repair. The mechanism is a complex and multi-gene involved event, coming down to several pathways and many proteins. It involves the classical pathways mediated by transmembrane transporters, multidrug resistance associated protein, lung resistance protein, and non-classical pathways mediated by non-transmembrane mechanism such as apoptosis, enzyme activity, intracellular PH. However, the cisplatin-resistant mechanism of lung cancer cells is still not fully understood. It's of great importance to keep looking for new drug resistance related genes and continue in-depth research to elucidate the resistant mechanism of lung cancer cells, and then we shall find ways of reversing the resistance.
Objective:Our study is to identify differently expressed proteins before and after cisplatin resistance of human lung adenocarcinoma cell A549 by using proteome analysis, so as to find new targets for the treatment of lung cancer, reveal drug-resistant mechanism, and provide clues for ways to reverse resistance.
Methods:Cisplatin-resistant cell strain A549/CDDP was established from their parental human lung adenocarcinoma cell line A549 by combining gradually increasing concentration of cisplatin with big dosage impact. Comparative proteome analysis of A549 and A549/CDDP were carried out by means of two-dimensional gel electrophoresis. The differentially expressed proteins were analyzed and identified by MALDI-TOF mass spectrometry. The siRNA for the gene of the identified protein was transfect to A549 and A549/CDDP cells by lentivirus. Western blot and methyl thiazolyl tetrazolium (MTT) assay were applied to explore the influence of silencing the gene expression on lung cancer cell biological behavior, and elucidate the function of the gene.
Results:82 differentially expressed proteins were screened by analyzing the electrophoretic maps of A549 and A549/CDDP.6 differential proteins were analyzed by peptide mass fingerprinting. Glusose regulating protein 75 (GRP75), ribosomal protein S4, mitochondrial ATP synthase Fl complex beta subunit, and immunoglobulin heavy chain variable region were identified. All four differentially expressed proteins were over-expressed in A549/CDDP, whereas low-expressed or no-expressed in A549. GRP75siRNA was successfully transfected to A549 and A549/CDDP. After transfection GRP75 protein in A549/CDDP dramatically decreased, bcl-2 protein decreased, p53 protein increased. And the sensitivity to cisplatin of the transfected cells was increased compared with A549/CDDP.
Conclusion:Our study Successfully established cisplatin-resistant A549/CDDP cell strain by combining gradually increasing concentration of cisplatin with big dosage impact. The differentially expressed proteins give some clues to elucidate the mechanism of lung cancer cell resistant of cisplatin, and provide the basis of searching for potential target of chemotherapy of lung cancer. The fact that cisplatin resistance of lung cancer cells may be associated with the over-expression of GRP75 gene gives priority to overcome the drug resistance of lung cancer cells.
引文
1. Kerr JF, Wyllie AH and Currie AR. Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer,1972,26:239-257
2. Fadeel B, Orrenius S and Zhivotovsky B. Apoptosis in human disease:a new skin for the old ceremony? Biochem Biophys Res Commun,1999,266:699-717
3.吴一龙.肺癌多学科综合治疗的现状和展望.中国肺癌杂志,2001,4(4)：241-242
4.吴一龙.肺癌多学科综合治疗的理论基础.吴一龙主编.肺癌多学科综合治疗的理论与实践.北京：人民卫生出版社,2000.1-2
5. Sugimura H, Nichols FC, Yang P, et al. Survival after recurrent non-small-cell lung cancer after complete pulmonary resection. Ann Thorac Surg,2007, 83(2):409-417
6. Gazak R, Walterova D, Kren V. Silybin and silymarin--new and emerging applications in medicine. Curr Med Chem,2007,14(3):315-338
7. Notter K, Herweijer H. Multi-drug resistance (MDR) genes in human cancer. Br J Cancer,1991,63(5):663-669
8.王涛.肿瘤多药耐药性与信号转导.国外医学呼吸系统分册,2003,23(3)：154-156
9. Stouch TR, Gudmundsson O. Progress in understanding the structure-activity relationships of P-glyco protein. Adv Drug Del Rev,2002,54(3):315-328
10. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer:a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ,1995,311(7010):899-909
11 Hoang T, Xu R, Schiller JH, et al. Clinical model to predict survival in chemo-naive patients with advanced non-small-cell-lung cancer treated with third-generation chemotherapy regimens based on eastern cooperative oncology group data. J Clin Oncol,2005,23(1):175-183
12 Jordan P, Carmo-Fonseca M. Molecular mechanisms involved in cisplatin cytotoxicity. Cell Mol Life Sci,2000,57(8-9):1229-1235
13. Piet Borst, Sven Rottenberg, Jos Jonkers. How do real tumors become resistant to cisplatin? Cell Cycle,2008,7(10):1353-1359
14 Guminski AD, Harnett PR, deFazio A. Scientists and clinicians test their metal-back to the future with platinum compounds. Lancet Oncol,2002,3(5):312-318
15 Link AJ, Eng J, Sehieltz DM, et al. Direct analysis of protein complexes using mass spectrometry. Nat Biotechnol,1999,17:676
16 Jr GW, Cazares LH, Leung SM, et al. Proteinchip(R) surface enhanced laser desorption-ionization (SELDI) mass spectrometry:A novel protein biochip technology for detection of prostate cancer biomarkers in complex protein mixtures. Prostate Cancer Prostatic Dis,1999,2:264
17 Gygi SP, Rist B, Gerber SA, et al. Quantitative analysis of complex protein mixtures using isotope-coded affinity tags. Nat Biotechnol,1999,17:994
18. Hu Y, Wang G, Grace YJ. Proteome analysis of Saccharomyces cerevisiae under metal stress by two-dimensional differential gel electrophoresis. Electrophoresis, 2003,24(9):1458
19. Nishio K, Nakamura T, Koh Y, et al. Drug resistance in lung cancer. Curr Opin Oncol,1999, 11(2):109-115
20. Kawai H, Kiura K, Tabata M, et al. Characterization of non-small cell lung cancer cell lines established before and after chemotherapy. Lung Cancer,2002, 35(3):305-314
21.蔡鹏,刘叙仪,韩复生.耐顺铂人肺腺癌细胞系A549DDP的建立及耐药机制.中国肿瘤临床,1995,22(8)：582-587
22. Wadhwa R, Pereira-Smith OM, Reddel RR, et al. Correlation between complementation group for immortality and the cellular distribution of mortalin. Exp Cell Res,1995,216(1):101-106
23. Kaula SC, Reddelb RR, Sugiharac T, et al. Inactivation of p53 and life span extension of human diploid fibroblasts by mot-2. FEBS Lett,2000,474(2-3): 159-164
24. Xu J, Xiao HH, Sartorelli AC. Attenuation of the induced differentiation of HL-60 leukemia cells by mitochondrial chaperone HSP70. Oncol Res,1999,11(9): 429-435
25. Mizukoshi E, Suzuki M, Loupatov A, et al. Fibroblast growth factor-1 interacts with the glucose-regulated protein GRP75/mortalin. Biochem J,1999,343(2): 461-466
26. Samali A, Cotter TG. Heat shock proteins increase resistance to apoptosis. Exp Cell Res,1996,223(1):163-170
27. Hartl FU, Hayer-Hartl M. Molecular chaperones in the cytosol:from nascent chain to folded protein. Science,2002,295(5561):1852-1858
28. Kimoto Y. Expression of heavy-chain constant region of immunoglobulin and T-cell receptor gene transcripts in human non-hematopoietic tumor cell lines. Genes Chromosomes Cancer,1998,22(1):83-86
29.黎明,唐敏,邓锡云等.上皮来源的肿瘤细胞可表达免疫球蛋白A.中华肿瘤杂志,2001,23(6)：451-453
30.杨少波,王孟薇,尤纬缔.胃癌细胞中免疫球蛋白轻链IgK和Igλ的共同表达.中华肿瘤杂志,2002,24(5)：465-466
31. Qiu X, Zhu X, Zhang L, et al. Human epithelial cancers secrete immunoglobuling with unidentified specificity to promote growth and survival of tumor cells. Cancer Res,2003,63(9):6488-6495
32. Torres M, Condon C, Balada JM, et al. Ribosomal protein S4 is a transcription factor with properties remarkably similar to NusA, a protein involved in both non-ribosomal and ribosomal RNA antitermination. EMBO J,2001,20(14): 3811-3820
33. Senior AE, Nadanaciva S, Weber J. The molecular mechanism of ATP synthesis by F1F0-ATP synthase. Biochim Biophys Acta,2002,1553(3):188-211
