人端粒酶逆转录酶启动子的调控及其诱导肿瘤靶向自杀基因治疗
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摘要
肿瘤自杀基因治疗是一种较为有效和具有临床应用潜力的治疗策略。目前肿瘤基因治疗面临的最大问题是基因的靶向性问题，自杀基因治疗也不例外。利用肿瘤特异性表达蛋白的肿瘤专一性基因表达调控序列驱动自杀基因，可望实现自杀基因在肿瘤细胞中的专一性表达，从而提高基因治疗的安全性和有效性。
近年研究表明，端粒酶可能是目前所见到的特异性较好的一种广泛的肿瘤新标志物。在正常体细胞中其活性受严格调控，在生理条件下，正常细胞大都没有端粒酶活性表达；而在90％以上的肿瘤细胞中有高水平表达，并且其活性高低与肿瘤恶化程度有关。人端粒酶逆转录酶(human telomerase reverse transcriptase,hTERT)是端粒酶复合物的核心成分，是细胞调控端粒酶活性的关键环节。癌变细胞中端粒酶重新激活的一个重要因素是由于hTERT基因在转录水平上被组成型激活造成的，研究表明这是由于癌变细胞中形成了一套不同于正常细胞的基因组表达调控模式，癌细胞表达出肿瘤特异性的转录因子，从而导致hTERT启动子活性在肿瘤细胞和正常细胞中的显著差异。已有的研究发现在转录起始位点上游约181bp片段包含有核心启动子序列，该序列对hTERT基因的表达和端粒酶活性起关键作用，它足以启动下游外源基因的表达同时仍保留其肿瘤专一活性。本研究克隆了包含该核心启动子序列的hTERT调控序列，对其肿瘤细胞专一活性进行了检测，并对其顺式调控元件Ebox和转录因子c-Myc进行了初步探讨；然后用该启动子驱动大肠杆菌
胞啼锭脱氨基酶（E colt cytosine deaminase，CD）基因，通过对人结直肠
癌细胞的体内外杀伤对其靶向治疗肿瘤的可行性进行了探讨。
研究结果表明：克隆的hTERT启动子（－378＋78）活性与端粒酶活
性密切相关，具有显著的肿瘤相关性，其在7种不同来源的肿瘤细胞中
活性升高，而在正常细胞中活性很低，这与国外文献报道的结果一致。
此外，位于l 位点的E bOX缺失（么MyCI）使hTERT启动子在细胞
中的转录效率大大降低，其中 Hela细胞下降了 70％，A549和 LoVo细胞
中下降了60％，提示此E b。x对启动子活性是必不可少的：有趣的是，
位于＋44位点的 E bOX缺失（凸MyCZ）对启动子在 A549和 LOVo细胞中
的转录活性几乎没有影响，然而在Hela细胞中却降低了3倍，表明此E
b。X的作用是细胞类型依赖性的。这在类似研究中为首次报道。凝胶滞
后实验显示在 LOVo细胞中 C－MyC与 E bOX 乙 165）结合能力较强，而
与 E box（＋44）结合能力较弱，提示 E box作用与其与 c－Myc的结合能
力有关。Western blot结果发现，hTERT启动子具有高转录活性的肿瘤细
胞Bcapl7、Hela显示高表达的c－Myc，而转录活性相对较低的A549细
胞其 C－MyC表达也较低，正常细胞 WI3 8则只能检测到极微量的 C－MyC
的表达，表明C－MyC的表达与hTERT启动子的转录水平具有相关性。这
些结果提示C－MyC作用于 hTERT启动子的）I顾式调控元件 E bOX参与启动
子活性的调控。
基于上述结果设计构建了hTERT启动于控制下的CD基因表达质粒
phTERT（D，结果显示，hTERT启动子控制下CD基因的表达使肿瘤细
胞LoVo对原药SFC的敏感性提高了800倍以上，同时具有明显的旁杀
伤效应；而正常细胞WISH仅提高了6倍，且对低于血药安全浓度
O70uM）的SFC不敏感。动物实验显示体内具有明显的抑制肿瘤效应。
这些结果表明hTERT－CD／SFC系统在体内外均具有显著的抑瘤效果，且
具有高度的肿瘤特异性。这在国内外为首次报道，为肿瘤靶向基因治疗
提供了一种很有希望的途径。
Suicide gene therapy has been recognized as an effective strategy for cancer treatment with potential application in clinic. Nowadays the major problems encountered tumor gene therapy is the specific expression of the therapeutic genes in cancer cells,including suicide gene therapy. Utilizing the expression regulation sequences of a gene encoding a tumor-specific protein to drive the suicide gene may be promising to restrict the expression of the therapeutic gene in tumor cells,thus to improve the safety and effect of gene therapy.
