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Cancer Research and Treatment > Volume 35(3); 2003 > Article
Cancer Research and Treatment 2003;35(3): 191-206. doi: https://doi.org/10.4143/crt.2003.35.3.191
Development of a Conditional Replication Competent Adenovirus, Controlled by the Human Telomerase Promoter (hTERT)
Eunhee Kim, Joo Hang Kim, Ha Youn Shin, Han Saem Lee, Joo Hyuk Sohn, Jai Myung Yang, Jungho Kim, Chae Ok Yun
1Institute for Cancer Research, Yonsei Cancer Center, YonseiUniversity College of Medicine, Seoul, Korea.chaeok@yumc.yonsei.ac.kr
2Department of Life Science, Sogang University, Seoul, Korea.
  Published online: June 30, 2003.
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.
Key words: Cancer gene therapy;hTERT;Replication competent adenovirus
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