34. Dudkina NV, Sunderhaus S, Braun HP, et al. Characterization of dimeric ATP synthase and cristae membrane ultrastructure from Saccharomyces and Polytomella mitochondria. FEBS Letters,2006,580(14):3427-3432
35. Peng G, Bostinaa M, Radermacher M, et al. Biochemical and electron microscopic characterization of the F1F0 ATP synthase from the hyperthermophilic eubacterium Aquifex aeolicus. FEBS Letters,2006,580(25):5934-5940
36. Walker JE, Dickson VK. The peripheral stalk of the mitochondrial ATP synthase. Biochimica et Biophysica Acta,2006,1757(5-6):286-296
37. Iizuka S, Kato S, Yoshida M, et al. γεsub-complex of thermophilic ATP synthase has the ability to bind ATP. Biochem Biophys Res Comm,2006, 349(4):1368-1371
38. Feniouk BA, Suzuki T, Yoshida M. The role of subunit epsilon in the catalysis and regulation of F0F1-ATP synthase. Biochimica et Biophysica Acta,2006, 1757:326-338
39. Gao YQ, Yang W, Karplus M. A structure-based model for the synthesis and hydrolysis of ATP by Fl-ATPase. Cell,2005,123(2):195-205
40. Wahl ML, Kenan DJ, Gonzalez-Gronow M, et al. Angiostatin's molecular mechanism:aspects of specificity and regulation elucidated. J Cell Biochem, 2005,96(2):242-261
41. Kim BW, Choo HJ, Lee JW, et al. Extracellular ATP is generated by ATP synthase complex in adipocyte lipid rafts. Exp Mol Med,2004,36(5):476-485
42. Burrell HE, Wlodarski B, Foster BJ, et al. Human keratinocytes release ATP and utilize three mechanisms for nucleotide interconversion at the cell surface. J Biol Chem,2005,280(33):29667-29676
43. Scotet E, Martinez LO, Grant E, et al. Tumor recognition following V gamma 9 V delta 2 T cell receptor interactions with a surface F1-ATPaserelated structure and apolipoprotein A-Ⅰ. Immunity,2005,22(1):71-80
44. Burwick NR, Wahl ML, Fang J, et al. An Inhibitor of the F1 subunit of ATPsynthase (IF1) modulates the activity of angiostatin on the endothelial cell surface. J Biol Chem,2005,280(3):1740-1745
45. Watabe M, Nakaki T. ATP depletion does not account for apoptosis induced by inhibition of mitochondrial electron transport chain in human dopaminergic cells. Neuropharmacology,2006,7(1):37-43
46. Champagne E, Martinez LO, Collet X, et al. Ecto-FIFO ATP synthase/F1 ATPase: metabolic and immunological functions. Curr Opin Lipidol,2006,17(3):279-284
47. Wu H, Hait WN, Yang JM. Small interfering RNA induced suppression of MDR1 (P-glycop ro tein) resto res sensitivity to multidrug resistant cancer cells. Cancer Res,2003,63(7):1515-1519
48. July LV, Beraldi E, So A, et al. 1N ucleo tide-based therapies targeting clusterin chemo sensitize human lung adenocarcinoma cells both in vitro and in vivo. Mol Cancer Ther,2004,3(3):223-232
49.冉志华,萧树东.小干扰RNA表达质粒转导逆转人结肠癌羟基喜树碱耐药表型的研究.中华消化杂志,2007,1(27)：7-11
50. YUAN Ya-wei, SUN Ai-min, LIU Ying. RNA Interference of mdrlGene in Breast Cancer Cell Line MCF-7/Adr Small Interference RNA (siRNA) Synthesized with In Vitro Transcription. The Practical Journal of Cancer,2007,1(22):13-17
51. Tsunoda Haruki, Terasawa Tomoko, et al. Effects of wild-type and mutated p53 and Id proteins on the induction of apoptosis by adenovirus E1A, c-Myc, Bax, and Nip3 in p53 null mouse cerebellum cells. Biochemical and Biophysical Research Communications,1999, (255):722-730
52. Yang Xudong, Klein Rudiger, et al. Notch activation induces apoptosis in neural progenitor cells through a P53-dependent phatway. Developmental Biology,2004, (269):81-94
53. Dlamini Zodwa, Mbita Zukile, et al. Genealogy, expression, and molecular mechanisms in apoptosis. Pharmacology and Therapeutics,2004, (101):1-15
54. Desagher S, Martinou JC. Mitochondria as the central control point of apoptosis. Trends Cell Biol,2000,10(9):369-377
55. Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol,1995,146:3-15
56. Sansome Christine, Zaika Alex, Marchenko Natalie D. Hypoxia death stimulus induces translocation of p53 protein to mitochondria:Detection by immunofluorescence on whole cells. FEBS Lett,2001, (488):110-115
57. Howard S, Bottino C, Brooke S, et al. Neuroprotective effects of bcl-2 overexpression in hippocampal cultures:interactions with pathways of oxidative damage. Neurochem,2002,83(4):914-923
58. Hochman A, Sternin H, Gorodin S, et al. Enhanced oxidative stress and altered antioxidants in brains of Bcl-2-deficient mice. J Neurochem,1998,71(2):741-748
1. Sugimura H, Nichols FC, Yang P, et al. Survival after recurrent non-small-cell lung cancer after complete pulmonary resection. Ann Thorac Surg,2007, 83(2):409-417.
2. Gazak R, Walterova D, Kren V. Silybin and silymarin-new and emerging applications in medicine. Curr Med Chem,2007,14(3):315-338.
3. Notter K, Herweijer H. Multi-drug resistance (MDR) genes in human cancer. Br J Cancer,1991,63(5):663-669.
4.王涛.肿瘤多药耐药性与信号转导.国外医学呼吸系统分册,2003,23(3)：154-156.
5. Stouch TR, Gudmundsson O. Progress in understanding the structure-activity relationships of P-glyco protein. Adv Drug Del Rev,2002,54(3):315-328.
6. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochem Biophys Acta,1976,455(1):152.
7. Wan L, Hyo-Im C, Mi-Jin K, et al. Depletion of mitochondrial DNA up-regulates the expression of MDR1 gene via an increase in mRNA stability. Exp Mol Med, 2008,40(1):109-117.
8. Anthony V, Skach WR. Molecular mechanism of P-glycoprotein assembly into cellular membrances. Currprotein Pept Sci,2002,3:485-501.
9. Kool M, van der Linden M, de Haas M, et al. MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci USA,1999, 96(12):6914-6919.
10.王飞,黄艳春,刘诚明.多药耐药基因在肺癌患者外周血中的表达及意义.新 疆医科大学学报,2007,30(10)：1137-1139.
11. Cole SPC, Downes HF, Mirski SEC. Overexpression of a transporter gene in a multidrug resistant human lung cancer cell line. Science,1992, 258(5088):1650-1654.
12. Benlloch M, Ortega A, Ferrer P. Acceleration of glutathione efflux and inhibition of gamma glutamyltranspeptidase sensitize metastatic B16 melanoma cells to endothelium-induced cytotoxicity. Journal of Biological Chemistry,2005, 280(8):6950-6959.
13. Borst P, Evers R, Ko LM, et al. A family of drug transporters:the multidrug resistance-associated proteins. J Natl Cancer Inst,2000,92 (6):1295.
14. Wright SR, Boag AH, Valdimarsson G, et al. Immunohistochemical detection of multidrug resistance protein in human lung cancer and normal lung. Clin Cancer Res,1998,4(9):2279-2289.
15. Brooks T, Minderman H, Kieran L, et al. Taxane-based reversal agents modulate drug resistance mediated by P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein. Cancer Ther,2003,2:1195.
16. Oshika Y, Nakamura M, Tokunaga T, et al. Multidrug resistance-associated protein and mutant p53 protein expression in non-small cell lung cancer. Mod Pathol, 1998, 11(11):1059-1063.
17. Hsia TC, Lin CC, Wang JJ, et al. Relationship between chemotherapy response of small cell lung cancer and P-glycoprotein or multidrug resistance-related protein expression. Lung,2002,180(3):173-179.
18. Scheper RJ, Broxterman HJ, Scheffer GL, et al. Overexpression of a M(r) 110,000 vesicular protein in non-P-glycoprotein-mediated Multidrug resistance. Cancer Res,1993,53(7):1475.
19. Berger W, Elbling L, Micksche M. Expression of the major vault protein LRP in human non-small cell lung cancer cells:activation by short-term exposure to antineoplastic drugs. Int J Cancer,2000,88(2):293-300.
20. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer:a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ,1995,311(7010):899-909.
21. Jordan P, Carmo-Fonseca M. Molecular mechanisms involved in cisplatin cytotoxicity. Cell Mol Life Sci,2000,57(8-9):1229-1235.
22. Sandri MI, Hochhauser D, Ayton P, et al. Differential expression of the topoisomerase Ⅱα and β genes in human breast cancers. Br J Cancer,1996, 73:1518-1524.
23. Meschini S, Marra M, Calcabrini A, et al. Role of the lung resistance-related protein (LRP) in the drug sensitivity of cultured tumor cells. Toxicol In Vitro, 2002,16(4):389-398.