Recently,telomerase has been recognized as a new wide-range tumor marker. Telomerase is silent in normal cells but active in more than 90% of cancers and correlates well with the degree of malignancy. The core component of telomerase-human telomerase reverse transcriptase (hTERT) is a key determinant of telomerase activity. Further research has demonstrated that one important reason for telomerase reactivation is that hTERT is constitutively activated at the transcriptional level. It is reported that in cancer cells,there has been forming a set of genomic expression model different from normal cells,leading to activation and expression of some specific transcription factors in cancer cells,thus resulting in the significant discrepancy in hTERT promoter activity between tumor and normal cells. Recent studies also found that the 5'-flanking sequences containing the region of 181bp upstream the transcription start site functions as a core promoter,which is sufficient to drive the expression of downstream exotic
gene and retain its tumor specificity. In the present study,the hTERT regulation sequence containing the core promoter region is cloned and its tumor specificity is studied,and the cw-element of E box and the c-Myc transcription factor are also preliminary studied;and then the hTERT promoter was used to induce the expression of cytosine deaminase (CD) suicide gene,and the feasibility was tested in cancer gene therapy.
Our results showed that:the hTERT promoter (-378-+78) we cloned correlated with the telomerase activity,both of which showed high tumor specificity. They were upregulated in seven tumor cells tested,but repressed in normal cells,which was consistent with the results reported by other independent studies. Furthermore,the transcription activity of the hTERT promoter containing the deletion of the E box at -165 was greatly decreased,with 70%,60% and 60% decrease in HeLa,A549 and LoVo cells respectively,indicating that this E box (-165) is indispensible for the promoter activity. Interestingly,the activity of the promoter containing the deletion of the E box at +44 site did not show any changes in A549 and LoVo cells,but was 3-fold decreased in Hela cells,indicating that the role of this E box (+44) depends on cell type. These results were first reported in similar studies. EMS A showed that the activity of c-Myc binding to E box (-165) was stronger than that of binding to E box (+44),suggesting that the role of the E box is correlated to the binding activity of c-Myc. By Western blot,higher expression of c-Myc is observed in Bcap-37 Hela cells with higher hTERT promoter activity and lower expression of c-Myc in A549 with lower hTERT promoter,while weak expression of c-Myc is found in normal cells WI38,indicating the high correlation of c-Myc expression and hTERT transcription activity. These results suggested that the effect of c-Myc through its target element E box may involved in the regulation of hTERT promoter.
