title: Tumor-specific transgene expression from the human telomerase reverse transcriptase promoter enables targeting of the therapeutic effects of the Bax gene to cancers.
abstract: Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase, which is highly active in immortalized cells and >85% of human cancers but is quiescent in most normal somatic cells. To test the feasibility of using the hTERT promoter to induce tumor-specific transgene expression in cancer gene therapy, we constructed an adenoviral vector expressing a LacZ reporter gene driven by the hTERT core promoter and evaluated its activity in vitro and in vivo. The hTERT promoter could drive high-level expression of LacZ in tumor cells but not in normal cells and normal mouse tissues. Using a binary adenoviral system that can induce Bax gene expression, we showed that induction of the Bax gene expression via the hTERT promoter elicited tumor-specific apoptosis in vitro, suppressed tumor growth in nude mice, and prevented the toxicity of the Bax gene in vitro and in vivo. Thus, the hTERT promoter is apparently a strong and tumor-selective promoter with potential application in targeted cancer gene therapy.
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gu
authors.forename: S
authors.initials: S
authors.lastname: Kagawa
authors.forename: M
authors.initials: M
authors.lastname: Takakura
authors.forename: S
authors.initials: S
authors.lastname: Kyo
authors.forename: M
authors.initials: M
authors.lastname: Inoue
authors.forename: J A
authors.initials: JA
authors.lastname: Roth
authors.forename: B
authors.initials: B
authors.lastname: Fang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2; D012313:RNA; D019098:Telomerase / Q000235:genetics*; D014158:Transcription, Genetic; D019076:Transgenes / Q000235:genetics*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; C494827:Bax protein, mouse; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase