利用拉曼光谱检测肝癌、鼻咽癌细胞及其在端粒酶抑制剂作用后的分子变化
|
摘要
癌症是目前世界上危害人类健康和生命的最主要疾病之一,大量的临床实践表明:通过早期诊断、及时有效的治疗,可以在相当程度上控制肿瘤的发展,并大大提高病人的生存机会。拉曼光谱技术是分析物质结构的有效手段,能够在分子水平上反映出肿瘤细胞早期在化学组成和分子结构上所发生的变化,为癌症的早期诊断及其癌变机理分析提供重要的信息。鉴于端粒酶的激活普遍存在于恶性肿瘤中,是肿瘤细胞获得永生性的关键和肿瘤组织无限增殖的必要条件,端粒酶已成为目前最为广谱的肿瘤分子标志物及肿瘤基因治疗的新靶点之一。但对于端粒酶活性的调节机制的研究仍处于探索阶段,端粒酶抑制剂的生化特性及抗肿瘤的作用机理还有待进一步的研究。
本文利用单细胞光镊拉曼光谱技术研究人肝癌细胞SMMC-7721、正常肝细胞LO_2及人鼻咽癌细胞CNE2、正常鼻咽部上皮细胞HBE,通过光谱的对比分析,从而寻找反映癌变的特征标志光谱。应用多种端粒酶抑制剂作用于肝癌、鼻咽癌细胞,通过对比端粒酶抑制剂作用前后的拉曼光谱,可见细胞在端粒酶抑制剂作用后的分子改变,探讨其抑制端粒酶活性的可能机制。结果如下:
1.实验结果显示正常细胞和癌细胞的拉曼光谱有明显的差异。根据光谱,可以看出细胞在癌变后,核酸、蛋白质、脂类等重要生物分子在结构或含量上都发生了不同的改变。在肝癌细胞SMMC-7721和鼻咽癌细胞CNE_2中核酸的含量大大增加,脂类物质明显减少。肝癌细胞的蛋白质二级结构、侧链氨基酸残基都发生了改变,分子间氢键受到破坏。用I_(1303)/I_(1336)的比值等于1.1来区分正常鼻咽部上皮细胞与鼻咽癌细胞的灵敏度、特异度
Cancer is one of the main diseases that threaten peoples' health and life at present. A great deal of clinical practice indicated that the development of cancer could be controlled through early diagnosis and valid treatment to improve the chance of survival. Raman spectrum is an effective method for analyzing substance structure .It can represent the differences of chemical composition and molecular constitution in the tumor cell at molecular level, and these differences may provide some important information for the diagnose of cancer and the analysis of canceration mechanism. Since the activation of telomerase has been found universally in human cancers and telomerase is the key for the existence of tumor cells and is also the necessary condition for the proliferation of tumor tissue, telomerase has been explored as a promising biomarker and target in cancer gene therapy. It is at the exploring stage to the research for regulatory mechanism of the telomerase activity, and the biochemical characteristic and antitumor mechanism of the telomerase inhibitors should be further researched.
In this thesis, unicell tweezers Raman spectroscopy is used to study the hepatocyte LO_2、hepatoma carcinoma cell SMMC-7721 and nasopharyngeal epithelial cell HBE、nasopharyngeal carcinoma cell CNE_2. Characteristic spectrum can be founded through the comparing and analyzing of the spectrum. To discuss the mechanism of telomerase inhibitors on cancer, hepatoma carcinoma cell SMMC-7721 and nasopharyngeal carcinoma cell CNE_2 treated by 8 telomerase inhibitors were studied. The molecule changes can be seen from the treated cancer cell. The main results are as follows:
1. Experimental results have demonstrated that Raman spectra of malignant cells were significantly different from those of normal cells. Biological molecules such as DNA, protein, lipid undergo a series of changes in content or structure .In hepatoma carcinoma cell SMMC-7721 and nasopharyngeal
本文利用单细胞光镊拉曼光谱技术研究人肝癌细胞SMMC-7721、正常肝细胞LO_2及人鼻咽癌细胞CNE2、正常鼻咽部上皮细胞HBE,通过光谱的对比分析,从而寻找反映癌变的特征标志光谱。应用多种端粒酶抑制剂作用于肝癌、鼻咽癌细胞,通过对比端粒酶抑制剂作用前后的拉曼光谱,可见细胞在端粒酶抑制剂作用后的分子改变,探讨其抑制端粒酶活性的可能机制。结果如下:
1.实验结果显示正常细胞和癌细胞的拉曼光谱有明显的差异。根据光谱,可以看出细胞在癌变后,核酸、蛋白质、脂类等重要生物分子在结构或含量上都发生了不同的改变。在肝癌细胞SMMC-7721和鼻咽癌细胞CNE_2中核酸的含量大大增加,脂类物质明显减少。肝癌细胞的蛋白质二级结构、侧链氨基酸残基都发生了改变,分子间氢键受到破坏。用I_(1303)/I_(1336)的比值等于1.1来区分正常鼻咽部上皮细胞与鼻咽癌细胞的灵敏度、特异度
Cancer is one of the main diseases that threaten peoples' health and life at present. A great deal of clinical practice indicated that the development of cancer could be controlled through early diagnosis and valid treatment to improve the chance of survival. Raman spectrum is an effective method for analyzing substance structure .It can represent the differences of chemical composition and molecular constitution in the tumor cell at molecular level, and these differences may provide some important information for the diagnose of cancer and the analysis of canceration mechanism. Since the activation of telomerase has been found universally in human cancers and telomerase is the key for the existence of tumor cells and is also the necessary condition for the proliferation of tumor tissue, telomerase has been explored as a promising biomarker and target in cancer gene therapy. It is at the exploring stage to the research for regulatory mechanism of the telomerase activity, and the biochemical characteristic and antitumor mechanism of the telomerase inhibitors should be further researched.
In this thesis, unicell tweezers Raman spectroscopy is used to study the hepatocyte LO_2、hepatoma carcinoma cell SMMC-7721 and nasopharyngeal epithelial cell HBE、nasopharyngeal carcinoma cell CNE_2. Characteristic spectrum can be founded through the comparing and analyzing of the spectrum. To discuss the mechanism of telomerase inhibitors on cancer, hepatoma carcinoma cell SMMC-7721 and nasopharyngeal carcinoma cell CNE_2 treated by 8 telomerase inhibitors were studied. The molecule changes can be seen from the treated cancer cell. The main results are as follows:
1. Experimental results have demonstrated that Raman spectra of malignant cells were significantly different from those of normal cells. Biological molecules such as DNA, protein, lipid undergo a series of changes in content or structure .In hepatoma carcinoma cell SMMC-7721 and nasopharyngeal
引文
[1] Stone N, Kendall C, Smith J, et al. Raman spectroscopy for identification of epithelial cancers. Faraday Discuss., 2004, 126: 141-157.
[2] Gniadecka M, Philipsen PA, Sigurdsson S, et al. Melanoma Diagnosis by Raman Spectroscopy and Neural Networks: Structure alterations in proteins and lipids in intact cancer tissue. The Journal of investigative in dermatology 122(2): 443-449.
[3] Yazdi Y ,Ramanujam N, Lotan R,et al. Resonance Raman Spectroscopy at 257 nm Excitation of Normal and Malignant Cultured Breast and Cervical Cells. Applide Spectroscopy 1999, 53 (1):82-85.
[4] Crow P , Stone N, Kendall CA, et al. The use of Raman spectroscopy to identify and grade prostatic adenocarcinoma in vitro. British Journal of Cancer 2003,89(1): 106 -108.