Based on the above results,an expression plasmid,phTERT-CD,was constructed,in which the E. coli. cytosine deaminase (CD) gene was controlled by the hTERT promoter. A colorectal cancer cell line (LoVo) and a
normal amnion cell line (WISH) were transfected by this plasmid. It was shown that the expression of the CD gene increased the sensitivity of LoVo cells to the prodrug,5-fluorocytosine (5FC),over 800 folds,and a strong "bystander effect" was also observed;while the sensitivity of WISH cells to 5FC was increased only 6 folds with no se
近年研究表明，端粒酶可能是目前所见到的特异性较好的一种广泛的肿瘤新标志物。在正常体细胞中其活性受严格调控，在生理条件下，正常细胞大都没有端粒酶活性表达；而在90％以上的肿瘤细胞中有高水平表达，并且其活性高低与肿瘤恶化程度有关。人端粒酶逆转录酶(human telomerase reverse transcriptase,hTERT)是端粒酶复合物的核心成分，是细胞调控端粒酶活性的关键环节。癌变细胞中端粒酶重新激活的一个重要因素是由于hTERT基因在转录水平上被组成型激活造成的，研究表明这是由于癌变细胞中形成了一套不同于正常细胞的基因组表达调控模式，癌细胞表达出肿瘤特异性的转录因子，从而导致hTERT启动子活性在肿瘤细胞和正常细胞中的显著差异。已有的研究发现在转录起始位点上游约181bp片段包含有核心启动子序列，该序列对hTERT基因的表达和端粒酶活性起关键作用，它足以启动下游外源基因的表达同时仍保留其肿瘤专一活性。本研究克隆了包含该核心启动子序列的hTERT调控序列，对其肿瘤细胞专一活性进行了检测，并对其顺式调控元件Ebox和转录因子c-Myc进行了初步探讨；然后用该启动子驱动大肠杆菌
胞啼锭脱氨基酶（E colt cytosine deaminase，CD）基因，通过对人结直肠
癌细胞的体内外杀伤对其靶向治疗肿瘤的可行性进行了探讨。
研究结果表明：克隆的hTERT启动子（－378＋78）活性与端粒酶活
性密切相关，具有显著的肿瘤相关性，其在7种不同来源的肿瘤细胞中
活性升高，而在正常细胞中活性很低，这与国外文献报道的结果一致。
此外，位于l 位点的E bOX缺失（么MyCI）使hTERT启动子在细胞
中的转录效率大大降低，其中 Hela细胞下降了 70％，A549和 LoVo细胞
中下降了60％，提示此E b。x对启动子活性是必不可少的：有趣的是，
位于＋44位点的 E bOX缺失（凸MyCZ）对启动子在 A549和 LOVo细胞中
的转录活性几乎没有影响，然而在Hela细胞中却降低了3倍，表明此E
b。X的作用是细胞类型依赖性的。这在类似研究中为首次报道。凝胶滞
后实验显示在 LOVo细胞中 C－MyC与 E bOX 乙 165）结合能力较强，而
与 E box（＋44）结合能力较弱，提示 E box作用与其与 c－Myc的结合能
力有关。Western blot结果发现，hTERT启动子具有高转录活性的肿瘤细
胞Bcapl7、Hela显示高表达的c－Myc，而转录活性相对较低的A549细
胞其 C－MyC表达也较低，正常细胞 WI3 8则只能检测到极微量的 C－MyC
的表达，表明C－MyC的表达与hTERT启动子的转录水平具有相关性。这
些结果提示C－MyC作用于 hTERT启动子的）I顾式调控元件 E bOX参与启动
子活性的调控。
基于上述结果设计构建了hTERT启动于控制下的CD基因表达质粒
phTERT（D，结果显示，hTERT启动子控制下CD基因的表达使肿瘤细
胞LoVo对原药SFC的敏感性提高了800倍以上，同时具有明显的旁杀
伤效应；而正常细胞WISH仅提高了6倍，且对低于血药安全浓度
O70uM）的SFC不敏感。动物实验显示体内具有明显的抑制肿瘤效应。
这些结果表明hTERT－CD／SFC系统在体内外均具有显著的抑瘤效果，且
具有高度的肿瘤特异性。这在国内外为首次报道，为肿瘤靶向基因治疗
提供了一种很有希望的途径。
Suicide gene therapy has been recognized as an effective strategy for cancer treatment with potential application in clinic. Nowadays the major problems encountered tumor gene therapy is the specific expression of the therapeutic genes in cancer cells,including suicide gene therapy. Utilizing the expression regulation sequences of a gene encoding a tumor-specific protein to drive the suicide gene may be promising to restrict the expression of the therapeutic gene in tumor cells,thus to improve the safety and effect of gene therapy.
