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Published on: January 15, 2016
Comparative effect of oncolytic adenoviruses with E1A-55 kDa or E1B-55 kDa deletions in malignant gliomas
Hong Jiang1, Candelaria Gomez-Manzano, Ramon Alemany
1Brain Tumor Center, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
Replication-competent oncolytic adenoviruses hold considerable promise for treating malignant gliomas. The toxicity of the clinically tested E1B-55 kDa mutant virus is negligible; however, its full clinical potential is still being evaluated. The purpose of the present study is to compare the antiglioma activity in vitro and in vivo between Delta-24, an E1A mutant adenovirus, and RA55, an E1B-55 kDa mutant adenovirus. We selected human glioma cell lines that were tumorigenic in nude mice and express wild-type p53 (U-87 MG, D54 MG) or mutant p53 (U-251 MG, U-373 MG) protein. Our studies demonstrated that Delta-24 induced a more potent antiglioma effect in vitro than RA55. Moreover, Delta-24 replicated markedly more efficiently than RA55 in both wild-type and mutant p53 scenarios. Importantly, direct intratumoral injection of Delta-24, but not RA55, significantly suppresses tumor growth in intracranial (U-87 MG, U-251 MG) or subcutaneous (D54 MG) animal models. Staining for hexon protein detected replicating adenoviruses in xenografts infected with Delta-24, but not with RA55. Collectively, these data indicate that E1A mutant adenoviruses targeting the Rb pathway are more powerful putative agents for antiglioma therapy than E1B mutant adenoviruses, and suggest that E1A mutant adenoviruses should be tested in the clinical setting for patients with malignant gliomas.
Insights
E1A mutant adenoviruses show greater potential than E1B mutant adenoviruses for treating malignant gliomas. Delta-24 demonstrated superior antiglioma activity and replication compared to RA55 in preclinical models.
Area of Science:
- Oncolytic virotherapy
- Gene therapy
- Cancer research
Background:
- Replication-competent oncolytic adenoviruses are promising for malignant glioma treatment.
- E1B-55 kDa mutant viruses have shown negligible toxicity but require further evaluation.
- Understanding the comparative efficacy of different oncolytic adenovirus mutants is crucial for clinical development.
Purpose of the Study:
- To compare the in vitro and in vivo antiglioma activity of Delta-24 (E1A mutant adenovirus) and RA55 (E1B-55 kDa mutant adenovirus).
- To assess the replication efficiency of these adenoviruses in glioma cells with varying p53 statuses.
- To evaluate the therapeutic potential of E1A vs. E1B mutant adenoviruses in preclinical glioma models.
Main Methods:
- Utilized human glioma cell lines (U-87 MG, D54 MG, U-251 MG, U-373 MG) with wild-type or mutant p53.
- Assessed antiglioma effects and viral replication in vitro.
- Evaluated tumor growth suppression following direct intratumoral injection in intracranial and subcutaneous xenograft models.
- Detected viral replication in vivo using hexon protein staining.
Main Results:
- Delta-24 exhibited more potent in vitro antiglioma activity than RA55.
- Delta-24 replicated significantly more efficiently than RA55 in both wild-type and mutant p53 glioma cells.
- Intratumoral injection of Delta-24, but not RA55, significantly suppressed tumor growth in animal models.
- Replicating adenoviruses were detected in Delta-24 infected xenografts, but not in RA55 infected ones.
Conclusions:
- E1A mutant adenoviruses targeting the Rb pathway demonstrate superior antiglioma efficacy compared to E1B mutant adenoviruses.
- Delta-24 shows greater potential as an oncolytic agent for malignant gliomas than RA55.
- E1A mutant adenoviruses warrant clinical investigation for malignant glioma therapy.
