Publication: A Novel Approach Using Transcomplementing Adenoviral Vectors for Gene Therapy of Adrenocortical Cancer
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2002-06
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Thieme Publishing
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Abstract
Current therapies for adrenocortical carcinomas do not improve
the life expectancy of patients. I n this study, we tested whether a
gene-transfer therapy based upon a suicide gene/prodrug system
would be effective in an animal model of the disease. We employed
E4- and ElA/B-depleted. herpes simplex virus-thymidine
kinase-expressing adenoviral mutants that transcomplement
each other within tumor cells, hereby improving transgene delivery
and efficacy by viral replication in situ. Transcomplementation
of vectors increased the fraction of transduced of tumor
cells. This increase was accompanied by greater tumor volume
reduction compared to non-transcomplementing approaches.
Survival time improved with non-replicating vectors plus GCV
compared to controls. However, transcomplementation/replication
of vectors led to a further significant increment in anti-tumor
activity and survival time (p <0.02). In treated animals, we
observed a high number of apoptotic nuclei both adjacent to
and distant from injection sites and sites of viral oncolysis. Ultrastructural
analyses exhibited nuclear inclusion bodies characteristic
of virus production in situ, and provided further evidence
that this therapy induced apoptotic cell death within tumor cells.
We conclude that the efficacy of suicide gene therapy is significantly
amplified by viral replication and, in combination with
GCV, significantly reduces tumor burden and increases survival
time.
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Keywords
Adrenal Gland, Cancer, Gene Therapy, Adenovirus -Transcomplementing, Bicistronic
Bibliographic citation
Hormone and Metabolic Research, vol. 34, n. 6, june 2002. Pp. 279-287