24. Rybarova S, Hajdukova M, Hodorova I, et al. Expression of the multidrug resistance-associated protein (MRP1) and the lung resistance-related protein (LRP) in human lung cancer. Neoplasma,2004,51(3):169-174.
25. Meschini S, Marra M, Calcabrini A. Role of the lung resistance-related protein (LRP) in the drug sensitivity of cultured tumor cell. Toxicol in Vitro,2002, 16(3):389-398.
26. Doyle LA, Yang W, Abruzzo LV, et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci U S A,1998, 95(26):15665-15670.
27. Knutsen T, Rao VK, Ried T, et al. Amplification of 4q21-q22 and the MXR gene in independently derived mitoxantrone-resistant cell lines. Genes Chromosomes Cancer,2000,27(1):110-116.
28. Shiozawa K, Oka M, Soda H, et al. Reversal of breast cancer resistance protein (BCRP/ABCG2)-mediated drug resistance by novobiocin, a coumermycin antibiotic. In J Cancer,2004,108(1):146.
29. Maliepaard M, van Gastelen MA, de Jong LA, et al. Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res,1999,59(18):4559.
30. Elkind NB, Szentpetery Z, Apati A, et al. Multidrug transporter ABCG2 prevents tumor cell death induced by the epidermal growth factor receptor inhibitor Iressa (ZD1839, Gefitinib). Cancer Res,2005,65(5):1770-1777.
31. Kiyotaka Y, Genichivo I, Tomoyuki Y, et al. Breast cancer resistance protein impacts clinical outcome in platinum-based chemotherapy for advanced non-small cell lung cancer. Clin Cancer Res,2004,10(3):1691-1697.
32. Gruss HJ, Dower SK. Tumor necrosis factor ligand superfamlily:involvement in the pathology of malignant lymphomas. Blood,1995,85(12):3378.
33. Volm M, Matteru J, Samsel B, et al. Overexpression of P-glycoprotein and gultathion S-transrerase-π in resistant non-small cell lung carcionomas of smokers. Br J Cancer,1991,6(4):700.
34.姬明丽,千智斌.MDR1、MRP和GST-π在非小细胞肺癌多药耐药机制中的作用.中国现代医学杂志,2006,16(1)：27-31.
35. Bai F, Nakanishi Y, Kawasaki M, et al. Immunohistochemical expression of glutathione S-transferase-Pi can predict chemotherapy response in patients with non-small cell lung carcinoma. Cancer,1996,78(3):416.
36. Nakanishi Y, Kawasaki M, Bai F, et al. Expression of p53 and glutathione S-transferase-pi relates to clinical drug resistance in non-small cell lung cancer. Oncology,1999,57 (6):318-323.
37. Kawai H, KJura K, Tabata M, et al. Characterization of non-small cell lung cancer cell lines established before and after chemotherapy. Lung Cancer,2002, 35(2):305-314.
38.王彦,吴焕明.肺癌中金属硫蛋白的表达及其与细胞增殖凋亡的关系.中国组织化学与细胞化学杂志,2003,12(4)：393-398.
39. Tsunoda Haruki, Terasawa Tomoko, et al. Effects of wild-type and mutated p53 and Id proteins on the induction of apoptosis by adenovirus E1A, c-Myc, Bax, and Nip3 in p53 null mouse cerebellum cells. Biochemical and Biophysical Research Communications,1999, (255):722-730.
40. Yang Xudong, Klein Rudiger, et al. Notch activation induces apoptosis in neural progenitor cells through a P53-dependent phatway. Developmental Biology,2004, (269):81-94.
41. Dlamini Zodwa, Mbita Zukile, et al. Genealogy, expression, and molecular mechanisms in apoptosis. Pharmacology and Therapeutics,2004, (101):1-15.
42. Desagher S, Martinou JC. Mitochondria as the central control point of apoptosis. Trends Cell Biol,2000,10(9):369-377.
43. Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol,1995,146:3-15.
44. Boldrini L, Faviana P, Cisfredi S, et al. Identification of Fas (APO-1/CD95) and p53 gene mutations in non-small cell lung cancer. Int Oncol,2002, 20(1):155-159.
45. Kawasaki, Nakanishi Y, Kuwano K, et al. The utility of p53 immunostaining of tranosbronchial biopsy specimens in advanced non-small cell lung cancer. Clin Cancer Res,1997,3(7):1195-1200.
46. Vogt U, Zaczek A, Klinke F, et al. P53 gene status in relation to exvivo chemosensitivity of non small cell lung cancer. Res Clin Oncol,2002, 128(5):141-147.
47. Howard S, Bottino C, Brooke S, et al. Neuroprotective effects of bcl-2 overexpression in hippocampal cultures:interactions with pathways of oxidative damage. Neurochem,2002,83(4):914-923.
48. Hochman A, Sternin H, Gorodin S, et al. Enhanced oxidative stress and altered antioxidants in brains of Bcl-2-deficient mice. J Neurochem,1998, 71(2):741-748.
49. Sartorius UA, Krammer PH. Upregulation of Bcl-2 is involved in the mediation of chemotherapy resistance in human small cell lung cancer cell lines. Int J Cancer, 2002,97(1):584-592.
50. Wang J, Liu X, Jiang W. Co-transfection of MRP and bcl-2 antisense S-oligedeoxynucleotides reduces drug resistance in cisplatin-resistant lung cancer cells. Chin Med J (Eng),2000,113(10):957-960.
51 Steck PA, Pershouse MA, Tasser SA, et al. Identification of a candidate tumor suppressor gene MM AC at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet,1997,15(4):357-362.
52. Nassif NT, Lobo GP, Wu X, et al. PTEN mutation are common in sporadic microsatellite stable colorectal cancer. Oncogene,2004,23(2):617-628.
53 Tanaka M, Grossman HB. In vivo gene therapy of human bladder cancer with PTEN suppresses tumor growth, downregulates phosphorylated Akt, and increases sensitivity to doxorubicin. Gene Ther,2003,10(19):1636-1642.
54.刘振虹,梅立新.肺癌组织中PTEN基因表达的临床意义.中国综合临床,2005,21(2)：169-170.
55张洪兰,舒红,姜卫国.PTEN、p53和P-gp在非小细胞肺癌中的表达及与预后的关系.中国肺癌杂志,2009,11(12)：1213-1216.
56 Mayo LD, Dixon JE, Durden DL, et al. PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J Biol Chem,2002,277(7):5484-5489.
57 Yan X, Fraser M, Qiu Q, et al. Over expression of PTEN sensitizes human ovarian cancer cells to cisplatin-induced apoptosis in a p53 depentent manner. Gynecol Oncol,2006,102(2):348-355
58 Mayo LD, Donner DB. The PTEN, Mdm2, p53 tumor suppressor oncoprotein network. Trends Biochem Sci,2002,27(9):462-467.
59 Tamm I, Wang Y, Sausville E, et al. IAP-family protein surviving inhibits caspase activity and apoptosis induced by fas, bax, caspases and anticancer drugs. Cancer Res,1998,58(23):53 15-5320.
60 Takai N, Miyazaki T, Nishida M, et al. Survivin expression correlates with clinical stage, histological grade, invasive behavior and survival rate in endometrial carcinoma. Cancer Lett,2001,184(1):105-116.
61 Kim PJ, Plescia J,Clevers H, et al. Survivin and molecular pathogenesis of colorectal cancer. Lancet,2003,362(9379):205-209.
62. Olie RA, Simoes-Wust AP, Baumann B, et al. A novel antisense oligonucleotide targeting survivin expression induces apoptosis and sensitizes lung cancer dells to chemotherapy. Cancer Res,2000,60(11):2805-2809.
63. Reed E, Ozols RF, Tarone R, et al. Platinum-DNA adducts in leukocyte DNA correlate with disease response in ovarian cancer patients receiving platinum-based chemotherapy. Proc Natl Acad Sci USA,1987,84:5024-5028.
64. van de Vaart PJ, Belderbos J, de Jong D, et al. DNA-adduct levels as a predictor of outcome for NSCLC patients receiving daily cisplatin and radiotherapy. Int J Cancer,2000,89:160-166.
65. Wei Q, Cheng L, Hong WK, et al. Reduced DNA repair capacity in lung cancer patients. Cancer Res,1996,56:4103-4107.
66. Zeng-Rong N, Paterson J, Alpert L, et al. Elevated DNA repair capacity is associated with intrinsic resistance of lung cancer to chemotherapy. Cancer Res, 1995,55:4760-4764.
67 Reed E. Platinum-DNA adduct, nucleotide excision repair and platinum based anti-cancer chemotherapy. Cancer Treat Rev,1998,24:331-344.
68 de Boer J, Hoeijmakers JH. Nucleotide excision repair and human syndromes. Carcinogenesis,2000,21:453-460.