[5] Crow P, Uff JS, Farmer JA, et al. The use of Raman spectroscopy to identify and characterize transitional cell carcinoma in vitro. Bju international 2004, 93:1232-1236.
[6] Kubota Y, Nakada T, Sagawa I,et al.Elevated levels of telomerase Activity in malignant pheochromocytoma. Cancer. 1998,82 :176-179.
[7] Ying-An J, He-sheng L, Li-Fang F, et al. Effect of antisense oligodeoxynucleotide of telomerase RNA on telomerase activity and cell apoptosis in human colon cancer[J]. World J Gastroenterol, 2004, 10(3): 443-445.
[8] Yokoyama Y, Takahashi Y, Shinohara A, et al. Attenuation of telomerase activity by a hummerhed ribozyme targeting the template region of telomerase RNA in endometrial carcinoma cells[J]. Cancer Res. 1998, 58(23): 5406-5410.
[9] Feng J, Funf W D, Sy-shi Wang, et al. The RNA component of humantelomerase. Science. 1995, 270: 1663-1667.
[10] 徐亦庄. 分子光谱理论. 清华大学出版社. 1988:344
[11] 郑顺旋. 激光喇曼光谱学. 上海科学技术出版社.1999:11-35.
[12] Li WH, Xu YZ, Wang SF, et al.FT-Raman and FTIR studies on the Normal and Maligant Tissues. Chinese Journal of Light Scattering, 1998, 10(3): 114-116.
[13] Stone N, Kendall C, Shepherd N, et al. Near-infrared Raman spectroscopy for the classification of epithelial pre-cancers and cancers .Journal of Raman Spectroscopy, 2002, 33(7): 564-573.
[14] Xie CA, Li YQ. Confocal biological cell using optical trapping and shifted excitation difference techniques. Journal of Applied Physics, 2003, 93(5): 2982-2986.
[15] Xie CA, Li YQ, Tang W, et al. Study of dynamical process of heat denaturation in optically trapped single microorganisms by near infrared Raman spectroscopy. Journal of Applied Physics,2003, 94(9): 6138-6142.
[16] Ashkin A, Dziedzic JM, Bjorkholm JE, et al. Observation of a single-beam gradient force optical trap for dielectric particles. Optics Letters, 1986, 11(5): 288-290.
[17] Xie CA, Li YQ. Raman spectra and optical trapping of highly refractive and nontransparent particles. Applied Physics Letters, 2002, 81(6): 951-953.
[18] Benedetti E,Teodori L, Trinca ML, et al. New approach to the study of human Solid Tumor Cell by Means of FT-lR Microspectroscopy. Applied Spectroscopy, l990, 44(1): 276-283.
[19] Wong PT, Cadrin M, French SW, et al. Distinctive infrared spectral features in liver tumor tissues of mice: evidence of structural modifications at molecular level. Exp Mol Pathol, 1991, 55: 269-284.
[20] Ashkin A, Schutze K, Dziedzic JM. Force Generation of Organelle Transport Measured In Vivo by an Infrared Laser. Nature 1990, 348:346-348.
[21] Hayashi K, Hecht P, Thabit G, et al . The biologic response to laser thermal modification in an in vivo sheep model. Clin Orthop, 2000, (373):265-276.
[22] Imhoff A, Ledermann T. Arthroscopic subacromial decompression with and without the Holmium: YAG - laser. A prospective comparative study. Arthroscopy, 1995, 11(5): 549 - 556.
[23] 缪柏其,宁静,肖婕. 主成分分析和因子分析在体检数据中的应用. 数理统计与管理, 2000,6: 16-19.
[24] 肖云茹. 概率统计计算方法. 南开大学出版社, 1994: 295-317.
[25] Moyzis PK. Concervation of the human telomere sequence (TTAGGG)n among vertebrades. Proc Natl Acad Sci USA 1988, 85: 6622-6626.
[26] Morin BG. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGG repeats. Cell 1989, 59: 521.
[27] Suzuki Y, Zsemuru M. Inhibitiory effect of epigallocatechina gallate on adhesion of murine melanoma cells to lamimin. Cancer Lett, 2001, 173:15.
[28] Ying An J, He-sheng L, Li-Fang F, et al. Effect of antisense oligodeoxynucleotide of telomerase RNA on telomerase activity and cell apoptosis in human colon cancer. World J Gastroenterol, 2004, 10(3): 443-445.
[29] 刘柏林, 屈艺, 刘菽秋, 等. Ribozyme 抑制端粒酶活性的肿瘤基因治疗.中国科学(C 辑), 2002, 32(2): 159-164.
[30] 张素珍, 黄培春, 徐永, 等. 端粒酶正义及反义寡核苷酸对鼻咽癌细胞生长分化的影响. 癌症, 2002, 21(5): 493-497.
[31] 刘磊 ,李成荣, 孙来保, 等. 人端粒酶反转录酶催化亚基对肝母细胞瘤细胞株体外生物学特性的影响. 中华儿科杂志. 2004, 42(7): 481-484.
[32] Manfait M,Alix AJ,et a1.Interaction of adriamycin with DNA as studied by resonance Raman spectroscopy. Nucleic Acids Res,1982,10:3803-3816.
[1] Frank CJ, McCreery RL, Redd DC. Raman spectroscopy of normal and diseased human breast tissues . Analytical Chemistry. 1995, 67(5): 777-783.
[2] 姚淑霞,赵元黎,张录,等. 乳腺组织切片的拉曼光谱的研究. 河南预防医学杂志,2004,15(3): 132-134.
[3] 闫循领, 董瑞新, 王秋国,等. 乳腺癌病人单个细胞的 Raman 光谱. 光谱与光谱分析, 2005, 25(1): 58-61.
[4] Gniadecka M, Wulf HC, Nymark Mortensen N, et al. Diagnosis of basal cell carcinoma by Raman spectroscopy. Raman Spectroscopy, 1997, 28: 125-129.
[5] Gniadecka M, Wulf HC, Nielsen OF, et al. Distinctive molecular abnormalities in benign and malignant skin lesions studies by Raman spectroscopy. Photochem Photobiol, 1997, 66: 418-423.
[6] Nijssen A , Bakker Schut TC, Heule F, et al. Discriminating basal cell carcinoma form its surrounding tissue by Raman spectroscopy. Investigative Dermatology, 2002, 119(1): 64-69.
[7] Choi J, Choo J, Chung H, et al. Direct observation of spectral differences between normal and basal cell carcinoma (BBC) tissues using confocal Raman microscopy. Biopolymers, 2005, 77(5): 264-272.
[8] Gniadecka M, Philipsen PA, Sigurdsson S, et al. Melanoma diagnosis by Raman spectroscopy and neural networks :structure alterations in proteins and lipids in intact cancer tissue. Investigative Dermatology, 2004, 122(2): 443-449.
[9] Ling XF, Song YY, Soloway RD, et al. Fourier transform Raman spectra can separate most normal and malignant tissue. Gastroenterology, 2000, 118: A1398.
[10] 凌晓锋, 李维红, 宋苑苑, 等. 胃癌组织的拉曼光谱初探. 光谱学与光谱分析, 2000, 20: 692-693.
[11] Short KW, Carpenter S, Freyer JP, et al. Raman Spectroscopy Detects Biochemical Changes Due to Proliferation in Mammalian Cell Cultures. Biophysical Journal, 2005, 88(6): 4274-4288.
