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Wild-Type Adenovirus Decreases Tumor Xenograft Growth, but Despite Viral Persistence Complete Tumor Responses Are Rarely Achieved—Deletion of the Viral E1b-19-kD Gene Increases the Viral Oncolytic Effect
- Source :
- Human Gene Therapy. 12:1323-1332
- Publication Year :
- 2001
- Publisher :
- Mary Ann Liebert Inc, 2001.
-
Abstract
- Strategies to target viral replication to tumor cells hold great promise for the treatment of cancer, but even with replicating adenoviruses complete tumor responses are rarely achieved. To evaluate replicating adenoviral vectors, we have used A549 human lung cancer nude mouse xenografts as a model system. Intratumoral injection of wild-type adenovirus (Ad309) significantly reduced tumor growth from day 14 (p = 0.04) onward; however, tumor volumes reached a plateau at day 50. At 100 days, high levels of titratable virus were present within persistent viable tumors. In contrast to viral injection into established tumors, when tumor cells were infected in vitro with wild-type virus and then mixed with uninfected tumor cells, 1% of infected cells was sufficient to prevent tumor establishment. An E1b-19kD-deleted viral mutant (Ad337) was more efficient than Ad309 in this cell-mixing model. Just 1 cell in 1000 infected with Ad337 prevented tumor growth. However, although better than wild-type virus, Ad337 was unable to eradicate established flank tumors. These data suggest that although replicating adenoviruses exhibit significant oncolytic activity, barriers within the established tumor, such as connective tissue and tumor matrix, may limit the spread of virus. Strategies to enhance viral spread through established tumors are therefore likely to greatly improve the therapeutic efficacy of replicating adenoviruses.
- Subjects :
- Time Factors
viruses
Genetic enhancement
Mice, Nude
Biology
medicine.disease_cause
Virus
Adenoviridae
Mice
Nude mouse
Tumor Cells, Cultured
Genetics
medicine
Animals
Humans
Vector (molecular biology)
Adenovirus E1B Proteins
Molecular Biology
Gene Transfer Techniques
Cancer
Genetic Therapy
medicine.disease
biology.organism_classification
Immunohistochemistry
Virology
Oncolytic virus
Viral replication
Mutation
Molecular Medicine
Cell Division
Gene Deletion
Neoplasm Transplantation
Subjects
Details
- ISSN :
- 15577422 and 10430342
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- Human Gene Therapy
- Accession number :
- edsair.doi.dedup.....3a5a8e0917826cfb8fbf4e0e8f2490cd