69. Elvakumaran M, Pisareik DA, Bao R, et al. Enhanced cisplatin cytotoxicity by disturbing the nueleotide excision repair pathway in ovarian cancer cell lines. Cancer Res,2003,63(6):1311-1316.
70. Reed E. ERCC-1 and clinical resistance to platinum-based therapy. Clin Cancer Res,2005,11:6100-6102.
71. Li Q, Yu JJ, Mu C, et al. Association between the level of ERCC-1 expression and the repair of cisplatin-induced DNA damage in human ovarian cancer cells. Anticancer Res,2000,20:645-652.
72. Dabholkar M, Vionnet J, Bostick-Bruton F, et al. Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. J Clin Invest,1994,94:703-708.
73. Yang LY, Lan L, Jiang H, et al. Expression of ERCC1 antisense RNA abrogates gemcitabine-mediated cytotoxic synergism with cisplatin in human colon tumor cells defective in mismatch repair but proficient in nucleotide excision repair. Clin Cancer Res,2000,6:773-781.
74. Zeng-Rong N, Paterson J,Alpert L, et al. Elevated DNA repair capacity is associated with intrinsic resistance of lung cancer to chemotherapy. Cancer Res, 1995,55:4760-4764.
75. Bosken CH, Wei Q, Amos CI, et al. An analysis of DNA repair as a determinant of survival in patients with non-small-cell lung cancer. J Natl Cancer Inst,2002, 14(94):1091-1099.
76. Lord RV, Brabender J, Gandara D, et al. Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res,2002,8(7):2286-2291.
77. Ryu JS, Hong YC, Han HS, et al. Association between polymorphisms of ERCC1 and XPD and survival in non-small cell lung cancer patients treated with cisplatin combination chemotherapy. Lung Cancer,2004,44(3):311-316.
78. George R, Simon S, Sharma D, et al. ERCC1 expression is a predictor of survival in resected patients with non-small cell lung cancer. Chest,2005,127(5):978-983.
79 Withoff S, Jong DS, VriesDe EG, et al. Humanal DNA topoisomerase biochemistry and role in chemotherapy resistance. Anticancer Res,1996, 16(4A):1867.
80. Mistry P, Stewart AJ, Dangerfield W, et al. In vitro and in vivo characterization of XR11576, a novel, orally active, dual inhibitor of topoisomerase Ⅰ and Ⅱ. Anticancer Drugs,2002,13(1):15-28.
81. Dingemans AC, van Ark-Otte J, Span S, et al. Topoisomerase Ⅱ alpha and other drug resistance markers in advanced non-small cell lung cancer. Lung Cancer, 2001,32(6):117-128.
82. Heim MM, Eberhardt W, Seeber S, et al. Differential modulation of chemosensitivity to alkylating agents and platinum compounds by DNA repair modulators in human cancer cell lines. Cancer Res Clin Oncol,2000, 126(4):198-204.
83.马文丽,郑文岭.分子肿瘤学.北京,科学出版社,2003：203-204.
84. Fink D, Zheng H, Nebel S, et al. In vitro and in vivo resistance to cisplatin in cells that have lost DNA mismatch repair. Cancer Res.1997,57:1841-1845.
85. Nehme A, Baskaran R, Nebel S, et al. Induction of JNK and cAbl signalling by cisplatin and oxaliplatin in mismatch repair-proficient and-deficient cells. Br J Cancer,1999,79:1104-1110.
86. Vaisman A,Varchenko M, Umar A, et al. The role of hMLH1, hMSH3 and hMSH6 defects in cisplatin and oxaliplatin resistance:correlation with replicative bypass of platinum-DNA adducts. Cancer Res,1998,58:3579-3585.
87. Rintoul RC, Sethi T. The role of extracellular matrix in small cell lung cancer. Lancet Oncol,2001,2(3):437-442.
88. Rintoul RC, Sethi T. Extracellular matrix regulation of drug resistance in small cell lung cancer. Clin Sci,2002,102(4):417-424.
89. Loeffler M, Kruger JA, Niethammer AG, et al. Targeting tumor-associatcd fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest,2006,116(7):1955-1962.
90. Shao L, Kasanov J, Homicek FJ. Ecteinascidin-743 drug resistance in sarcoma ceils:transcriptional and cellular alterations. Biochem Pharmacol,2003, 66(5):2381-2395.
91. Shain KH, Dalton WS. Cell adhesion is a key determinant in de novo multidrug resistance (MDR):new targets for the prevention of acquired MDR. Mol Cancer Ther,2001,1(1):69-78.
92. Sonnemann J, Gekeler V, Ahlbrecht K, et al. Down-regulation of protein kinase Ceta by antisense oligonucleotides sensitises A549 lung cancer cells to vincristine and paclitaxel. Cancer Lett,2004,209(2):177-185.
93. Clark AS, West KA, Blumberg PM, et al. Altered protein kinase C (PKC) isoform in non-small cell lung cancer cells:PKC delta promotes cellular survival and chemotherapeutic resistance. Cancer Res,2003,63(4):780-786.
94. Katso R, Okkenhaug K, Ahmadi K, et al. Cellular function of phosphoinositide 3-kinases:implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol,2001,17:615-675.
95. Mabuchi S, Ohmichi M, Kimura A, et al. Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel. J Biol Chem, 2002,277:33490-33500.
96. Brognard J, Clar AS, Ni Y, et al. Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radition. Cancer Res,2001,61(10):3986-3997.
97. Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequence. Cell,1986,46:705-716.
98. Bellas RE, FitzGerald MJ, Fausto N, et al. Inhibition of NF-κB activity induces apoptosis in murine hepatocytes. Am J Pathol,1997,151:891-896.
99. Bentires Alj M, Barbu V, Fillet M, et al. NF-kappa B transcription factor induce drug resistance through MDR1 expression in cancer cells. Oncogene,2003, 22(1):90-97.
100. Yiwei L, Fakhara A, Shadan A, et al. Inaction of nuclear factor κB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in huamn cancer cells. Cancer Res,2005, 65(8):6934-6942.
101. Rosell R, Scagliotti G, Danenberg KD, et al. Transcripts in pretreatment biopsies from a three-arm randomized trail in metastatic non-small cell lung cancer. Oncogene,2003,22(23):3548-3553.
102. Sere P, Mackey J, Isaac S, et al. Class Ⅲ beta-tubulin expression in tumor cells predicts response and outcome in patients with non-small cell lung cancer receiving paclitaxel. Mol Cancer Ther,2005,4(12):2001-2007.
103. Wong TW, Yu HY, Kong SK, et al. The decrease of mitochondrial NADH dehydrogenease and drug induced apoptosis in doxorubicin resistant A431 cells. Life Sci,2000,67(9):1111-1118.
104. Wu H, Hait WN, Yang JM. Small interfering RNA induced suppression of MDR1 (P-glycop ro tein) resto res sensitivity to multidrug resistant cancer cells. Cancer Res,2003,63(7):1515-1519.
105. July LV, Beraldi E, So A, et al. 1N ucleo tide-based therapies targeting clusterin chemo sensitize human lung adenocarcinoma cells both in vitro and in vivo. Mol Cancer Ther,2004,3(3):223-232.
106.冉志华,萧树东.小干扰RNA表达质粒转导逆转人结肠癌羟基喜树碱耐药表型的研究.中华消化杂志,2007,1(27)：7-11.
107. YUAN Ya-wei, SUN Ai-min, LIU Ying. RNA Interference of mdrlGene in Breast Cancer Cell Line MCF-7/Adr Small Interference RNA (siRNA) Synthesized with In Vitro Transcription. The Practical Journal of Cancer,2007,1(22):13-17.
108.李惠芳,孙桂香,卢薇薇等.多药耐药基因反义寡核苷酸逆转肿瘤细胞耐药的初步研究.中华血液学杂志,1997,18：76-77.
109. Cucco C, Calabretta B. In vitro and vivo reversal of multidrug resistance in a human leukemia-resistant cell line by MDR1 antisense oligo deoxynucleotides. Cancer Res,1996,56:4330-4334.
110. Agrawal S, Temsamani J, Tang J Y. Pharmacokinetics, biodistribution, and stability of oligodeoxynucleoide in mice. Proc Natl Acacl Sci USA,1991, 88:7595-7598.
111. Jekerle V, Kassack MU, Reilly RM, et al. Functional comparison of single-and double-stranded mdrl antisense oligodeoxynucleotides in human ovarian cancer cell lines. J Pharm Pharm Sci,2005,8(3):516.
112. Gao P, Zhou GY, Zhang QH, et al. Reversal MDR in breast carcinoma cells by transfection of ribozyme designed according the secondary structure of mdrl mRNA. Chin J Physiol,2006,49(2):96.
113. Watanabe T, Tsuge H, Oh-Hara T, et al. Comparative study on reversal efficacy of SDZ PSC833, Cyclosporin A and verapamil on multidrug resistance in vitro and in vivo. Acta Oncol,1995,34(2):235.
114. Lopes EC, Scolnik M, Alvarez E, et al. Modulator activity of PSC833 and cyclosporine-A in vincristine and doxorubicin-selected multidrug resistant murine leukemic cells. Leuk Res,2001,25(1):85.
115.彭司勋主编.药物化学进展.北京,化学工业出版社,2001,184-205.
116.常宏宇,潘凯丽.白血病多药耐药逆转研究进展.细胞与分子免疫学杂志,2005,21(1)：101.
117.孙士勇,韩锐.谷胱甘肽S-转移酶与肿瘤防治.国外医学药学分册,1992,19(2)：66-71.
118.刘新恒,曹蕾.细胞因子在肿瘤治疗中的应用.上海,上海科学技术出版社,1997,134-160.
119.魏志霞,田韧.α-干扰素对肝癌多药耐药株SMMC-7221/ADM的逆转及其机制研究.临床肿瘤学杂志,2001,6(4)：339-341.
120.王其,陈孝平,海山等.肿瘤坏死因子对人肝癌多药耐药逆转作用的实验研究.中华外科杂志,2007,45(9)：602.
121.粱蓉,杨平地,陈协群.川芎嗪和(或)环孢素A对HL60／HT细胞耐药的逆转.中华内科杂志,1999,38(4)：260.
2. Fadeel B, Orrenius S and Zhivotovsky B. Apoptosis in human disease:a new skin for the old ceremony? Biochem Biophys Res Commun,1999,266:699-717
3.吴一龙.肺癌多学科综合治疗的现状和展望.中国肺癌杂志,2001,4(4)：241-242
4.吴一龙.肺癌多学科综合治疗的理论基础.吴一龙主编.肺癌多学科综合治疗的理论与实践.北京：人民卫生出版社,2000.1-2
5. Sugimura H, Nichols FC, Yang P, et al. Survival after recurrent non-small-cell lung cancer after complete pulmonary resection. Ann Thorac Surg,2007, 83(2):409-417
6. Gazak R, Walterova D, Kren V. Silybin and silymarin--new and emerging applications in medicine. Curr Med Chem,2007,14(3):315-338
7. Notter K, Herweijer H. Multi-drug resistance (MDR) genes in human cancer. Br J Cancer,1991,63(5):663-669
8.王涛.肿瘤多药耐药性与信号转导.国外医学呼吸系统分册,2003,23(3)：154-156
9. Stouch TR, Gudmundsson O. Progress in understanding the structure-activity relationships of P-glyco protein. Adv Drug Del Rev,2002,54(3):315-328
10. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer:a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ,1995,311(7010):899-909
11 Hoang T, Xu R, Schiller JH, et al. Clinical model to predict survival in chemo-naive patients with advanced non-small-cell-lung cancer treated with third-generation chemotherapy regimens based on eastern cooperative oncology group data. J Clin Oncol,2005,23(1):175-183
12 Jordan P, Carmo-Fonseca M. Molecular mechanisms involved in cisplatin cytotoxicity. Cell Mol Life Sci,2000,57(8-9):1229-1235
13. Piet Borst, Sven Rottenberg, Jos Jonkers. How do real tumors become resistant to cisplatin? Cell Cycle,2008,7(10):1353-1359
14 Guminski AD, Harnett PR, deFazio A. Scientists and clinicians test their metal-back to the future with platinum compounds. Lancet Oncol,2002,3(5):312-318
15 Link AJ, Eng J, Sehieltz DM, et al. Direct analysis of protein complexes using mass spectrometry. Nat Biotechnol,1999,17:676
16 Jr GW, Cazares LH, Leung SM, et al. Proteinchip(R) surface enhanced laser desorption-ionization (SELDI) mass spectrometry:A novel protein biochip technology for detection of prostate cancer biomarkers in complex protein mixtures. Prostate Cancer Prostatic Dis,1999,2:264
17 Gygi SP, Rist B, Gerber SA, et al. Quantitative analysis of complex protein mixtures using isotope-coded affinity tags. Nat Biotechnol,1999,17:994
18. Hu Y, Wang G, Grace YJ. Proteome analysis of Saccharomyces cerevisiae under metal stress by two-dimensional differential gel electrophoresis. Electrophoresis, 2003,24(9):1458
19. Nishio K, Nakamura T, Koh Y, et al. Drug resistance in lung cancer. Curr Opin Oncol,1999, 11(2):109-115
20. Kawai H, Kiura K, Tabata M, et al. Characterization of non-small cell lung cancer cell lines established before and after chemotherapy. Lung Cancer,2002, 35(3):305-314
21.蔡鹏,刘叙仪,韩复生.耐顺铂人肺腺癌细胞系A549DDP的建立及耐药机制.中国肿瘤临床,1995,22(8)：582-587
22. Wadhwa R, Pereira-Smith OM, Reddel RR, et al. Correlation between complementation group for immortality and the cellular distribution of mortalin. Exp Cell Res,1995,216(1):101-106
23. Kaula SC, Reddelb RR, Sugiharac T, et al. Inactivation of p53 and life span extension of human diploid fibroblasts by mot-2. FEBS Lett,2000,474(2-3): 159-164
24. Xu J, Xiao HH, Sartorelli AC. Attenuation of the induced differentiation of HL-60 leukemia cells by mitochondrial chaperone HSP70. Oncol Res,1999,11(9): 429-435
25. Mizukoshi E, Suzuki M, Loupatov A, et al. Fibroblast growth factor-1 interacts with the glucose-regulated protein GRP75/mortalin. Biochem J,1999,343(2): 461-466
26. Samali A, Cotter TG. Heat shock proteins increase resistance to apoptosis. Exp Cell Res,1996,223(1):163-170
27. Hartl FU, Hayer-Hartl M. Molecular chaperones in the cytosol:from nascent chain to folded protein. Science,2002,295(5561):1852-1858
28. Kimoto Y. Expression of heavy-chain constant region of immunoglobulin and T-cell receptor gene transcripts in human non-hematopoietic tumor cell lines. Genes Chromosomes Cancer,1998,22(1):83-86
29.黎明,唐敏,邓锡云等.上皮来源的肿瘤细胞可表达免疫球蛋白A.中华肿瘤杂志,2001,23(6)：451-453
30.杨少波,王孟薇,尤纬缔.胃癌细胞中免疫球蛋白轻链IgK和Igλ的共同表达.中华肿瘤杂志,2002,24(5)：465-466
31. Qiu X, Zhu X, Zhang L, et al. Human epithelial cancers secrete immunoglobuling with unidentified specificity to promote growth and survival of tumor cells. Cancer Res,2003,63(9):6488-6495
32. Torres M, Condon C, Balada JM, et al. Ribosomal protein S4 is a transcription factor with properties remarkably similar to NusA, a protein involved in both non-ribosomal and ribosomal RNA antitermination. EMBO J,2001,20(14): 3811-3820
33. Senior AE, Nadanaciva S, Weber J. The molecular mechanism of ATP synthesis by F1F0-ATP synthase. Biochim Biophys Acta,2002,1553(3):188-211
34. Dudkina NV, Sunderhaus S, Braun HP, et al. Characterization of dimeric ATP synthase and cristae membrane ultrastructure from Saccharomyces and Polytomella mitochondria. FEBS Letters,2006,580(14):3427-3432
35. Peng G, Bostinaa M, Radermacher M, et al. Biochemical and electron microscopic characterization of the F1F0 ATP synthase from the hyperthermophilic eubacterium Aquifex aeolicus. FEBS Letters,2006,580(25):5934-5940
36. Walker JE, Dickson VK. The peripheral stalk of the mitochondrial ATP synthase. Biochimica et Biophysica Acta,2006,1757(5-6):286-296
37. Iizuka S, Kato S, Yoshida M, et al. γεsub-complex of thermophilic ATP synthase has the ability to bind ATP. Biochem Biophys Res Comm,2006, 349(4):1368-1371
38. Feniouk BA, Suzuki T, Yoshida M. The role of subunit epsilon in the catalysis and regulation of F0F1-ATP synthase. Biochimica et Biophysica Acta,2006, 1757:326-338
39. Gao YQ, Yang W, Karplus M. A structure-based model for the synthesis and hydrolysis of ATP by Fl-ATPase. Cell,2005,123(2):195-205
40. Wahl ML, Kenan DJ, Gonzalez-Gronow M, et al. Angiostatin's molecular mechanism:aspects of specificity and regulation elucidated. J Cell Biochem, 2005,96(2):242-261
41. Kim BW, Choo HJ, Lee JW, et al. Extracellular ATP is generated by ATP synthase complex in adipocyte lipid rafts. Exp Mol Med,2004,36(5):476-485
42. Burrell HE, Wlodarski B, Foster BJ, et al. Human keratinocytes release ATP and utilize three mechanisms for nucleotide interconversion at the cell surface. J Biol Chem,2005,280(33):29667-29676
43. Scotet E, Martinez LO, Grant E, et al. Tumor recognition following V gamma 9 V delta 2 T cell receptor interactions with a surface F1-ATPaserelated structure and apolipoprotein A-Ⅰ. Immunity,2005,22(1):71-80
44. Burwick NR, Wahl ML, Fang J, et al. An Inhibitor of the F1 subunit of ATPsynthase (IF1) modulates the activity of angiostatin on the endothelial cell surface. J Biol Chem,2005,280(3):1740-1745