[12] 张京伟, 沈爱国, 魏芸, 等. 胃癌和胃正常黏膜拉曼光谱检测. 生物医学工程学杂志, 2004, 21(6): 910-912.
[13] Kendall C, Stone N, Shepherd N, et al. Raman spectroscopy, a potential tool for the objective identification and classification of neoplasia in Barrett’s oesophagus. Pathol, 2003, 200(5): 602-609.
[14] Lorincz A ,Haddad D, Naik R, et al. Raman spectroscopy for neoplastic tissue differentiation: a pilot study. Pediatr Surg, 2004, 39(6): 953-956.
[15] Feld M S, Manoharan R, Salenius J, et al. Detection and characterization of human tissue lesions with near-infrared Raman spectroscopy. Proc SPIE, 1995,2388:99-105.
[16] 闫循领, 王秋国, 董瑞新, 等. 结肠癌病人几种细胞的 Raman 光谱. 光谱与光谱分析, 2003, 23(6): 1129-1131.
[17] Yan XL, Dong RX , Zhang L, et al. Raman spectra of single cell from gastrointestinal cancer patients. World Journal of Gastroenterology, 2005,11(21): 3290-3292.
[18] Molckovsky A, Song LM, Shim MG, et al. Diagnostic potential of near-infrared Raman spectroscopy in the colon: differentiating adenomatous form hyperplastic polyps. Gastrointest Endosc, 2003, 57(3): 396-402.
[19] Mizuno A, Kitajima H, Kawauchi K, et al. Near-infrared Fourier transform Raman spectroscopic study of human brain tissues and tumors. Raman Spectrosc, 1994, 25: 25-29.
[20] Koljenovic S,Choo Smith LP, Bakker Schut TC, et al. Discriminating vital tumor form necrotic tissue in human glioblastoma tissue samples by Raman spectroscopy. Lab Invest, 2002, 82(10): 1265-1277.
[21] Stone N, Kendall C, Smith J, et al. Raman spectroscopy for identification ofepithelial cancers. Faraday Discuss, 2004, 126: 141-157.
[22] Crow P, Uff JS, Farmer JA, et al. The use of Raman spectroscopy to identify and characterize transitional cell carcinoma in vitro. Br J Urol Int, 2004, 93(9): 1232-1236.
[23] Crow P, Stone N, Kendall CA, et al. The use of Raman spectroscopy to identify and grade prostatic adenocarcinoma in vitro. Br J cancer, 2003, 89(1): 106-108.
[24] Mahadevan JA, Mitchell MF, Ramanujam N, et al. Near-infrared Raman spectroscopy for in vitro detection of cervical precancers[J]. Photochem Photobiol, 1998, 68(1): 123-132.
[25] Mahadevan JA, Mitchell MF, Ramanujam N, et al. Development of a fiber optic probe to measure NIR Raman spectra of cervical tissue in vivo. Photochem Photobiol, 1997, 66: 418-423.
[26] Utzinger U, Heintzelman.DL, Mahadevan JA, et al. Near-infrared Raman spectroscopy for in vivo detection of cervical precancers. Applied Spectroscopy, 2001, 25(8): 955-959.
[27] Huang Z, Mcwilliams A, Lui H, et al. Near-infrared Raman spectroscopy for optical diagnosis of lung cancer. Int J Cancer, 2003, 107(6):1047-1052.
[28] Yamazaki H, Kaminaka S, Kohda E, et al. The diagnosis of lung cancer using 1064-nm excited near-infrared multichannel Raman spectroscopy. Radiat Med, 2003, 21(1): 1-6
[29] Lau DP, Huang Z, Lui H, et al. Raman spectroscopy for optical diagnosis in normal and cancerous tissue of the nasopharynx-preliminary findings. Lasers Surg Med, 2003, 32(3): 210-214.
[30] Stone N, Stavroulaki P, Kendall C, et al. Raman spectroscopy for early detection of laryngeal malignancy: preliminary results. Laryngoscope, 2000, 110: 1756-1763.
[1] Gomez DE,Tejera AM, Olivero A. Ineversible telomere shortenics by 3'-azido-deoxythymidine (AZT) treatment. Biochem Biophys Res Commun. 1998, 246(1): 107.
[2] Allsopp RC, Vaziri H, Patterson C, et al. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA, 1992, 89: 10114-10118.
[3] Greider CW, Blackburn EH. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature, 1989, 337: 331-337.
[4] Kim NW. Specific association of human telomerase activity with immortal cells and cancer. Science, 1994, 266: 2011-2015.
[5] Kin NW. clinical implications of telomerase in cancer. Eur J Cancer,1997, 33(5): 781.
[6] Shay JW. Baccbetti S. A survey of telomerase activity in human cancer. Eur J Cancer, 1997, 33(5): 787.
[7] Chang JT, Liao CT, Jung SM, et al. Telomerase activity is frequently found in metaplastic and malignant human nasopharyngeal tissues. Br J Cancer, 2000, 82(12): 1946.
[8] Hiyama E, Hiyama K. Telomerase as tumor marker. Cancer Lett, 2003, 194(2): 221-233.
[9] Galderisi U, Cascino A,Giordano A, et a1. Antisense oligonucleorides as therapeutic agents. J Cell physio1, 1999,181:251-257.
[10] Feng J, Funk WD, Wang SS, et a1. The RNA component of human telomerase. Science, 1995,269(5228): 1236-1241.
[11] 张运涛,姜茹,刘利, 等. 端粒酶反义RNA对人肾癌细胞系GRC-1的生长的影响. 实用癌症杂志,2001,16(3): 233-235.
[12] Kondo Y,Kondo S,Tanaka Y,et a1. Inhibition of telomerase increases the susceptibility of human malignant glioblastoma cells to cisplatin-induced opoptosis. Oncogene, 1998, 16(17): 2243-2248.
[13] Herbert BS, Pongracz K, Shay JW, et al. Oligonucleotide N3'-5' phosphoramidates as efficent telomerase inhibitors. Oncongene, 2002, 21(4): 638-642.
[14] Gan Y, Mo Y,Johnston J, et a1. Telomere maintenance in telomerase positive human ovarian SKOV-3 cells cannot be retarded by complete inhibition of telomerase. FEBS Lett,2002,527(13): 10.
[15] Kondo S, Kondo Y, Li G,et al. Targeted therapy of human malignant glioma in a mouse model by 2-5A antisense directed against telomerase RNA. Oncogene,1998, 16(25): 3323-3330.
[16] Kushner DM, Paranjape JM, Bandyopadhyay B, et a1. 2-5A antisense directed against telomerase RNA produces apoptosis in ovarian cancer cells. Gyneco1 Oncal,2000,76(2): 183-192.
[17] Kondo Y, Koga S,Komata T, et a1. Treatment of prostate cancer in vitro and in vivo with 2-5A anti telomerase RNA component. Oncogene, 2000, 19(18): 2205-2211.
[18] Meta JE,Joshi SS,Palen B,et al. A hexameric phosphorothioate oligonucleotide telomerase inhibitor arreats growth of Burkitt’s lymphoma cells in vitro and vivo. Toxicol Appl Pharmacol, 1997, 144(1): 189-197.
[19] Wu Ning, Zhao W, Shi AP,et a1. Effect of antisense oligonucleotides of telomerase on the growth of RCZ cells derived from rena1 cel1 carcinoma in cuture. J.N. Bethune Univ. MED. SCI, 2000, 26 (1):32-34.
