E1A- and E1B-Double mutant replicating adenovirus elicits enhanced oncolytic and antitumor effects.
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-DeltaE1B19/55) 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-DeltaE1Bmt7 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-DeltaE1Bmt7 exerted marked enhancement in cancer cell-specific killing as well as viral replication in comparison with its comparative controls (Ad-E1mt7, Ad-DeltaE1B55). Furthermore, the growth of established human cervical carcinoma in nude mice was significantly suppressed by intratumoral injection of Ad-DeltaE1Bmt7. In summary, we have developed an oncolytic adenovirus with a significantly improved therapeutic profile for cancer treatment.
Kim
Jaesung
J
Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, South Korea.
Kim
Joo-Hang
JH
Choi
Kyung-Ju
KJ
Kim
Pyung-Hwan
PH
Yun
Chae-Ok
CO
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D017500:Adenovirus E1A Proteins / Q000235:genetics*; D017501:Adenovirus E1B Proteins / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D017353:Gene Deletion; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007668:Kidney / Q000166:cytology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy; D050130:Oncolytic Virotherapy; D014779:Virus Replication
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins