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, Ha Youn Shin, Hansaem Lee, Jai Myung Yang, Jungho Kim, Joo Hyuk Sohn, Hoguen Kim, Chae Ok Yun

Research output: Contribution to journalArticle

90 Citations (Scopus)

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 replication-competent 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.

Original languageEnglish
Pages (from-to)1415-1428
Number of pages14
JournalHuman Gene Therapy
Volume14
Issue number15
DOIs
StatePublished - 2003 Oct 10

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Human Adenoviruses
Telomerase
Neoplasms
human TERT protein
Adenoviridae
Viral Cytopathogenic Effect
Telomere
Gene Expression Regulation
Tumor Cell Line
Nude Mice
Genetic Therapy

Cite this

Kim, Eunhee ; Kim, Joo Hang ; Shin, Ha Youn ; Lee, Hansaem ; Yang, Jai Myung ; Kim, Jungho ; Sohn, Joo Hyuk ; Kim, Hoguen ; Yun, Chae Ok. / 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. In: Human Gene Therapy. 2003 ; Vol. 14, No. 15. pp. 1415-1428.
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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 replication-competent 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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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. / Kim, Eunhee; Kim, Joo Hang; Shin, Ha Youn; Lee, Hansaem; Yang, Jai Myung; Kim, Jungho; Sohn, Joo Hyuk; Kim, Hoguen; Yun, Chae Ok.

In: Human Gene Therapy, Vol. 14, No. 15, 10.10.2003, p. 1415-1428.

Research output: Contribution to journalArticle

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T1 - 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

AU - Kim, Eunhee

AU - Kim, Joo Hang

AU - Shin, Ha Youn

AU - Lee, Hansaem

AU - Yang, Jai Myung

AU - Kim, Jungho

AU - Sohn, Joo Hyuk

AU - Kim, Hoguen

AU - Yun, Chae Ok

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AB - 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 replication-competent 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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