[20] Fontes JD,Jiang B,Peterlin BM. The class Ⅱ trans-activator CⅡ TA interacts with the TBP-associated factor TAFII 32. Nucleic Acids Res, 1997, 25(12): 2522-2528.
[21] Alama A,Barbieri F,Bottini F,et al. The use of antisense oligonucleotidesfor the therapy of cancer. Drugs Exp Clin Res, 1991, 17(12): 575-579.
[22] Norton JC, Piatyszek MA, Wright WE, et all. Inhibition of human telomerase activity by peptide nucleic acids. Nature Biotech, 1996, 14(5): 615-619.
[23] Hamilton SE, Simmons CG, Kathiriya IS, et a1. Cellular delivery of peptide nucleic-acids and inhibition of human telomerase. Chemistry & Biology, 1999, 6(6): 343-351.
[24] Kanazawa Y,ohkawa K, Ueda K, at al Hammerhead ribozyme mediated inhibition of telomerase activity in extracts of human hepatocellular carcinoma cells. Biochem Biophys Res Commun, 1996 225(2):570.
[25] Yokoyama Y, Takahashi Y, Shino hara A, et a1. Attenuation of telomerase activity by a haimmerhead ribozyme targeting the template region of telomerase RNA in endometrial carcinoma cell. Cancer Res, 1998, 58(23): 5406-5410.
[26] Wan MS, Fell PL, Akhtar S. Synthetic 2'-O-methy1 modified hammerhead ribozymed targeted to the RNA component of telomerase as sequence-specific inhibitors of telomerase activity. Antisense & Nucleic Acid Drug Develop, 1998,8(4): 309-317.
[27] 刘柏林,屈艺,刘菽秋,等. Ribozyme 抑制端粒酶活性的肿瘤基因治疗.中国科学(C 辑), 2002, 32(2): 159-164.
[28] 宋东坡,林菊生,傅桂莲,等.人端粒酶催化亚单位锤头状核酶诱导肝癌细胞凋亡的作用. 中华肝脏病杂志, 2004, 12(10): 616-619.
[29] 赵颖海, 陈小毅, John RA. 抗端粒酶核酶质粒的构建筛选及其对 CNE-2Z 细胞增殖与凋亡的影响. 癌症, 2004 ,23(1):50-55.
[30] 屈艺, 欧阳雪松, 刘菽秋, 等. 核酶抑制端粒酶活性的实验研究. 中华医学遗传学杂志, 1999, 16(3):133-137.
[31] 屈艺, 刘菽秋, 张朝良, 等. 端粒酶核酶抑制裸鼠抑制瘤生长的实验研究. 中华医学遗传学杂志, 1999, 16(6): 368-370.
[32] McEachern MJ,Blackburn EH Runaway telomere elongation caused by telomerase RNA gene mutation. Nature, 1995, 346: 403-407.
[33] Yu GL, Bradley JD, Attardi LD, et a1. In vivo alteration of telomere sequences and senescence caused by mutated tetrahymena telomerase RNAs. Nature, 1990, 344(8):126-132.
[34] Takakura M, Kyo S, Kanaya T, et al. Cloning of human telomerese catalytic subunit(hTERT) gene promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res, 1999, 59(3): 551-557.
[35] 徐萍端, 厉有名. 端粒酶抑制剂与肿瘤. 国外医学肿瘤学分册, 1998, 25(4):217-219.
[36] Strahl C, Blackburn EH. Effects of reverse transcriptase inhibitors on telomere length and telomerase activity in two immortalized human cell lines, Mol Cell Bio1, 1996, 16:53.
[37] Yegorov YE, Chemov DN,Akimov SS.Et al. Reverse transcriptase inbibitors suppress telomerase function and induce senescence like processes in cultured mouse fibroblases. FEBS Lert, 1996, 389:115.
[38] Melana SM, Holland JF, Pogo BG. Inhibition of cell growth and telomerase activity of breast cancer cells in vitro 3-azido-3-deoxythymidine. Clin Cancer Res, 1998, 4(3): 693—696.
[39] Murakami J, Nagai N, Shigemasa K, et a1. Inhibition of telomerase activity and cell proliferation by a reverse transcriptase inhibitor in gynaecological cancer lines. Eur J Cancer, 1999,35(6): 1027-1034.
[40] Fletcher TM, Salazar M, Chen SF. Human telomerase inhibition by 7-deaza-2-dexoxypurinnucleoside triphosphates. Biochemistry, 1996, 35(49): 15611-15617.
[41] Leszcynski D, Joenaara s, Foegh ML. Protein kinase C-alpha regulates pro1iferation but not apoptosis in rat coronary cascular muscle cells. LifeSci, 1996,58(7): 599-606.
[42] Ku Wu,Cheng Aj, Wang Tc.Inhibition of telomerase activity by PKC inhibitors in human nasopharyngeal cancer cells in culture. Bioehem Biophys Res Commun, 1997, 241(3): 730-736.
[43] Sato N,Mizumoto K,Kusumoto M,et a1. 9-Hydroxyellipticine inhibits telomerase activity in human pancreatic cancer cells. FEBS Lett, 1998, 441(2):3l8.
[44] Kang SS, Kang Sang Sun, Kwen Tuegun,et al. Protein Kinase Enhances Human Telomerase Activity throtIgh Phosphory1ation of Telomerase Reverse Transcriptase Subunit. Biol Chem,1999,274: 13085～13090.
[45] Sharma HW, Sokoloski JA, Perez JR, et al. Differentiation of immortal cells inhibits telomerase activity. Proc Natl Acad Sci, 1996, 92: 12343-12346.
[46] Bestilny LJ, Brown CB, Miura Y, et a1. Selective inhibition of telomerase activity during terminal differentiation of immortal cell line. Cancer Res, 1996, 56: 3796— 3802.
[47] Xu D, Gruber A, Peterson C, et a1. Supression of telomerase activity in HL60 cells after treatment with differentiating agents. Leukemia ,1996, 10(9): 1354-1357.
[48] 马东礼, 童善庆, 肖家祁, 等. 橄香烯对Hala细胞端粒酶催化亚单位基因表达的作用. 中国癌症杂志,2000,11(1): 9-13.
[49] Liu WH, Yung BY. Mortalization of human promyelocyte leukemia HL-60 cells to be more susceptible to sodium butyrate induced apoptosis and inhibition of telomerase activity by down-regulation of nucleophosmin/B23. Oncogene, 1998, 17(23): 3055-3064.
[50] Izbicka E, Wheelhouse RT, Raymond E, et a1. Effects of cationic porphyrins as G-quadruplex interactive agents in human tumor cells[J].Cancer Res, 1999, 59(3):639.
[51] Gowan SM,Harrison JR,Patterson L,et a1. A G-quadruplex-interactive potent small molecule inhibitor of telomerase exhibiting in vitro and in vivo antitumor activity. Mol Pharmacol, 2002, 61(5): l154—1162.
[52] Zhu X, Kumar R, Mandal M, et al. Cell cycle-dependent modulation of telomerase activity in tumor cells. Proc Natl Acad Sci USA, 1997, 93(12): 6091～6095.
[53] Holt SE, Aisner DL, Shay JW, et a1. Lack of cell cycle regulation of telomerase activity in human cel1. Proc Natl Acad Sci USA,1997 , 94 : 1086.
[54] Burger AM, Double JA,Newell DR. Inhibition of telomerase activity by cisplatin in human testicular cancer cells. Eur J Gancer, 1997, 33(4): 638.
