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Abstract
Top of pageAbstract Human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase functions to stabilize telomere length during chromosomal replication. Previous studies have shown that hTERT promoter is highly active in most tumor and immortal cell lines but inactive in normal somatic cell types. The use of wild type hTERT promoter however, may be limited by its inability to direct high level and cancer cell-specific expression necessary for effective targeted gene therapy. To improve cancer cell-specificity and strength of the hTERT promoter, a modified hTERT, m-hTERT promoter was generated in which additional copies of c-Myc and Sp1 binding sites were incorporated adjacent to the promoter. As assessed using relative LacZ expression, hTERT and m-hTERT promoter activity was significantly upregulated in cancer cells but not in normal cells; and within this upregulated cancer cells, m-hTERT promoter strength was substantially higher than that of the wild type hTERT. Next, to restrict viral replication to tumor cells, a conditional replication-competent adenoviruses, Ad-TERT-Δ19 and Ad-mTERT-Δ19 were generated in which E1A gene that is essential for viral replication was placed under the control of the hTERT and m-hTERT promoter, respectively. While the wild type Ad-TERT-Δ19 replicated in and induced cytopathic effect in cancer and in some normal cell lines, Ad-mTERT-Δ19 enhanced viral replication and cytopathic effect in cancer cells only. Finally, the growth of established human cervical carcinoma in nude mice was significantly suppressed by intra-tumoral injection of Ad-mTERT-Δ19. Taken together, present results strongly suggest that the use of m-hTERT promoter is not only useful in the regulation of therapeutic gene expression but also that replication-competent oncolytic adenovirus under the control of m-hTERT promoter may be a new promising tool for the treatment of human malignancies.
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