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Updated: Oct 11, 2026
A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
Published on: July 6, 2017
Therapy of peritoneal carcinomatosis from colon cancer with oncolytic adenoviruses
1Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1851, USA. wildner@rrk-berlin.de
Background:
The major emphasis on the safety of viral vectors for gene delivery has led to the generally accepted approach of disabling their ability to replicate and thus their potential capacity to spread throughout a tumor by consecutive rounds of infection and lysing neighboring cells.
Methods:
In this study we evaluated three herpes simplex virus-1 thymidine kinase (HSV-tk) carrying replication-competent adenoviral vectors with and without the Ad5 E1B 55-kDa gene, wild-type adenovirus type 5 (Ad5wt), and a prototypical replication-deficient adenovirus expressing HSV-tk (Ad.TK) for their cytoreductive effects in a peritoneal carcinomatosis model from human HT-29 colon cancer cells in nude mice.
Results:
The survival of nude mice treated with the replication-defective adenoviral vector Ad.TK was enhanced when followed by GCV. In contrast, administration of GCV diminished the anti-tumor efficacy of the replication-competent HSV-tk expressing vectors. However, the intrinsic oncolytic effect of all replication-competent viruses was superior to that of Ad.TK+GCV. Furthermore, the oncolysis of the E1B 55-kDa-positive viruses was significantly greater than that of the E1B 55-kDa-deleted vector.
Conclusions:
The more efficient diffusion of viral particles in the peritoneal cavity, when compared to the microenvironment of solid tumors and the virostatic effects of GCV, most likely antagonized the anticipated enhanced cytotoxicity of the replication-competent vectors from the use of its gene directed enzyme prodrug system. Nevertheless, in a clinical setting, the HSV-tk/GCV system allows efficient termination of viral replication in the case of a runaway infection. The results of this study warrant further evaluation of controllable viral replication as a treatment modality for cancer, especially in combination with conventional therapies (e.g. chemotherapy).
Insights
Replication-competent adenoviruses showed superior oncolytic effects compared to replication-deficient ones, even when combined with GCV. Controllable viral replication warrants further investigation for cancer treatment.
Area of Science:
- Oncolytic virotherapy
- Gene therapy
- Cancer research
Background:
- Viral vectors for gene delivery typically disable replication for safety.
- Replication-competent viruses offer potential for tumor spread and cell lysis.
Purpose of the Study:
- To evaluate replication-competent and deficient adenoviral vectors expressing HSV-tk for cytoreductive effects.
- To compare their efficacy with and without Ganciclovir (GCV) in a colon cancer model.
Main Methods:
- Three replication-competent adenoviral vectors (HSV-tk positive, with/without E1B 55-kDa gene) and one replication-deficient vector (Ad.TK) were tested.
- Experiments were conducted in a peritoneal carcinomatosis model using human HT-29 colon cancer cells in nude mice.
- Cytoreductive effects were assessed with and without Ganciclovir (GCV) administration.
Main Results:
- Replication-defective Ad.TK combined with GCV enhanced survival.
- GCV diminished the anti-tumor efficacy of replication-competent HSV-tk vectors.
- Replication-competent viruses demonstrated superior intrinsic oncolytic effects compared to Ad.TK+GCV.
- E1B 55-kDa-positive viruses showed significantly greater oncolysis than E1B 55-kDa-deleted vectors.
Conclusions:
- GCV's virostatic effect and viral diffusion in the peritoneum may antagonize replication-competent vector efficacy.
- The HSV-tk/GCV system provides a safety mechanism to terminate viral replication.
- Controllable viral replication is a promising cancer treatment modality, potentially combined with conventional therapies.