[55] 孟志强, 于尔辛, 宋明志, 等. 化疗对人肝癌细胞SMMC-7721端粒酶活性细胞周期影响. 世界华人消化杂志, 1999, 7(3): 252—254.
[56] 张玲,王芸,毛海婷. 淫羊藿甙抑制肿瘤细胞端粒酶活性及其调节机制的研究. 中国免疫学杂志,2OO2,18(3): 191-194
[57] 陈泽雄,陈雯,彭俊生,等. 中药复方抗癌方抑制人结肠癌细胞株端粒酶活性. 中国胃肠外科杂志,1999,2(2): 117—118.
[58] 唐发清, 田道法, 陈朝晖. 益气解毒颗粒对大鼠鼻咽癌变中端粒酶和端粒酶RNA表达的影响. 湖南医科大学学报,2001,26(4): 301-304.
[59] 戴恩来,赵健雄,朱玉真,等. 扶正抑瘤汤对肿瘤细胞周期及端粒酶影响的实验研究. 中国中西医结合杂志,2001,21(10): 760-762.
[60] 盂志强,于尔辛, 宋明志, 等. 健脾理气中药对肝癌端粒酶括性的影响. 中国中医基础医学杂志,2000,6(1): 23—26.
[61] Mittal A, Pate MS, Wylie RC, et al. EGCG down-regulates telomerase in human breast carcinoma MCF-7 cells, leading to suppression of cell viability and induction of apoptosis. Int J Oncol, 2004, 24(3): 703-710.
[62] Yokoyama M, Noguchi M, Nakao Y, et al. The tea polyphenol- Epigallocatechin gallate effects on growth, apoptosis, and telomeraseactivity in cervical cell lines. Gynecol Oncol, 2004 , 92(1): 197-204.
[63]朱忠超,刘志苏,艾中立,表没食子儿茶素没食子酸酯诱导肿瘤细胞凋亡并伴随端粒酶活性下调武汉大学学报(医学版).2004,2566:663-666.
[64] Naasani I, Seimiya H, Yamori T,et a1. FJ5002: a potent telomerase inhibitor indentified by exploiting the disease - oriented screening program with compare analysis. Cancer Res,1999,59(16): 4 OO4-4Oll.
[65] Lee CC,Huang TS. A novel topoisomerase II poison GL331 preferentially induces DNA cleavage at (C/G)T sites and can cause telomere DNA damage. Pharm Res,2001,18(6): 846-851.
[66] Nernolo K,Kondo Y, Himeno S et al. Modulation of te1omerase activity by zinc in human prostatic and renal cancer cells. Biochemical pharmacology, 2000, 59(4): 401-405.
[67] Hernandez J, Garcia PF, Lone YC, et a1. Identification of a human telomerase reverse transcriplase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocytes and mediates lysis of tumor cells. Proc Natl Acad Sci USA, 2002, 99(19): 12275.
[68] SuZ, Vieweg J, Weizer AZ, et a1. Enhanced induction of telomerase- specific CD4(+) T cells using dendritic cells transfected with RNA encoding a chimeric gene product. Cancer Res,2002, 62(17): 5041.
[69] Leteurtre F, Li X,Guardiola P, et al. Telomerase activity during the cell cycle and in gamma-irradiated hematopoietic cells.Leukemia,1997, 11: 1681.
[70] Hyeon J0, Hande MP, Lansdrop OM, et a1. Induction of telomerase activity and chromosome aberrations in human tumor cell lines following X-irradiation. Mutat Res, 1998,401: 121.
[2] Gniadecka M, Philipsen PA, Sigurdsson S, et al. Melanoma Diagnosis by Raman Spectroscopy and Neural Networks: Structure alterations in proteins and lipids in intact cancer tissue. The Journal of investigative in dermatology 122(2): 443-449.
[3] Yazdi Y ,Ramanujam N, Lotan R,et al. Resonance Raman Spectroscopy at 257 nm Excitation of Normal and Malignant Cultured Breast and Cervical Cells. Applide Spectroscopy 1999, 53 (1):82-85.
[4] Crow P , Stone N, Kendall CA, et al. The use of Raman spectroscopy to identify and grade prostatic adenocarcinoma in vitro. British Journal of Cancer 2003,89(1): 106 -108.
[5] Crow P, Uff JS, Farmer JA, et al. The use of Raman spectroscopy to identify and characterize transitional cell carcinoma in vitro. Bju international 2004, 93:1232-1236.
[6] Kubota Y, Nakada T, Sagawa I,et al.Elevated levels of telomerase Activity in malignant pheochromocytoma. Cancer. 1998,82 :176-179.
[7] Ying-An J, He-sheng L, Li-Fang F, et al. Effect of antisense oligodeoxynucleotide of telomerase RNA on telomerase activity and cell apoptosis in human colon cancer[J]. World J Gastroenterol, 2004, 10(3): 443-445.
[8] Yokoyama Y, Takahashi Y, Shinohara A, et al. Attenuation of telomerase activity by a hummerhed ribozyme targeting the template region of telomerase RNA in endometrial carcinoma cells[J]. Cancer Res. 1998, 58(23): 5406-5410.
[9] Feng J, Funf W D, Sy-shi Wang, et al. The RNA component of humantelomerase. Science. 1995, 270: 1663-1667.
[10] 徐亦庄. 分子光谱理论. 清华大学出版社. 1988:344
[11] 郑顺旋. 激光喇曼光谱学. 上海科学技术出版社.1999:11-35.
[12] Li WH, Xu YZ, Wang SF, et al.FT-Raman and FTIR studies on the Normal and Maligant Tissues. Chinese Journal of Light Scattering, 1998, 10(3): 114-116.
[13] Stone N, Kendall C, Shepherd N, et al. Near-infrared Raman spectroscopy for the classification of epithelial pre-cancers and cancers .Journal of Raman Spectroscopy, 2002, 33(7): 564-573.
[14] Xie CA, Li YQ. Confocal biological cell using optical trapping and shifted excitation difference techniques. Journal of Applied Physics, 2003, 93(5): 2982-2986.
[15] Xie CA, Li YQ, Tang W, et al. Study of dynamical process of heat denaturation in optically trapped single microorganisms by near infrared Raman spectroscopy. Journal of Applied Physics,2003, 94(9): 6138-6142.
[16] Ashkin A, Dziedzic JM, Bjorkholm JE, et al. Observation of a single-beam gradient force optical trap for dielectric particles. Optics Letters, 1986, 11(5): 288-290.
[17] Xie CA, Li YQ. Raman spectra and optical trapping of highly refractive and nontransparent particles. Applied Physics Letters, 2002, 81(6): 951-953.
[18] Benedetti E,Teodori L, Trinca ML, et al. New approach to the study of human Solid Tumor Cell by Means of FT-lR Microspectroscopy. Applied Spectroscopy, l990, 44(1): 276-283.
[19] Wong PT, Cadrin M, French SW, et al. Distinctive infrared spectral features in liver tumor tissues of mice: evidence of structural modifications at molecular level. Exp Mol Pathol, 1991, 55: 269-284.
[20] Ashkin A, Schutze K, Dziedzic JM. Force Generation of Organelle Transport Measured In Vivo by an Infrared Laser. Nature 1990, 348:346-348.
[21] Hayashi K, Hecht P, Thabit G, et al . The biologic response to laser thermal modification in an in vivo sheep model. Clin Orthop, 2000, (373):265-276.
[22] Imhoff A, Ledermann T. Arthroscopic subacromial decompression with and without the Holmium: YAG - laser. A prospective comparative study. Arthroscopy, 1995, 11(5): 549 - 556.
