Tumor-specific transgene expression from the human telomerase reverse transcriptase promoter enables targeting of the therapeutic effects of the Bax gene to cancers.
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.
Gu
J
J
Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Kagawa
S
S
Takakura
M
M
Kyo
S
S
Inoue
M
M
Roth
J A
JA
Fang
B
B
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
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