논문검색
Author Eunhee Kim1, Joo-Hang Kim, M.D.1, Ha-Youn Shin2, Han Saem Lee2, Joo-Hyuk Sohn, M.D.1, Jai Myung Yang, Ph.D.2, Jungho Kim, Ph.D.2 and Chae-Ok Yun, Ph.D.1
Place of duty 1Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul; 2Department of Life Science, Sogang University, Seoul, Korea
Title Development of a Conditional Replication Competent Adenovirus, Controlled by the Human Telomerase Promoter (hTERT)
Publicationinfo Cancer Research and Treatment 2003 Jun; 035(03): 191-206.
Key_word Cancer gene therapy, hTERT, Replication competent adenovirus
Full-Text
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-Δ19 and Ad-mTERT- 19, 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- E1B19. 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- 19 replicated in and induced cytopathic effect in cancer and in some normal cell lines, Ad-mTERT- 19 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- 19. 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. (Cancer Research and Treatment 2003;35:191 206)