[23] 缪柏其,宁静,肖婕. 主成分分析和因子分析在体检数据中的应用. 数理统计与管理, 2000,6: 16-19.
[24] 肖云茹. 概率统计计算方法. 南开大学出版社, 1994: 295-317.
[25] Moyzis PK. Concervation of the human telomere sequence (TTAGGG)n among vertebrades. Proc Natl Acad Sci USA 1988, 85: 6622-6626.
[26] Morin BG. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGG repeats. Cell 1989, 59: 521.
[27] Suzuki Y, Zsemuru M. Inhibitiory effect of epigallocatechina gallate on adhesion of murine melanoma cells to lamimin. Cancer Lett, 2001, 173:15.
[28] Ying An J, He-sheng L, Li-Fang F, et al. Effect of antisense oligodeoxynucleotide of telomerase RNA on telomerase activity and cell apoptosis in human colon cancer. World J Gastroenterol, 2004, 10(3): 443-445.
[29] 刘柏林, 屈艺, 刘菽秋, 等. Ribozyme 抑制端粒酶活性的肿瘤基因治疗.中国科学(C 辑), 2002, 32(2): 159-164.
[30] 张素珍, 黄培春, 徐永, 等. 端粒酶正义及反义寡核苷酸对鼻咽癌细胞生长分化的影响. 癌症, 2002, 21(5): 493-497.
[31] 刘磊 ,李成荣, 孙来保, 等. 人端粒酶反转录酶催化亚基对肝母细胞瘤细胞株体外生物学特性的影响. 中华儿科杂志. 2004, 42(7): 481-484.
[32] Manfait M,Alix AJ,et a1.Interaction of adriamycin with DNA as studied by resonance Raman spectroscopy. Nucleic Acids Res,1982,10:3803-3816.
[1] Frank CJ, McCreery RL, Redd DC. Raman spectroscopy of normal and diseased human breast tissues . Analytical Chemistry. 1995, 67(5): 777-783.
[2] 姚淑霞,赵元黎,张录,等. 乳腺组织切片的拉曼光谱的研究. 河南预防医学杂志,2004,15(3): 132-134.
[3] 闫循领, 董瑞新, 王秋国,等. 乳腺癌病人单个细胞的 Raman 光谱. 光谱与光谱分析, 2005, 25(1): 58-61.
[4] Gniadecka M, Wulf HC, Nymark Mortensen N, et al. Diagnosis of basal cell carcinoma by Raman spectroscopy. Raman Spectroscopy, 1997, 28: 125-129.
[5] Gniadecka M, Wulf HC, Nielsen OF, et al. Distinctive molecular abnormalities in benign and malignant skin lesions studies by Raman spectroscopy. Photochem Photobiol, 1997, 66: 418-423.
[6] Nijssen A , Bakker Schut TC, Heule F, et al. Discriminating basal cell carcinoma form its surrounding tissue by Raman spectroscopy. Investigative Dermatology, 2002, 119(1): 64-69.
[7] Choi J, Choo J, Chung H, et al. Direct observation of spectral differences between normal and basal cell carcinoma (BBC) tissues using confocal Raman microscopy. Biopolymers, 2005, 77(5): 264-272.
[8] Gniadecka M, Philipsen PA, Sigurdsson S, et al. Melanoma diagnosis by Raman spectroscopy and neural networks :structure alterations in proteins and lipids in intact cancer tissue. Investigative Dermatology, 2004, 122(2): 443-449.
[9] Ling XF, Song YY, Soloway RD, et al. Fourier transform Raman spectra can separate most normal and malignant tissue. Gastroenterology, 2000, 118: A1398.
[10] 凌晓锋, 李维红, 宋苑苑, 等. 胃癌组织的拉曼光谱初探. 光谱学与光谱分析, 2000, 20: 692-693.
[11] Short KW, Carpenter S, Freyer JP, et al. Raman Spectroscopy Detects Biochemical Changes Due to Proliferation in Mammalian Cell Cultures. Biophysical Journal, 2005, 88(6): 4274-4288.
[12] 张京伟, 沈爱国, 魏芸, 等. 胃癌和胃正常黏膜拉曼光谱检测. 生物医学工程学杂志, 2004, 21(6): 910-912.
[13] Kendall C, Stone N, Shepherd N, et al. Raman spectroscopy, a potential tool for the objective identification and classification of neoplasia in Barrett’s oesophagus. Pathol, 2003, 200(5): 602-609.
[14] Lorincz A ,Haddad D, Naik R, et al. Raman spectroscopy for neoplastic tissue differentiation: a pilot study. Pediatr Surg, 2004, 39(6): 953-956.
[15] Feld M S, Manoharan R, Salenius J, et al. Detection and characterization of human tissue lesions with near-infrared Raman spectroscopy. Proc SPIE, 1995,2388:99-105.
[16] 闫循领, 王秋国, 董瑞新, 等. 结肠癌病人几种细胞的 Raman 光谱. 光谱与光谱分析, 2003, 23(6): 1129-1131.
[17] Yan XL, Dong RX , Zhang L, et al. Raman spectra of single cell from gastrointestinal cancer patients. World Journal of Gastroenterology, 2005,11(21): 3290-3292.
[18] Molckovsky A, Song LM, Shim MG, et al. Diagnostic potential of near-infrared Raman spectroscopy in the colon: differentiating adenomatous form hyperplastic polyps. Gastrointest Endosc, 2003, 57(3): 396-402.
[19] Mizuno A, Kitajima H, Kawauchi K, et al. Near-infrared Fourier transform Raman spectroscopic study of human brain tissues and tumors. Raman Spectrosc, 1994, 25: 25-29.
[20] Koljenovic S,Choo Smith LP, Bakker Schut TC, et al. Discriminating vital tumor form necrotic tissue in human glioblastoma tissue samples by Raman spectroscopy. Lab Invest, 2002, 82(10): 1265-1277.
[21] Stone N, Kendall C, Smith J, et al. Raman spectroscopy for identification ofepithelial cancers. Faraday Discuss, 2004, 126: 141-157.
[22] Crow P, Uff JS, Farmer JA, et al. The use of Raman spectroscopy to identify and characterize transitional cell carcinoma in vitro. Br J Urol Int, 2004, 93(9): 1232-1236.
[23] Crow P, Stone N, Kendall CA, et al. The use of Raman spectroscopy to identify and grade prostatic adenocarcinoma in vitro. Br J cancer, 2003, 89(1): 106-108.
[24] Mahadevan JA, Mitchell MF, Ramanujam N, et al. Near-infrared Raman spectroscopy for in vitro detection of cervical precancers[J]. Photochem Photobiol, 1998, 68(1): 123-132.
[25] Mahadevan JA, Mitchell MF, Ramanujam N, et al. Development of a fiber optic probe to measure NIR Raman spectra of cervical tissue in vivo. Photochem Photobiol, 1997, 66: 418-423.
[26] Utzinger U, Heintzelman.DL, Mahadevan JA, et al. Near-infrared Raman spectroscopy for in vivo detection of cervical precancers. Applied Spectroscopy, 2001, 25(8): 955-959.
[27] Huang Z, Mcwilliams A, Lui H, et al. Near-infrared Raman spectroscopy for optical diagnosis of lung cancer. Int J Cancer, 2003, 107(6):1047-1052.