Recently,telomerase has been recognized as a new wide-range tumor marker. Telomerase is silent in normal cells but active in more than 90% of cancers and correlates well with the degree of malignancy. The core component of telomerase-human telomerase reverse transcriptase (hTERT) is a key determinant of telomerase activity. Further research has demonstrated that one important reason for telomerase reactivation is that hTERT is constitutively activated at the transcriptional level. It is reported that in cancer cells,there has been forming a set of genomic expression model different from normal cells,leading to activation and expression of some specific transcription factors in cancer cells,thus resulting in the significant discrepancy in hTERT promoter activity between tumor and normal cells. Recent studies also found that the 5'-flanking sequences containing the region of 181bp upstream the transcription start site functions as a core promoter,which is sufficient to drive the expression of downstream exotic
gene and retain its tumor specificity. In the present study,the hTERT regulation sequence containing the core promoter region is cloned and its tumor specificity is studied,and the cw-element of E box and the c-Myc transcription factor are also preliminary studied;and then the hTERT promoter was used to induce the expression of cytosine deaminase (CD) suicide gene,and the feasibility was tested in cancer gene therapy.
Our results showed that:the hTERT promoter (-378-+78) we cloned correlated with the telomerase activity,both of which showed high tumor specificity. They were upregulated in seven tumor cells tested,but repressed in normal cells,which was consistent with the results reported by other independent studies. Furthermore,the transcription activity of the hTERT promoter containing the deletion of the E box at -165 was greatly decreased,with 70%,60% and 60% decrease in HeLa,A549 and LoVo cells respectively,indicating that this E box (-165) is indispensible for the promoter activity. Interestingly,the activity of the promoter containing the deletion of the E box at +44 site did not show any changes in A549 and LoVo cells,but was 3-fold decreased in Hela cells,indicating that the role of this E box (+44) depends on cell type. These results were first reported in similar studies. EMS A showed that the activity of c-Myc binding to E box (-165) was stronger than that of binding to E box (+44),suggesting that the role of the E box is correlated to the binding activity of c-Myc. By Western blot,higher expression of c-Myc is observed in Bcap-37 Hela cells with higher hTERT promoter activity and lower expression of c-Myc in A549 with lower hTERT promoter,while weak expression of c-Myc is found in normal cells WI38,indicating the high correlation of c-Myc expression and hTERT transcription activity. These results suggested that the effect of c-Myc through its target element E box may involved in the regulation of hTERT promoter.
Based on the above results,an expression plasmid,phTERT-CD,was constructed,in which the E. coli. cytosine deaminase (CD) gene was controlled by the hTERT promoter. A colorectal cancer cell line (LoVo) and a
normal amnion cell line (WISH) were transfected by this plasmid. It was shown that the expression of the CD gene increased the sensitivity of LoVo cells to the prodrug,5-fluorocytosine (5FC),over 800 folds,and a strong "bystander effect" was also observed;while the sensitivity of WISH cells to 5FC was increased only 6 folds with no se
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Kanaya T, Kyo S, Hamada K, Takakura M, Kitagawa Y, Harada H, Inoue M. Adenoviral expression of p53 represses telomerase activity through down-regulation of human telomerase reverse transcriptase transcription. Clin Cancer Res. 2000 Apr;6(4):1239-47.
Kyo S, Kunimi K, Uchibayashi T, Namiki M, Inoue M. Telomerase activity in human urothelial tumors. Am J Clin Pathol.1997 May;107(5):555-60.
Kyo S, Takakura M, Taira T, Kanaya T, Itoh H, Yutsudo M, Ariga H, Inoue M. Spl cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene(hTERT). Nucleic Acids Res. 2000 Feb 1;28(3):669-77.
Lee SE, Jin RJ, Lee SG, Yoon SJ, Park MS, Heo DS, Choi H. Development of a new plasmid vector with PSA-promoter and enhancer expressing tissue-specificity in prostate carcinoma cell lines. Anticancer Res. 2000 Jan-Feb;20(1A):417-22.
Majumdar AS, Hughes DE, Lichtsteiner SP, Wang Z, Lebkowski JS, Vasserot AP. The telomerase reverse transcriptase promoter drives efficacious tumor suicide gene therapy while preventing hepatotoxicity encountered with constitutive promoters.Gene Ther. 2001 Apr;8(7):568-78.
Manome Y, Wen PY, Chen L, Tanaka T, Dong Y, Yamazoe M, Hirshowitz A, Kufe DW,Fine HA. Gene therapy for malignant gliomas using replication incompetent retroviral and adenovirai vectors encoding the cytochrome P450 2B1 gene together with cyclophosphamide. Gene Ther. 1996 Jun;3(6):513-20.
Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddie SD, Ziaugra L,Beijersbergen RL, Davidoff MJ, Liu Q, Bacchetti S, Haber DA, Weinberg RA. hEST2,the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell. 1997 Aug 22;90(4):785-95.
Misiti S, Nanni S, Fontemaggi G, Cong YS, Wen J, Hirte HW, Piaggio G, Sacchi A, Pontecorvi A, Bacchetti S, Farsetti A.Induction of hTERT expression and telomerase activity by estrogens in human ovary epithelium cells. Mol Cell Biol. 2000 Jun;20(11):3764-71.
Mullen CA, Coale MM, Lowe R, Blaese RM. Tumors expressing the cytosine deaminase suicide gene can be eliminated in vivo with 5-fluorocytosine and induce protective immunity to wild type tumor. Cancer Res. 1994 Mar 15;54(6):1503-6.
Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, Harley CB, Cech TR. Telomerase catalytic subunit homologs from fission yeast and human.Science. 1997 Aug 15;277(5328):955-9.
Nakamura TM, Cech TR. Reversing time: origin of telomerase. Cell. 1998 Mar 6;92(5):587-90. Review.
Nakayama J, Saito M, Nakamura H, Matsuura A, Ishikawa F. TLP1: a gene encoding a protein component of mammalian telomerase is a novel member of WD repeats family.Cell. 1997 Mar 21;88(6):875-84.
Nakayama J, Tahara H, Tahara E, Saito M, Ito K, Nakamura H, Nakanishi T, Tahara E,Ide T, Ishikawa F.Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas. Nat Genet. 1998 Jan;18(1):65-8.
Nettelbeck DM, Jerome V, Muller R. A strategy for enhancing the transcriptional activity of weak cell type-specific promoters. Gene Ther. 1998 Dec;5(12):1656-64.
Oh S, Song YH, Kim UJ, Yim J, Kim TK. In vivo and in vitro analyses of Myc for differential promoter activities of the human telomerase(hTERT)gene in normal and tumor cells. Biochem Biophys Res Commun. 1999 Sep 24;263(2):361-5.
Oh S, Song Y, Yim J, Kim TK. The Wilms' tumor 1 tumor suppressor gene represses transcription of the human telomerase reverse transcriptase gene. J Biol Chem. 1999 Dec 24;274(52):37473-8.
Pope IM, Poston GJ, Kinsella AR. The role of the bystander effect in suicide gene therapy. Eur J Cancer. 1997 Jun;33(7):1005-16. Review.
Rogulski KR, Kim JH, Kim SH, Freytag SO. Glioma cells transduced with an Escherichia coli CD/HSV-1 TK fusion gene exhibit enhanced metabolic suicide and radiosensitivity. Hum Gene Ther. 1997 Jan 1;8(1):73-85.