45. Watabe M, Nakaki T. ATP depletion does not account for apoptosis induced by inhibition of mitochondrial electron transport chain in human dopaminergic cells. Neuropharmacology,2006,7(1):37-43
46. Champagne E, Martinez LO, Collet X, et al. Ecto-FIFO ATP synthase/F1 ATPase: metabolic and immunological functions. Curr Opin Lipidol,2006,17(3):279-284
47. Wu H, Hait WN, Yang JM. Small interfering RNA induced suppression of MDR1 (P-glycop ro tein) resto res sensitivity to multidrug resistant cancer cells. Cancer Res,2003,63(7):1515-1519
48. July LV, Beraldi E, So A, et al. 1N ucleo tide-based therapies targeting clusterin chemo sensitize human lung adenocarcinoma cells both in vitro and in vivo. Mol Cancer Ther,2004,3(3):223-232
49.冉志华,萧树东.小干扰RNA表达质粒转导逆转人结肠癌羟基喜树碱耐药表型的研究.中华消化杂志,2007,1(27)：7-11
50. YUAN Ya-wei, SUN Ai-min, LIU Ying. RNA Interference of mdrlGene in Breast Cancer Cell Line MCF-7/Adr Small Interference RNA (siRNA) Synthesized with In Vitro Transcription. The Practical Journal of Cancer,2007,1(22):13-17
51. Tsunoda Haruki, Terasawa Tomoko, et al. Effects of wild-type and mutated p53 and Id proteins on the induction of apoptosis by adenovirus E1A, c-Myc, Bax, and Nip3 in p53 null mouse cerebellum cells. Biochemical and Biophysical Research Communications,1999, (255):722-730
52. Yang Xudong, Klein Rudiger, et al. Notch activation induces apoptosis in neural progenitor cells through a P53-dependent phatway. Developmental Biology,2004, (269):81-94
53. Dlamini Zodwa, Mbita Zukile, et al. Genealogy, expression, and molecular mechanisms in apoptosis. Pharmacology and Therapeutics,2004, (101):1-15
54. Desagher S, Martinou JC. Mitochondria as the central control point of apoptosis. Trends Cell Biol,2000,10(9):369-377
55. Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol,1995,146:3-15
56. Sansome Christine, Zaika Alex, Marchenko Natalie D. Hypoxia death stimulus induces translocation of p53 protein to mitochondria:Detection by immunofluorescence on whole cells. FEBS Lett,2001, (488):110-115
57. Howard S, Bottino C, Brooke S, et al. Neuroprotective effects of bcl-2 overexpression in hippocampal cultures:interactions with pathways of oxidative damage. Neurochem,2002,83(4):914-923
58. Hochman A, Sternin H, Gorodin S, et al. Enhanced oxidative stress and altered antioxidants in brains of Bcl-2-deficient mice. J Neurochem,1998,71(2):741-748
1. Sugimura H, Nichols FC, Yang P, et al. Survival after recurrent non-small-cell lung cancer after complete pulmonary resection. Ann Thorac Surg,2007, 83(2):409-417.
2. Gazak R, Walterova D, Kren V. Silybin and silymarin-new and emerging applications in medicine. Curr Med Chem,2007,14(3):315-338.
3. Notter K, Herweijer H. Multi-drug resistance (MDR) genes in human cancer. Br J Cancer,1991,63(5):663-669.
4.王涛.肿瘤多药耐药性与信号转导.国外医学呼吸系统分册,2003,23(3)：154-156.
5. Stouch TR, Gudmundsson O. Progress in understanding the structure-activity relationships of P-glyco protein. Adv Drug Del Rev,2002,54(3):315-328.
6. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochem Biophys Acta,1976,455(1):152.
7. Wan L, Hyo-Im C, Mi-Jin K, et al. Depletion of mitochondrial DNA up-regulates the expression of MDR1 gene via an increase in mRNA stability. Exp Mol Med, 2008,40(1):109-117.
8. Anthony V, Skach WR. Molecular mechanism of P-glycoprotein assembly into cellular membrances. Currprotein Pept Sci,2002,3:485-501.
9. Kool M, van der Linden M, de Haas M, et al. MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci USA,1999, 96(12):6914-6919.
10.王飞,黄艳春,刘诚明.多药耐药基因在肺癌患者外周血中的表达及意义.新 疆医科大学学报,2007,30(10)：1137-1139.
11. Cole SPC, Downes HF, Mirski SEC. Overexpression of a transporter gene in a multidrug resistant human lung cancer cell line. Science,1992, 258(5088):1650-1654.
12. Benlloch M, Ortega A, Ferrer P. Acceleration of glutathione efflux and inhibition of gamma glutamyltranspeptidase sensitize metastatic B16 melanoma cells to endothelium-induced cytotoxicity. Journal of Biological Chemistry,2005, 280(8):6950-6959.
13. Borst P, Evers R, Ko LM, et al. A family of drug transporters:the multidrug resistance-associated proteins. J Natl Cancer Inst,2000,92 (6):1295.
14. Wright SR, Boag AH, Valdimarsson G, et al. Immunohistochemical detection of multidrug resistance protein in human lung cancer and normal lung. Clin Cancer Res,1998,4(9):2279-2289.
15. Brooks T, Minderman H, Kieran L, et al. Taxane-based reversal agents modulate drug resistance mediated by P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein. Cancer Ther,2003,2:1195.
16. Oshika Y, Nakamura M, Tokunaga T, et al. Multidrug resistance-associated protein and mutant p53 protein expression in non-small cell lung cancer. Mod Pathol, 1998, 11(11):1059-1063.
17. Hsia TC, Lin CC, Wang JJ, et al. Relationship between chemotherapy response of small cell lung cancer and P-glycoprotein or multidrug resistance-related protein expression. Lung,2002,180(3):173-179.
18. Scheper RJ, Broxterman HJ, Scheffer GL, et al. Overexpression of a M(r) 110,000 vesicular protein in non-P-glycoprotein-mediated Multidrug resistance. Cancer Res,1993,53(7):1475.
19. Berger W, Elbling L, Micksche M. Expression of the major vault protein LRP in human non-small cell lung cancer cells:activation by short-term exposure to antineoplastic drugs. Int J Cancer,2000,88(2):293-300.
20. Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer:a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ,1995,311(7010):899-909.
21. Jordan P, Carmo-Fonseca M. Molecular mechanisms involved in cisplatin cytotoxicity. Cell Mol Life Sci,2000,57(8-9):1229-1235.
22. Sandri MI, Hochhauser D, Ayton P, et al. Differential expression of the topoisomerase Ⅱα and β genes in human breast cancers. Br J Cancer,1996, 73:1518-1524.
23. Meschini S, Marra M, Calcabrini A, et al. Role of the lung resistance-related protein (LRP) in the drug sensitivity of cultured tumor cells. Toxicol In Vitro, 2002,16(4):389-398.
24. Rybarova S, Hajdukova M, Hodorova I, et al. Expression of the multidrug resistance-associated protein (MRP1) and the lung resistance-related protein (LRP) in human lung cancer. Neoplasma,2004,51(3):169-174.
25. Meschini S, Marra M, Calcabrini A. Role of the lung resistance-related protein (LRP) in the drug sensitivity of cultured tumor cell. Toxicol in Vitro,2002, 16(3):389-398.
26. Doyle LA, Yang W, Abruzzo LV, et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci U S A,1998, 95(26):15665-15670.
27. Knutsen T, Rao VK, Ried T, et al. Amplification of 4q21-q22 and the MXR gene in independently derived mitoxantrone-resistant cell lines. Genes Chromosomes Cancer,2000,27(1):110-116.
28. Shiozawa K, Oka M, Soda H, et al. Reversal of breast cancer resistance protein (BCRP/ABCG2)-mediated drug resistance by novobiocin, a coumermycin antibiotic. In J Cancer,2004,108(1):146.
29. Maliepaard M, van Gastelen MA, de Jong LA, et al. Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res,1999,59(18):4559.
30. Elkind NB, Szentpetery Z, Apati A, et al. Multidrug transporter ABCG2 prevents tumor cell death induced by the epidermal growth factor receptor inhibitor Iressa (ZD1839, Gefitinib). Cancer Res,2005,65(5):1770-1777.
