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Ad-mTERT-Δ19, a Conditional Replication-Competent Adenovirus Driven by the Human Telomerase Promoter, Selectively Replicates in and Elicits Cytopathic Effect in a Cancer Cell-Specific Manner

 Eunhee Kim  ;  Joo-Hang Kim  ;  Chae-Ok Yun  ;  Hoguen Kim  ;  Joo-Hyuk Sohn  ;  Jungho Kim  ;  Jai Myung Yang  ;  Hansaem Lee  ;  Ha-Youn Shin 
 HUMAN GENE THERAPY, Vol.14(15) : 1415-1427, 2003 
Journal Title
Issue Date
Adenoviridae/genetics* ; Animals ; Antineoplastic Agents/pharmacology ; Base Sequence ; Blotting, Western ; Cell Line, Tumor ; Coloring Agents/pharmacology ; Gene Expression Regulation ; Gene Transfer Techniques* ; Genes, Reporter ; Genetic Vectors* ; HeLa Cells ; Humans ; Lac Operon ; Mice ; Mice, Nude ; Models, Genetic ; Molecular Sequence Data ; Neoplasm Transplantation ; Neoplasms, Experimental/therapy ; Promoter Regions, Genetic* ; Proto-Oncogene Proteins c-myc/metabolism ; Sp1 Transcription Factor/metabolism ; Telomerase/genetics* ; Telomerase/metabolism ; Tetrazolium Salts/pharmacology ; Thiazoles/pharmacology ; Time Factors ; Transcription, Genetic ; Up-Regulation ; beta-Galactosidase/metabolism
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 the 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 these 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 replicationcompetent adenoviruses, Ad-TERT-Δ19 and Ad-mTERT-Δ19 were generated in which the E1A gene, which 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 only in cancer cells. Furthermore, the growth of established human cervical carcinoma in nude mice was significantly suppressed by intratumoral injection of Ad-mTERT-Δ19. Taken together, present results strongly suggest that the use of the 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 the m-hTERT promoter may be a new promising tool for the treatment of human malignancies.
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Joo Hang(김주항)
Kim, Hogeun(김호근)
Sohn, Joo Hyuk(손주혁) ORCID logo https://orcid.org/0000-0002-2303-2764
Yun, Chae Ok(윤채옥)
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