Ross G, Erickson R, Knorr D, Motulsky AG, Parkman R, Samulski J, Straus SE, Smith BR. Gene therapy in the United States: a five-year status report. Hum Gene Ther. 1996 Sep 10;7(14):1781-90. No abstract available.
Sato N, Wang S, Li L, Okabe K, Hashimoto M, Yaginuma H, Mikoshiba K, Uchiyama Y,Uetsuki T, Yoshikawa K, Milligan CE, Oppenheim RW. A novel strategy for introducing exogenous bcl-2 into neuronal cells: the Cre/loxP system-mediated activation of bcl-2 for preventing programmed cell death using recombinant adenoviruses. Mol Cell Neurosci. 1998 Sep;12(1-2):65-78.
Segawa T, Takebayashi H, Kakehi Y, Yoshida O, Narumiya S, Kakizuka A.Prostate-specific amplification of expanded polyglutamine expression: a novel approach for cancer gene therapy. Cancer Res. 1998 Jun 1;58(11):2282-7.
Shay JW, Wright WE. The reactivation of telomerase activity in cancer progression.Trends Genet. 1996 Apr; 12(4): 129-31. Review.
Shay JW, Wright WE. Telomeres and telomerase: implications for cancer and aging.Radiat Res. 2001 Jan;155(1 Pt 2):188-193. Review.
Spencer CA, Groudine M, Control of c-myc regulation in normal and neoplastic cells.Adv Cancer Res. 1991;56:1-48. Review.
Stewart SA, Weinberg RA. Telomerase and human tumorigenesis. Semin Cancer Biol.2000 Dec;10(6):399-406. Review.
Takakura M, Kyo S, Kanaya T, Hirano H, Takeda J, Yutsudo M, Inoue M. Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res. 1999 Feb 1;59(3):551-7.
Trinh QT, Austin EA, Murray DM, Knick VC, Huber BE. Enzyme/prodrug gene therapy:comparison of cytosine deaminase/5-fluorocytosine versus thymidine kinase/ganciclovir enzyme/prodrug systems in a human colorectal carcinoma cell line. Cancer Res. 1995 Nov 1;55(21):4808-12.
Ulaner GA, Hu JF, Vu TH, Giudice LC, Hoffman AR. Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts. Cancer Res. 1998 Sep 15;58(18):4168-72.
Weinrich SL, Pruzan R, Ma L, Ouellette M, Tesmer VM, Holt SE, Bodnar AG,Lichtsteiner S, Kim NW, Trager JB, Taylor RD, Carlos R, Andrews WH, Wright WE,Shay JW, Harley CB, Morin GB. Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat Genet. 1997 Dec;17(4):498-502.
Weng NP, Levine BL, June CH, Hodes RJ. Regulated expression of telomerase activity in human T lymphocyte development and activation. J Exp Med.1996 Jun 1;183(6):2471-9.
Wu KJ, Grandori C, Amacker M, Simon-Vermot N, Polack A, Lingner J, Dalla-Favera R.Direct activation of TERT transcription by c-MYC. Nat Genet. 1999 Feb;21(2):220-4.
汤钊猷等，现代肿瘤学，1993年第一版，上海，上海医科大学出版社。
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Komata T, Kondo Y, Kanzawa T, Hirohata S, Koga S, Sumiyoshi H, Srinivasula SM,Barna BP, Germano IM, Takakura M, Inoue M, Alnemri ES, Shay JW, Kyo S, Kondo S.Treatment of malignant glioma cells with the transfer of constitutively active caspase-6 using the human telomerase catalytic subunit(human telomerase reverse transcriptase)gene promoter.Cancer Res.2001 Aug 1;61(15):5796-802.
Komata T, Koga S, Hirohata S, Takakura M, Germano IM, Inoue M, Kyo S, Kondo S,Kondo Y.A novel treatment of human malignant gliomas in vitro and in vivo: FADD gene transfer under the control of the human telomerase reverse transcriptase gene promoter, Int J Oncol. 2001 Nov;19(5):1015-20.
