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E1A, E1B double-restricted adenovirus for oncolytic gene therapy of gallbladder cancer
Kuniaki Fukuda1, Masato Abei, Hideyo Ugai
1Divisions of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba, Tennoudai 1-1-1, Tsukuba-shi, Ibaraki 305-8575, Japan.
Abstract:
New treatments, such as gene therapy, are necessary for advanced gallbladder cancer (GBC), but little has been studied. Recent studies have introduced mutant adenoviruses (Ads) with either defective E1B-55kD or mutated E1A, focusing on tumor-specific replication, and the results have been promising. To enhance the safety of this approach, we constructed AxdAdB-3, a double-restricted Ad with a mutant E1A and E1B-55kD deletion. We studied the effects of this Ad in vitro and in vivo on GBC, as well as its safety for normal human cells. We compared the replication and cytopathic effects of AxdAdB-3 in several lines of GBC and primary normal cells with those of wild-type Ad or of AxE1AdB, an E1B-55kD-deleted Ad. The efficacy in vivo was examined in nude mice with s.c. implanted or i.p. disseminated GBC. AxdAdB-3 replicated in and caused oncolysis of GBC cell lines (TGBC-44TKB and Mz-ChA2) as efficiently as wild-type Ad or AxE1AdB in vitro. By contrast, AxdAdB-3 replicated much less effectively in primary normal cells (e.g., epithelial cells, endothelial cells, and hepatocytes) than in GBC cells and had only mild cytopathic effects, unlike wild-type Ad. Furthermore, cytotoxicity of AxdAdB-3 in normal cells was milder than that of AxE1AdB. AxdAdB-3 significantly (P < 0.01) suppressed the growth of GBC (TGBC-44TKB) xenografts. AxdAdB-3 was also effective in the treatment of mice with peritoneally disseminated GBC (TGBC-44TKB), demonstrating tumor-selective replication and oncolysis that resulted in significantly (P < 0.05) prolonged survival. The present study shows that the E1 double-restricted Ad effectively and selectively replicates in and causes oncolysis of GBC in vitro and in vivo with reduced negative effects on normal cells, suggesting that this approach could be a promising tool for gene therapy of GBC.
Insights
A novel gene therapy using a double-restricted adenovirus (AxdAdB-3) effectively targets gallbladder cancer (GBC) cells. This new treatment shows promising tumor-selective replication and oncolysis with reduced impact on normal cells.
Area of Science:
- Oncolytic virotherapy
- Gene therapy for cancer
- Adenovirus vector engineering
Background:
- Advanced gallbladder cancer (GBC) requires novel treatment strategies.
- Mutant adenoviruses (Ads) show potential for tumor-specific replication in cancer therapy.
- Enhancing the safety and efficacy of oncolytic adenoviruses is crucial.
Purpose of the Study:
- To develop and evaluate a double-restricted adenovirus (AxdAdB-3) for GBC gene therapy.
- To assess the in vitro and in vivo efficacy and safety of AxdAdB-3 in GBC models.
- To compare AxdAdB-3's performance against wild-type Ad and a single-restricted Ad (AxE1AdB).
Main Methods:
- Construction of AxdAdB-3, a double-restricted Ad with mutant E1A and E1B-55kD deletion.
- In vitro studies: Replication and cytopathic effects in GBC cell lines and normal human cells.
- In vivo studies: Efficacy in nude mice with implanted or disseminated GBC xenografts.
Main Results:
- AxdAdB-3 demonstrated efficient replication and oncolysis in GBC cells, comparable to wild-type Ad.
- Significantly reduced replication and milder cytopathic effects were observed in normal cells compared to GBC cells.
- AxdAdB-3 showed superior safety profile in normal cells compared to AxE1AdB.
- Significant suppression of GBC xenograft growth and prolonged survival in disseminated GBC models were achieved.
Conclusions:
- The E1 double-restricted Ad (AxdAdB-3) effectively and selectively targets GBC cells for oncolysis.
- AxdAdB-3 exhibits reduced toxicity to normal cells, enhancing its safety profile.
- This engineered adenovirus represents a promising candidate for GBC gene therapy.