[28] Yamazaki H, Kaminaka S, Kohda E, et al. The diagnosis of lung cancer using 1064-nm excited near-infrared multichannel Raman spectroscopy. Radiat Med, 2003, 21(1): 1-6
[29] Lau DP, Huang Z, Lui H, et al. Raman spectroscopy for optical diagnosis in normal and cancerous tissue of the nasopharynx-preliminary findings. Lasers Surg Med, 2003, 32(3): 210-214.
[30] Stone N, Stavroulaki P, Kendall C, et al. Raman spectroscopy for early detection of laryngeal malignancy: preliminary results. Laryngoscope, 2000, 110: 1756-1763.
[1] Gomez DE,Tejera AM, Olivero A. Ineversible telomere shortenics by 3'-azido-deoxythymidine (AZT) treatment. Biochem Biophys Res Commun. 1998, 246(1): 107.
[2] Allsopp RC, Vaziri H, Patterson C, et al. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA, 1992, 89: 10114-10118.
[3] Greider CW, Blackburn EH. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature, 1989, 337: 331-337.
[4] Kim NW. Specific association of human telomerase activity with immortal cells and cancer. Science, 1994, 266: 2011-2015.
[5] Kin NW. clinical implications of telomerase in cancer. Eur J Cancer,1997, 33(5): 781.
[6] Shay JW. Baccbetti S. A survey of telomerase activity in human cancer. Eur J Cancer, 1997, 33(5): 787.
[7] Chang JT, Liao CT, Jung SM, et al. Telomerase activity is frequently found in metaplastic and malignant human nasopharyngeal tissues. Br J Cancer, 2000, 82(12): 1946.
[8] Hiyama E, Hiyama K. Telomerase as tumor marker. Cancer Lett, 2003, 194(2): 221-233.
[9] Galderisi U, Cascino A,Giordano A, et a1. Antisense oligonucleorides as therapeutic agents. J Cell physio1, 1999,181:251-257.
[10] Feng J, Funk WD, Wang SS, et a1. The RNA component of human telomerase. Science, 1995,269(5228): 1236-1241.
[11] 张运涛,姜茹,刘利, 等. 端粒酶反义RNA对人肾癌细胞系GRC-1的生长的影响. 实用癌症杂志,2001,16(3): 233-235.
[12] Kondo Y,Kondo S,Tanaka Y,et a1. Inhibition of telomerase increases the susceptibility of human malignant glioblastoma cells to cisplatin-induced opoptosis. Oncogene, 1998, 16(17): 2243-2248.
[13] Herbert BS, Pongracz K, Shay JW, et al. Oligonucleotide N3'-5' phosphoramidates as efficent telomerase inhibitors. Oncongene, 2002, 21(4): 638-642.
[14] Gan Y, Mo Y,Johnston J, et a1. Telomere maintenance in telomerase positive human ovarian SKOV-3 cells cannot be retarded by complete inhibition of telomerase. FEBS Lett,2002,527(13): 10.
[15] Kondo S, Kondo Y, Li G,et al. Targeted therapy of human malignant glioma in a mouse model by 2-5A antisense directed against telomerase RNA. Oncogene,1998, 16(25): 3323-3330.
[16] Kushner DM, Paranjape JM, Bandyopadhyay B, et a1. 2-5A antisense directed against telomerase RNA produces apoptosis in ovarian cancer cells. Gyneco1 Oncal,2000,76(2): 183-192.
[17] Kondo Y, Koga S,Komata T, et a1. Treatment of prostate cancer in vitro and in vivo with 2-5A anti telomerase RNA component. Oncogene, 2000, 19(18): 2205-2211.
[18] Meta JE,Joshi SS,Palen B,et al. A hexameric phosphorothioate oligonucleotide telomerase inhibitor arreats growth of Burkitt’s lymphoma cells in vitro and vivo. Toxicol Appl Pharmacol, 1997, 144(1): 189-197.
[19] Wu Ning, Zhao W, Shi AP,et a1. Effect of antisense oligonucleotides of telomerase on the growth of RCZ cells derived from rena1 cel1 carcinoma in cuture. J.N. Bethune Univ. MED. SCI, 2000, 26 (1):32-34.
[20] Fontes JD,Jiang B,Peterlin BM. The class Ⅱ trans-activator CⅡ TA interacts with the TBP-associated factor TAFII 32. Nucleic Acids Res, 1997, 25(12): 2522-2528.
[21] Alama A,Barbieri F,Bottini F,et al. The use of antisense oligonucleotidesfor the therapy of cancer. Drugs Exp Clin Res, 1991, 17(12): 575-579.
[22] Norton JC, Piatyszek MA, Wright WE, et all. Inhibition of human telomerase activity by peptide nucleic acids. Nature Biotech, 1996, 14(5): 615-619.
[23] Hamilton SE, Simmons CG, Kathiriya IS, et a1. Cellular delivery of peptide nucleic-acids and inhibition of human telomerase. Chemistry & Biology, 1999, 6(6): 343-351.
[24] Kanazawa Y,ohkawa K, Ueda K, at al Hammerhead ribozyme mediated inhibition of telomerase activity in extracts of human hepatocellular carcinoma cells. Biochem Biophys Res Commun, 1996 225(2):570.
[25] Yokoyama Y, Takahashi Y, Shino hara A, et a1. Attenuation of telomerase activity by a haimmerhead ribozyme targeting the template region of telomerase RNA in endometrial carcinoma cell. Cancer Res, 1998, 58(23): 5406-5410.
[26] Wan MS, Fell PL, Akhtar S. Synthetic 2'-O-methy1 modified hammerhead ribozymed targeted to the RNA component of telomerase as sequence-specific inhibitors of telomerase activity. Antisense & Nucleic Acid Drug Develop, 1998,8(4): 309-317.
[27] 刘柏林,屈艺,刘菽秋,等. Ribozyme 抑制端粒酶活性的肿瘤基因治疗.中国科学(C 辑), 2002, 32(2): 159-164.
[28] 宋东坡,林菊生,傅桂莲,等.人端粒酶催化亚单位锤头状核酶诱导肝癌细胞凋亡的作用. 中华肝脏病杂志, 2004, 12(10): 616-619.
[29] 赵颖海, 陈小毅, John RA. 抗端粒酶核酶质粒的构建筛选及其对 CNE-2Z 细胞增殖与凋亡的影响. 癌症, 2004 ,23(1):50-55.
[30] 屈艺, 欧阳雪松, 刘菽秋, 等. 核酶抑制端粒酶活性的实验研究. 中华医学遗传学杂志, 1999, 16(3):133-137.
[31] 屈艺, 刘菽秋, 张朝良, 等. 端粒酶核酶抑制裸鼠抑制瘤生长的实验研究. 中华医学遗传学杂志, 1999, 16(6): 368-370.
[32] McEachern MJ,Blackburn EH Runaway telomere elongation caused by telomerase RNA gene mutation. Nature, 1995, 346: 403-407.
[33] Yu GL, Bradley JD, Attardi LD, et a1. In vivo alteration of telomere sequences and senescence caused by mutated tetrahymena telomerase RNAs. Nature, 1990, 344(8):126-132.
[34] Takakura M, Kyo S, Kanaya T, et al. Cloning of human telomerese catalytic subunit(hTERT) gene promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res, 1999, 59(3): 551-557.
[35] 徐萍端, 厉有名. 端粒酶抑制剂与肿瘤. 国外医学肿瘤学分册, 1998, 25(4):217-219.
[36] Strahl C, Blackburn EH. Effects of reverse transcriptase inhibitors on telomere length and telomerase activity in two immortalized human cell lines, Mol Cell Bio1, 1996, 16:53.
[37] Yegorov YE, Chemov DN,Akimov SS.Et al. Reverse transcriptase inbibitors suppress telomerase function and induce senescence like processes in cultured mouse fibroblases. FEBS Lert, 1996, 389:115.
[38] Melana SM, Holland JF, Pogo BG. Inhibition of cell growth and telomerase activity of breast cancer cells in vitro 3-azido-3-deoxythymidine. Clin Cancer Res, 1998, 4(3): 693—696.
[39] Murakami J, Nagai N, Shigemasa K, et a1. Inhibition of telomerase activity and cell proliferation by a reverse transcriptase inhibitor in gynaecological cancer lines. Eur J Cancer, 1999,35(6): 1027-1034.
[40] Fletcher TM, Salazar M, Chen SF. Human telomerase inhibition by 7-deaza-2-dexoxypurinnucleoside triphosphates. Biochemistry, 1996, 35(49): 15611-15617.
[41] Leszcynski D, Joenaara s, Foegh ML. Protein kinase C-alpha regulates pro1iferation but not apoptosis in rat coronary cascular muscle cells. LifeSci, 1996,58(7): 599-606.
[42] Ku Wu,Cheng Aj, Wang Tc.Inhibition of telomerase activity by PKC inhibitors in human nasopharyngeal cancer cells in culture. Bioehem Biophys Res Commun, 1997, 241(3): 730-736.
[43] Sato N,Mizumoto K,Kusumoto M,et a1. 9-Hydroxyellipticine inhibits telomerase activity in human pancreatic cancer cells. FEBS Lett, 1998, 441(2):3l8.
[44] Kang SS, Kang Sang Sun, Kwen Tuegun,et al. Protein Kinase Enhances Human Telomerase Activity throtIgh Phosphory1ation of Telomerase Reverse Transcriptase Subunit. Biol Chem,1999,274: 13085～13090.
[45] Sharma HW, Sokoloski JA, Perez JR, et al. Differentiation of immortal cells inhibits telomerase activity. Proc Natl Acad Sci, 1996, 92: 12343-12346.
[46] Bestilny LJ, Brown CB, Miura Y, et a1. Selective inhibition of telomerase activity during terminal differentiation of immortal cell line. Cancer Res, 1996, 56: 3796— 3802.
[47] Xu D, Gruber A, Peterson C, et a1. Supression of telomerase activity in HL60 cells after treatment with differentiating agents. Leukemia ,1996, 10(9): 1354-1357.
[48] 马东礼, 童善庆, 肖家祁, 等. 橄香烯对Hala细胞端粒酶催化亚单位基因表达的作用. 中国癌症杂志,2000,11(1): 9-13.
[49] Liu WH, Yung BY. Mortalization of human promyelocyte leukemia HL-60 cells to be more susceptible to sodium butyrate induced apoptosis and inhibition of telomerase activity by down-regulation of nucleophosmin/B23. Oncogene, 1998, 17(23): 3055-3064.
[50] Izbicka E, Wheelhouse RT, Raymond E, et a1. Effects of cationic porphyrins as G-quadruplex interactive agents in human tumor cells[J].Cancer Res, 1999, 59(3):639.
[51] Gowan SM,Harrison JR,Patterson L,et a1. A G-quadruplex-interactive potent small molecule inhibitor of telomerase exhibiting in vitro and in vivo antitumor activity. Mol Pharmacol, 2002, 61(5): l154—1162.
[52] Zhu X, Kumar R, Mandal M, et al. Cell cycle-dependent modulation of telomerase activity in tumor cells. Proc Natl Acad Sci USA, 1997, 93(12): 6091～6095.
[53] Holt SE, Aisner DL, Shay JW, et a1. Lack of cell cycle regulation of telomerase activity in human cel1. Proc Natl Acad Sci USA,1997 , 94 : 1086.
[54] Burger AM, Double JA,Newell DR. Inhibition of telomerase activity by cisplatin in human testicular cancer cells. Eur J Gancer, 1997, 33(4): 638.
[55] 孟志强, 于尔辛, 宋明志, 等. 化疗对人肝癌细胞SMMC-7721端粒酶活性细胞周期影响. 世界华人消化杂志, 1999, 7(3): 252—254.
[56] 张玲,王芸,毛海婷. 淫羊藿甙抑制肿瘤细胞端粒酶活性及其调节机制的研究. 中国免疫学杂志,2OO2,18(3): 191-194
[57] 陈泽雄,陈雯,彭俊生,等. 中药复方抗癌方抑制人结肠癌细胞株端粒酶活性. 中国胃肠外科杂志,1999,2(2): 117—118.
[58] 唐发清, 田道法, 陈朝晖. 益气解毒颗粒对大鼠鼻咽癌变中端粒酶和端粒酶RNA表达的影响. 湖南医科大学学报,2001,26(4): 301-304.
[59] 戴恩来,赵健雄,朱玉真,等. 扶正抑瘤汤对肿瘤细胞周期及端粒酶影响的实验研究. 中国中西医结合杂志,2001,21(10): 760-762.
[60] 盂志强,于尔辛, 宋明志, 等. 健脾理气中药对肝癌端粒酶括性的影响. 中国中医基础医学杂志,2000,6(1): 23—26.
[61] Mittal A, Pate MS, Wylie RC, et al. EGCG down-regulates telomerase in human breast carcinoma MCF-7 cells, leading to suppression of cell viability and induction of apoptosis. Int J Oncol, 2004, 24(3): 703-710.
[62] Yokoyama M, Noguchi M, Nakao Y, et al. The tea polyphenol- Epigallocatechin gallate effects on growth, apoptosis, and telomeraseactivity in cervical cell lines. Gynecol Oncol, 2004 , 92(1): 197-204.
[63]朱忠超,刘志苏,艾中立,表没食子儿茶素没食子酸酯诱导肿瘤细胞凋亡并伴随端粒酶活性下调武汉大学学报(医学版).2004,2566:663-666.
[64] Naasani I, Seimiya H, Yamori T,et a1. FJ5002: a potent telomerase inhibitor indentified by exploiting the disease - oriented screening program with compare analysis. Cancer Res,1999,59(16): 4 OO4-4Oll.
[65] Lee CC,Huang TS. A novel topoisomerase II poison GL331 preferentially induces DNA cleavage at (C/G)T sites and can cause telomere DNA damage. Pharm Res,2001,18(6): 846-851.
[66] Nernolo K,Kondo Y, Himeno S et al. Modulation of te1omerase activity by zinc in human prostatic and renal cancer cells. Biochemical pharmacology, 2000, 59(4): 401-405.
[67] Hernandez J, Garcia PF, Lone YC, et a1. Identification of a human telomerase reverse transcriplase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocytes and mediates lysis of tumor cells. Proc Natl Acad Sci USA, 2002, 99(19): 12275.
[68] SuZ, Vieweg J, Weizer AZ, et a1. Enhanced induction of telomerase- specific CD4(+) T cells using dendritic cells transfected with RNA encoding a chimeric gene product. Cancer Res,2002, 62(17): 5041.
[69] Leteurtre F, Li X,Guardiola P, et al. Telomerase activity during the cell cycle and in gamma-irradiated hematopoietic cells.Leukemia,1997, 11: 1681.
[70] Hyeon J0, Hande MP, Lansdrop OM, et a1. Induction of telomerase activity and chromosome aberrations in human tumor cell lines following X-irradiation. Mutat Res, 1998,401: 121.