31. Kiyotaka Y, Genichivo I, Tomoyuki Y, et al. Breast cancer resistance protein impacts clinical outcome in platinum-based chemotherapy for advanced non-small cell lung cancer. Clin Cancer Res,2004,10(3):1691-1697.
32. Gruss HJ, Dower SK. Tumor necrosis factor ligand superfamlily:involvement in the pathology of malignant lymphomas. Blood,1995,85(12):3378.
33. Volm M, Matteru J, Samsel B, et al. Overexpression of P-glycoprotein and gultathion S-transrerase-π in resistant non-small cell lung carcionomas of smokers. Br J Cancer,1991,6(4):700.
34.姬明丽,千智斌.MDR1、MRP和GST-π在非小细胞肺癌多药耐药机制中的作用.中国现代医学杂志,2006,16(1)：27-31.
35. Bai F, Nakanishi Y, Kawasaki M, et al. Immunohistochemical expression of glutathione S-transferase-Pi can predict chemotherapy response in patients with non-small cell lung carcinoma. Cancer,1996,78(3):416.
36. Nakanishi Y, Kawasaki M, Bai F, et al. Expression of p53 and glutathione S-transferase-pi relates to clinical drug resistance in non-small cell lung cancer. Oncology,1999,57 (6):318-323.
37. Kawai H, KJura K, Tabata M, et al. Characterization of non-small cell lung cancer cell lines established before and after chemotherapy. Lung Cancer,2002, 35(2):305-314.
38.王彦,吴焕明.肺癌中金属硫蛋白的表达及其与细胞增殖凋亡的关系.中国组织化学与细胞化学杂志,2003,12(4)：393-398.
39. Tsunoda Haruki, Terasawa Tomoko, et al. Effects of wild-type and mutated p53 and Id proteins on the induction of apoptosis by adenovirus E1A, c-Myc, Bax, and Nip3 in p53 null mouse cerebellum cells. Biochemical and Biophysical Research Communications,1999, (255):722-730.
40. Yang Xudong, Klein Rudiger, et al. Notch activation induces apoptosis in neural progenitor cells through a P53-dependent phatway. Developmental Biology,2004, (269):81-94.
41. Dlamini Zodwa, Mbita Zukile, et al. Genealogy, expression, and molecular mechanisms in apoptosis. Pharmacology and Therapeutics,2004, (101):1-15.
42. Desagher S, Martinou JC. Mitochondria as the central control point of apoptosis. Trends Cell Biol,2000,10(9):369-377.
43. Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol,1995,146:3-15.
44. Boldrini L, Faviana P, Cisfredi S, et al. Identification of Fas (APO-1/CD95) and p53 gene mutations in non-small cell lung cancer. Int Oncol,2002, 20(1):155-159.
45. Kawasaki, Nakanishi Y, Kuwano K, et al. The utility of p53 immunostaining of tranosbronchial biopsy specimens in advanced non-small cell lung cancer. Clin Cancer Res,1997,3(7):1195-1200.
46. Vogt U, Zaczek A, Klinke F, et al. P53 gene status in relation to exvivo chemosensitivity of non small cell lung cancer. Res Clin Oncol,2002, 128(5):141-147.
47. Howard S, Bottino C, Brooke S, et al. Neuroprotective effects of bcl-2 overexpression in hippocampal cultures:interactions with pathways of oxidative damage. Neurochem,2002,83(4):914-923.
48. Hochman A, Sternin H, Gorodin S, et al. Enhanced oxidative stress and altered antioxidants in brains of Bcl-2-deficient mice. J Neurochem,1998, 71(2):741-748.
49. Sartorius UA, Krammer PH. Upregulation of Bcl-2 is involved in the mediation of chemotherapy resistance in human small cell lung cancer cell lines. Int J Cancer, 2002,97(1):584-592.
50. Wang J, Liu X, Jiang W. Co-transfection of MRP and bcl-2 antisense S-oligedeoxynucleotides reduces drug resistance in cisplatin-resistant lung cancer cells. Chin Med J (Eng),2000,113(10):957-960.
51 Steck PA, Pershouse MA, Tasser SA, et al. Identification of a candidate tumor suppressor gene MM AC at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet,1997,15(4):357-362.
52. Nassif NT, Lobo GP, Wu X, et al. PTEN mutation are common in sporadic microsatellite stable colorectal cancer. Oncogene,2004,23(2):617-628.
53 Tanaka M, Grossman HB. In vivo gene therapy of human bladder cancer with PTEN suppresses tumor growth, downregulates phosphorylated Akt, and increases sensitivity to doxorubicin. Gene Ther,2003,10(19):1636-1642.
54.刘振虹,梅立新.肺癌组织中PTEN基因表达的临床意义.中国综合临床,2005,21(2)：169-170.
55张洪兰,舒红,姜卫国.PTEN、p53和P-gp在非小细胞肺癌中的表达及与预后的关系.中国肺癌杂志,2009,11(12)：1213-1216.
56 Mayo LD, Dixon JE, Durden DL, et al. PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J Biol Chem,2002,277(7):5484-5489.
57 Yan X, Fraser M, Qiu Q, et al. Over expression of PTEN sensitizes human ovarian cancer cells to cisplatin-induced apoptosis in a p53 depentent manner. Gynecol Oncol,2006,102(2):348-355
58 Mayo LD, Donner DB. The PTEN, Mdm2, p53 tumor suppressor oncoprotein network. Trends Biochem Sci,2002,27(9):462-467.
59 Tamm I, Wang Y, Sausville E, et al. IAP-family protein surviving inhibits caspase activity and apoptosis induced by fas, bax, caspases and anticancer drugs. Cancer Res,1998,58(23):53 15-5320.
60 Takai N, Miyazaki T, Nishida M, et al. Survivin expression correlates with clinical stage, histological grade, invasive behavior and survival rate in endometrial carcinoma. Cancer Lett,2001,184(1):105-116.
61 Kim PJ, Plescia J,Clevers H, et al. Survivin and molecular pathogenesis of colorectal cancer. Lancet,2003,362(9379):205-209.
62. Olie RA, Simoes-Wust AP, Baumann B, et al. A novel antisense oligonucleotide targeting survivin expression induces apoptosis and sensitizes lung cancer dells to chemotherapy. Cancer Res,2000,60(11):2805-2809.
63. Reed E, Ozols RF, Tarone R, et al. Platinum-DNA adducts in leukocyte DNA correlate with disease response in ovarian cancer patients receiving platinum-based chemotherapy. Proc Natl Acad Sci USA,1987,84:5024-5028.
64. van de Vaart PJ, Belderbos J, de Jong D, et al. DNA-adduct levels as a predictor of outcome for NSCLC patients receiving daily cisplatin and radiotherapy. Int J Cancer,2000,89:160-166.
65. Wei Q, Cheng L, Hong WK, et al. Reduced DNA repair capacity in lung cancer patients. Cancer Res,1996,56:4103-4107.
66. Zeng-Rong N, Paterson J, Alpert L, et al. Elevated DNA repair capacity is associated with intrinsic resistance of lung cancer to chemotherapy. Cancer Res, 1995,55:4760-4764.
67 Reed E. Platinum-DNA adduct, nucleotide excision repair and platinum based anti-cancer chemotherapy. Cancer Treat Rev,1998,24:331-344.
68 de Boer J, Hoeijmakers JH. Nucleotide excision repair and human syndromes. Carcinogenesis,2000,21:453-460.
69. Elvakumaran M, Pisareik DA, Bao R, et al. Enhanced cisplatin cytotoxicity by disturbing the nueleotide excision repair pathway in ovarian cancer cell lines. Cancer Res,2003,63(6):1311-1316.
70. Reed E. ERCC-1 and clinical resistance to platinum-based therapy. Clin Cancer Res,2005,11:6100-6102.
71. Li Q, Yu JJ, Mu C, et al. Association between the level of ERCC-1 expression and the repair of cisplatin-induced DNA damage in human ovarian cancer cells. Anticancer Res,2000,20:645-652.
72. Dabholkar M, Vionnet J, Bostick-Bruton F, et al. Messenger RNA levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. J Clin Invest,1994,94:703-708.
73. Yang LY, Lan L, Jiang H, et al. Expression of ERCC1 antisense RNA abrogates gemcitabine-mediated cytotoxic synergism with cisplatin in human colon tumor cells defective in mismatch repair but proficient in nucleotide excision repair. Clin Cancer Res,2000,6:773-781.
74. Zeng-Rong N, Paterson J,Alpert L, et al. Elevated DNA repair capacity is associated with intrinsic resistance of lung cancer to chemotherapy. Cancer Res, 1995,55:4760-4764.
75. Bosken CH, Wei Q, Amos CI, et al. An analysis of DNA repair as a determinant of survival in patients with non-small-cell lung cancer. J Natl Cancer Inst,2002, 14(94):1091-1099.
