Development of a Conditional Replication Competent Adenovirus, Controlled by the Human Telomerase Promoter (hTERT).
- Author:
Eunhee KIM
1
;
Joo Hang KIM
;
Ha Youn SHIN
;
Han Saem LEE
;
Joo Hyuk SOHN
;
Jai Myung YANG
;
Jungho KIM
;
Chae Ok YUN
Author Information
1. Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea. chaeok@yumc.yonsei.ac.kr
- Publication Type:In Vitro ; Original Article
- Keywords:
Cancer gene therapy;
hTERT;
Replication competent adenovirus
- MeSH:
Adenoviridae*;
Animals;
Binding Sites;
Cell Line;
Gene Expression;
Genes, Neoplasm;
Heterografts;
Humans*;
Injections, Subcutaneous;
Mice;
Mice, Nude;
Sensitivity and Specificity;
Telomerase*
- From:Cancer Research and Treatment
2003;35(3):191-206
- CountryRepublic of Korea
- Language:Korean
-
Abstract:
PURPOSE: This study has been planned to generate a replication-competent adenovirus which replicates in a cancer cell-specific manner, thus minimizing the side effects and toxicity of cancer gene therapy. MATERIALS AND METHODS: we have generated an E1B 19 kD attenuated recombinant adenoviruses, Ad-TERT-delta19 and Ad-mTERT-delta19, which encode E1A gene driven by the wild type hTERT and modified m-hTERT promoter containing additional c-myc and Sp1 binding sites in the backbone of Ad-deltaE1B19. The in vitro efficacy and specificity of the hTERT and m-hTERT promoter have been evaluated by the comparison of viral replication and cytopathic effect in cancer cells and normal cell lines. To assess anti-tumor effect and safety of hTERT or m-hTERT promoter driven replication competent adenoviruses, tumor regression after subcutaneous injection in subcutaneous C33A xenografts and lacZ expression after systemic injection in organs were examined. RESULTS: The activation of hTERT or m-hTERT promoter was significantly up-regulated only in hTERT-positive cells, but not in hTERT-negative cells. Moreover, the activity of m-hTERT promoter was substantially increased in hTERT-positive cancer cells, but not in hTERT-negative cells. While Ad-TERT-delta19 replicated in and induced cytopathic effect in cancer and in some normal cell lines, Ad-mTERT-delta19 enhanced viral replication and cytopathic effect in cancer cells only. Furthermore, the growth of established human cervical carcinoma in nude mice was significantly suppressed by intratumoral injection of Ad-mTERT-delta19. CONCLUSIONS: 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.
