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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

Authors
 Eunhee Kim  ;  Joo-Hang Kim  ;  Chae-Ok Yun  ;  Hoguen Kim  ;  Joo-Hyuk Sohn  ;  Jungho Kim  ;  Jai Myung Yang  ;  Hansaem Lee  ;  Ha-Youn Shin 
Citation
 Human Gene Therapy, Vol.14(15) : 1415-1427, 2003 
Journal Title
 Human Gene Therapy 
ISSN
 1043-0342 
Issue Date
2003
Abstract
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.
Full Text
http://online.liebertpub.com/doi/abs/10.1089/104303403769211637
DOI
10.1089/104303403769211637
Appears in Collections:
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
5. Research Institutes (연구소) > Institute for Cancer Research (암연구소) > 1. Journal Papers
Yonsei Authors
김주항(Kim, Joo Hang)
김호근(Kim, Ho Keun)
손주혁(Sohn, Joo Hyuk) ORCID logo https://orcid.org/0000-0002-2303-2764
윤채옥(Yun, Chae Ok)
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/114420
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