Kanaya T, Kyo S, Hamada K, Takakura M, Kitagawa Y, Harada H, Inoue M. Adenoviral expression of p53 represses telomerase activity through down-regulation of human telomerase reverse transcriptase transcription. Clin Cancer Res. 2000 Apr;6(4):1239-47.
Kyo S, Kunimi K, Uchibayashi T, Namiki M, Inoue M. Telomerase activity in human urothelial tumors. Am J Clin Pathol.1997 May;107(5):555-60.
Kyo S, Takakura M, Taira T, Kanaya T, Itoh H, Yutsudo M, Ariga H, Inoue M. Spl cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene(hTERT). Nucleic Acids Res. 2000 Feb 1;28(3):669-77.
Lee SE, Jin RJ, Lee SG, Yoon SJ, Park MS, Heo DS, Choi H. Development of a new plasmid vector with PSA-promoter and enhancer expressing tissue-specificity in prostate carcinoma cell lines. Anticancer Res. 2000 Jan-Feb;20(1A):417-22.
Majumdar AS, Hughes DE, Lichtsteiner SP, Wang Z, Lebkowski JS, Vasserot AP. The telomerase reverse transcriptase promoter drives efficacious tumor suicide gene therapy while preventing hepatotoxicity encountered with constitutive promoters.Gene Ther. 2001 Apr;8(7):568-78.
Manome Y, Wen PY, Chen L, Tanaka T, Dong Y, Yamazoe M, Hirshowitz A, Kufe DW,Fine HA. Gene therapy for malignant gliomas using replication incompetent retroviral and adenovirai vectors encoding the cytochrome P450 2B1 gene together with cyclophosphamide. Gene Ther. 1996 Jun;3(6):513-20.
Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddie SD, Ziaugra L,Beijersbergen RL, Davidoff MJ, Liu Q, Bacchetti S, Haber DA, Weinberg RA. hEST2,the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell. 1997 Aug 22;90(4):785-95.
Misiti S, Nanni S, Fontemaggi G, Cong YS, Wen J, Hirte HW, Piaggio G, Sacchi A, Pontecorvi A, Bacchetti S, Farsetti A.Induction of hTERT expression and telomerase activity by estrogens in human ovary epithelium cells. Mol Cell Biol. 2000 Jun;20(11):3764-71.
Mullen CA, Coale MM, Lowe R, Blaese RM. Tumors expressing the cytosine deaminase suicide gene can be eliminated in vivo with 5-fluorocytosine and induce protective immunity to wild type tumor. Cancer Res. 1994 Mar 15;54(6):1503-6.
Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, Harley CB, Cech TR. Telomerase catalytic subunit homologs from fission yeast and human.Science. 1997 Aug 15;277(5328):955-9.
Nakamura TM, Cech TR. Reversing time: origin of telomerase. Cell. 1998 Mar 6;92(5):587-90. Review.
Nakayama J, Saito M, Nakamura H, Matsuura A, Ishikawa F. TLP1: a gene encoding a protein component of mammalian telomerase is a novel member of WD repeats family.Cell. 1997 Mar 21;88(6):875-84.
Nakayama J, Tahara H, Tahara E, Saito M, Ito K, Nakamura H, Nakanishi T, Tahara E,Ide T, Ishikawa F.Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas. Nat Genet. 1998 Jan;18(1):65-8.
Nettelbeck DM, Jerome V, Muller R. A strategy for enhancing the transcriptional activity of weak cell type-specific promoters. Gene Ther. 1998 Dec;5(12):1656-64.
Oh S, Song YH, Kim UJ, Yim J, Kim TK. In vivo and in vitro analyses of Myc for differential promoter activities of the human telomerase(hTERT)gene in normal and tumor cells. Biochem Biophys Res Commun. 1999 Sep 24;263(2):361-5.
