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E1A- and E1B-double mutant replicating adenovirus elicits enhanced oncolytic and antitumor effects

 Jaesung Kim  ;  Joo-Hang Kim  ;  Chae-Ok Yun  ;  Pyung-Hwan Kim  ;  Kyung-Ju Choi 
 HUMAN GENE THERAPY, Vol.18(9) : 773-786, 2007 
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Adenoviridae*/genetics ; Adenoviridae*/physiology ; Adenovirus E1A Proteins/genetics* ; Adenovirus E1B Proteins/genetics* ; Animals ; Blotting, Western ; Cell Line ; Cell Line, Tumor ; Gene Deletion ; Genetic Therapy ; Genetic Vectors* ; Humans ; Kidney/cytology ; Male ; Mice ; Mice, Nude ; Mutation ; Neoplasm Transplantation ; Neoplasms, Experimental/pathology ; Neoplasms, Experimental/therapy ; Oncolytic Virotherapy* ; Virus Replication*
Gene-modified replication-competent adenoviruses (Ads) are emerging as a promising new modality for the treatment of cancer. We have previously shown that E1B 19kDa and E1B 55kDa gene-deleted Ad (Ad-ΔE1B19/55) exhibits improved tumor-specific replication and cell lysis, leading to an enhanced antitumor effect. In an effort to increase cancer cell selectivity of a replicating adenovirus, we first generated 11 E1A mutant Ads (Ad-E1mt1 to Ad-E1mt11) with deletion or substitution in retinoblastoma (pRb)-binding sites of E1A. Of these, Ad-E1mt7 demonstrated significant improvement in cytopathic effect (CPE) and viral replication in a cancer cell-specific manner. To further enhance the cancer cell specificity of Ad-E1mt7, Ad-ΔE1Bmt7 was generated, in which both the E1B 19kDa and E1B 55kDa genes were deleted. As assessed in CPE assay and immunoblot analysis for Ad fiber expression, Ad-ΔE1Bmt7 exerted marked enhancement in cancer cell-specific killing as well as viral replication in comparison with its comparative controls (Ad-E1mt7, Ad-ΔE1B55). Furthermore, the growth of established human cervical carcinoma in nude mice was significantly suppressed by intratumoral injection of Ad-ΔE1Bmt7. In summary, we have developed an oncolytic adenovirus with a significantly improved therapeutic profile for cancer treatment.
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1. College of Medicine (의과대학) > Dept. of Medical Education (의학교육학과) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터) > 1. Journal Papers
5. Research Institutes (연구소) > Institute for Cancer Research (암연구소) > 1. Journal Papers
Yonsei Authors
Kim, Jaesung(김재성)
Kim, Joo Hang(김주항)
Kim, Pyung Hwan(김평환)
Yun, Chae Ok(윤채옥)
Choi, Kyung Ju(최경주)
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