76. Lord RV, Brabender J, Gandara D, et al. Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res,2002,8(7):2286-2291.
77. Ryu JS, Hong YC, Han HS, et al. Association between polymorphisms of ERCC1 and XPD and survival in non-small cell lung cancer patients treated with cisplatin combination chemotherapy. Lung Cancer,2004,44(3):311-316.
78. George R, Simon S, Sharma D, et al. ERCC1 expression is a predictor of survival in resected patients with non-small cell lung cancer. Chest,2005,127(5):978-983.
79 Withoff S, Jong DS, VriesDe EG, et al. Humanal DNA topoisomerase biochemistry and role in chemotherapy resistance. Anticancer Res,1996, 16(4A):1867.
80. Mistry P, Stewart AJ, Dangerfield W, et al. In vitro and in vivo characterization of XR11576, a novel, orally active, dual inhibitor of topoisomerase Ⅰ and Ⅱ. Anticancer Drugs,2002,13(1):15-28.
81. Dingemans AC, van Ark-Otte J, Span S, et al. Topoisomerase Ⅱ alpha and other drug resistance markers in advanced non-small cell lung cancer. Lung Cancer, 2001,32(6):117-128.
82. Heim MM, Eberhardt W, Seeber S, et al. Differential modulation of chemosensitivity to alkylating agents and platinum compounds by DNA repair modulators in human cancer cell lines. Cancer Res Clin Oncol,2000, 126(4):198-204.
83.马文丽,郑文岭.分子肿瘤学.北京,科学出版社,2003：203-204.
84. Fink D, Zheng H, Nebel S, et al. In vitro and in vivo resistance to cisplatin in cells that have lost DNA mismatch repair. Cancer Res.1997,57:1841-1845.
85. Nehme A, Baskaran R, Nebel S, et al. Induction of JNK and cAbl signalling by cisplatin and oxaliplatin in mismatch repair-proficient and-deficient cells. Br J Cancer,1999,79:1104-1110.
86. Vaisman A,Varchenko M, Umar A, et al. The role of hMLH1, hMSH3 and hMSH6 defects in cisplatin and oxaliplatin resistance:correlation with replicative bypass of platinum-DNA adducts. Cancer Res,1998,58:3579-3585.
87. Rintoul RC, Sethi T. The role of extracellular matrix in small cell lung cancer. Lancet Oncol,2001,2(3):437-442.
88. Rintoul RC, Sethi T. Extracellular matrix regulation of drug resistance in small cell lung cancer. Clin Sci,2002,102(4):417-424.
89. Loeffler M, Kruger JA, Niethammer AG, et al. Targeting tumor-associatcd fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest,2006,116(7):1955-1962.
90. Shao L, Kasanov J, Homicek FJ. Ecteinascidin-743 drug resistance in sarcoma ceils:transcriptional and cellular alterations. Biochem Pharmacol,2003, 66(5):2381-2395.
91. Shain KH, Dalton WS. Cell adhesion is a key determinant in de novo multidrug resistance (MDR):new targets for the prevention of acquired MDR. Mol Cancer Ther,2001,1(1):69-78.
92. Sonnemann J, Gekeler V, Ahlbrecht K, et al. Down-regulation of protein kinase Ceta by antisense oligonucleotides sensitises A549 lung cancer cells to vincristine and paclitaxel. Cancer Lett,2004,209(2):177-185.
93. Clark AS, West KA, Blumberg PM, et al. Altered protein kinase C (PKC) isoform in non-small cell lung cancer cells:PKC delta promotes cellular survival and chemotherapeutic resistance. Cancer Res,2003,63(4):780-786.
94. Katso R, Okkenhaug K, Ahmadi K, et al. Cellular function of phosphoinositide 3-kinases:implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol,2001,17:615-675.
95. Mabuchi S, Ohmichi M, Kimura A, et al. Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel. J Biol Chem, 2002,277:33490-33500.
96. Brognard J, Clar AS, Ni Y, et al. Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radition. Cancer Res,2001,61(10):3986-3997.
97. Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequence. Cell,1986,46:705-716.
98. Bellas RE, FitzGerald MJ, Fausto N, et al. Inhibition of NF-κB activity induces apoptosis in murine hepatocytes. Am J Pathol,1997,151:891-896.
99. Bentires Alj M, Barbu V, Fillet M, et al. NF-kappa B transcription factor induce drug resistance through MDR1 expression in cancer cells. Oncogene,2003, 22(1):90-97.
100. Yiwei L, Fakhara A, Shadan A, et al. Inaction of nuclear factor κB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in huamn cancer cells. Cancer Res,2005, 65(8):6934-6942.
101. Rosell R, Scagliotti G, Danenberg KD, et al. Transcripts in pretreatment biopsies from a three-arm randomized trail in metastatic non-small cell lung cancer. Oncogene,2003,22(23):3548-3553.
102. Sere P, Mackey J, Isaac S, et al. Class Ⅲ beta-tubulin expression in tumor cells predicts response and outcome in patients with non-small cell lung cancer receiving paclitaxel. Mol Cancer Ther,2005,4(12):2001-2007.
103. Wong TW, Yu HY, Kong SK, et al. The decrease of mitochondrial NADH dehydrogenease and drug induced apoptosis in doxorubicin resistant A431 cells. Life Sci,2000,67(9):1111-1118.
104. Wu H, Hait WN, Yang JM. Small interfering RNA induced suppression of MDR1 (P-glycop ro tein) resto res sensitivity to multidrug resistant cancer cells. Cancer Res,2003,63(7):1515-1519.
105. July LV, Beraldi E, So A, et al. 1N ucleo tide-based therapies targeting clusterin chemo sensitize human lung adenocarcinoma cells both in vitro and in vivo. Mol Cancer Ther,2004,3(3):223-232.
106.冉志华,萧树东.小干扰RNA表达质粒转导逆转人结肠癌羟基喜树碱耐药表型的研究.中华消化杂志,2007,1(27)：7-11.
107. YUAN Ya-wei, SUN Ai-min, LIU Ying. RNA Interference of mdrlGene in Breast Cancer Cell Line MCF-7/Adr Small Interference RNA (siRNA) Synthesized with In Vitro Transcription. The Practical Journal of Cancer,2007,1(22):13-17.
108.李惠芳,孙桂香,卢薇薇等.多药耐药基因反义寡核苷酸逆转肿瘤细胞耐药的初步研究.中华血液学杂志,1997,18：76-77.
109. Cucco C, Calabretta B. In vitro and vivo reversal of multidrug resistance in a human leukemia-resistant cell line by MDR1 antisense oligo deoxynucleotides. Cancer Res,1996,56:4330-4334.
110. Agrawal S, Temsamani J, Tang J Y. Pharmacokinetics, biodistribution, and stability of oligodeoxynucleoide in mice. Proc Natl Acacl Sci USA,1991, 88:7595-7598.
111. Jekerle V, Kassack MU, Reilly RM, et al. Functional comparison of single-and double-stranded mdrl antisense oligodeoxynucleotides in human ovarian cancer cell lines. J Pharm Pharm Sci,2005,8(3):516.
112. Gao P, Zhou GY, Zhang QH, et al. Reversal MDR in breast carcinoma cells by transfection of ribozyme designed according the secondary structure of mdrl mRNA. Chin J Physiol,2006,49(2):96.
113. Watanabe T, Tsuge H, Oh-Hara T, et al. Comparative study on reversal efficacy of SDZ PSC833, Cyclosporin A and verapamil on multidrug resistance in vitro and in vivo. Acta Oncol,1995,34(2):235.
114. Lopes EC, Scolnik M, Alvarez E, et al. Modulator activity of PSC833 and cyclosporine-A in vincristine and doxorubicin-selected multidrug resistant murine leukemic cells. Leuk Res,2001,25(1):85.
115.彭司勋主编.药物化学进展.北京,化学工业出版社,2001,184-205.
116.常宏宇,潘凯丽.白血病多药耐药逆转研究进展.细胞与分子免疫学杂志,2005,21(1)：101.
117.孙士勇,韩锐.谷胱甘肽S-转移酶与肿瘤防治.国外医学药学分册,1992,19(2)：66-71.
118.刘新恒,曹蕾.细胞因子在肿瘤治疗中的应用.上海,上海科学技术出版社,1997,134-160.
119.魏志霞,田韧.α-干扰素对肝癌多药耐药株SMMC-7221/ADM的逆转及其机制研究.临床肿瘤学杂志,2001,6(4)：339-341.
120.王其,陈孝平,海山等.肿瘤坏死因子对人肝癌多药耐药逆转作用的实验研究.中华外科杂志,2007,45(9)：602.
121.粱蓉,杨平地,陈协群.川芎嗪和(或)环孢素A对HL60／HT细胞耐药的逆转.中华内科杂志,1999,38(4)：260.