hTERT promoter induces tumor-specific Bax gene expression and cell killing in syngenic mouse tumor model and prevents systemic toxicity.
We recently showed that the human telomerase reverse transcriptase (hTERT) promoter induces tumor-specific Bax gene expression and selectively kills various human cancer cells both in vitro and in xenograft tumors. However, it remains unclear whether the hTERT promoter can be used to induce transgene expression in syngenic tumors in mice and whether Bax gene expression driven by the hTERT promoter will cause long-term, stem cell-related toxicity. To address these questions, we tested hTERT promoter-driven, adenovirus-mediated Bax transgene expression in an established syngenic mouse tumor model and its effects on tumor and normal murine tissues. The hTERT promoter was highly active in several murine tumor cell lines and a transformed cell line, but not in non-transformed and normal murine cell lines. The hTERT promoter induced tumor-specific Bax gene expression in mouse UV-2237m fibrosarcoma cells both in vitro and in vivo and suppressed syngenic tumor growth in immune-competent mice with no obvious acute or long-term toxic effects. Moreover, hTERT promoter-driven transgene expression in human CD34(+) bone marrow progenitor cells had effects similar to those observed in other normal human cells, suggesting that the hTERT promoter is much less active in CD34(+) cells than in tumor cells. Together, our data demonstrate that the hTERT promoter may allow the use of proapoptotic genes for cancer treatment without noticeable effects on progenitor cells.
Gu
J
J
Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Andreeff
M
M
Roth
J A
JA
Fang
B
B
D000256:Adenoviridae / Q000235:genetics; D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001219:Aspartate Aminotransferases / Q000097:blood; D004268:DNA-Binding Proteins; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D015552:Injections, Intralesional; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D023421:Models, Animal; D009374:Neoplasms, Experimental / Q000628:therapy*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D019098:Telomerase / Q000235:genetics*; D019076:Transgenes; D014407:Tumor Cells, Cultured; 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; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D019098:Telomerase