Oh S, Song Y, Yim J, Kim TK. The Wilms' tumor 1 tumor suppressor gene represses transcription of the human telomerase reverse transcriptase gene. J Biol Chem. 1999 Dec 24;274(52):37473-8.
Pope IM, Poston GJ, Kinsella AR. The role of the bystander effect in suicide gene therapy. Eur J Cancer. 1997 Jun;33(7):1005-16. Review.
Rogulski KR, Kim JH, Kim SH, Freytag SO. Glioma cells transduced with an Escherichia coli CD/HSV-1 TK fusion gene exhibit enhanced metabolic suicide and radiosensitivity. Hum Gene Ther. 1997 Jan 1;8(1):73-85.
Ross G, Erickson R, Knorr D, Motulsky AG, Parkman R, Samulski J, Straus SE, Smith BR. Gene therapy in the United States: a five-year status report. Hum Gene Ther. 1996 Sep 10;7(14):1781-90. No abstract available.
Sato N, Wang S, Li L, Okabe K, Hashimoto M, Yaginuma H, Mikoshiba K, Uchiyama Y,Uetsuki T, Yoshikawa K, Milligan CE, Oppenheim RW. A novel strategy for introducing exogenous bcl-2 into neuronal cells: the Cre/loxP system-mediated activation of bcl-2 for preventing programmed cell death using recombinant adenoviruses. Mol Cell Neurosci. 1998 Sep;12(1-2):65-78.
Segawa T, Takebayashi H, Kakehi Y, Yoshida O, Narumiya S, Kakizuka A.Prostate-specific amplification of expanded polyglutamine expression: a novel approach for cancer gene therapy. Cancer Res. 1998 Jun 1;58(11):2282-7.
Shay JW, Wright WE. The reactivation of telomerase activity in cancer progression.Trends Genet. 1996 Apr; 12(4): 129-31. Review.
Shay JW, Wright WE. Telomeres and telomerase: implications for cancer and aging.Radiat Res. 2001 Jan;155(1 Pt 2):188-193. Review.
Spencer CA, Groudine M, Control of c-myc regulation in normal and neoplastic cells.Adv Cancer Res. 1991;56:1-48. Review.
Stewart SA, Weinberg RA. Telomerase and human tumorigenesis. Semin Cancer Biol.2000 Dec;10(6):399-406. Review.
Takakura M, Kyo S, Kanaya T, Hirano H, Takeda J, Yutsudo M, Inoue M. Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res. 1999 Feb 1;59(3):551-7.
Trinh QT, Austin EA, Murray DM, Knick VC, Huber BE. Enzyme/prodrug gene therapy:comparison of cytosine deaminase/5-fluorocytosine versus thymidine kinase/ganciclovir enzyme/prodrug systems in a human colorectal carcinoma cell line. Cancer Res. 1995 Nov 1;55(21):4808-12.
Ulaner GA, Hu JF, Vu TH, Giudice LC, Hoffman AR. Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts. Cancer Res. 1998 Sep 15;58(18):4168-72.
Weinrich SL, Pruzan R, Ma L, Ouellette M, Tesmer VM, Holt SE, Bodnar AG,Lichtsteiner S, Kim NW, Trager JB, Taylor RD, Carlos R, Andrews WH, Wright WE,Shay JW, Harley CB, Morin GB. Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat Genet. 1997 Dec;17(4):498-502.
Weng NP, Levine BL, June CH, Hodes RJ. Regulated expression of telomerase activity in human T lymphocyte development and activation. J Exp Med.1996 Jun 1;183(6):2471-9.
Wu KJ, Grandori C, Amacker M, Simon-Vermot N, Polack A, Lingner J, Dalla-Favera R.Direct activation of TERT transcription by c-MYC. Nat Genet. 1999 Feb;21(2):220-4.
汤钊猷等，现代肿瘤学，1993年第一版，上海，上海医科大学出版社。
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