A novel approach using transcomplementing adenoviral vectors for gene therapy of adrenocortical cancer.
Current therapies for adrenocortical carcinomas do not improve the life expectancy of patients. In 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 E1A/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.
Wolkersdörfer
G W
GW
Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Bethesda, Maryland USA.
Bornstein
S R
SR
Higginbotham
J N
JN
Hiroi
N
N
Vaquero
J J
JJ
Green
M V
MV
Blaese
R M
RM
Aguilera
G
G
Chrousos
G P
GP
Ramsey
W J
WJ
D000256:Adenoviridae / Q000235:genetics*; D000306:Adrenal Cortex Neoplasms / Q000628:therapy*; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage; D017209:Apoptosis; D053938:DNA Fragmentation; D005260:Female; D005434:Flow Cytometry; D015774:Ganciclovir / Q000008:administration & dosage; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008854:Microscopy, Electron; D009368:Neoplasm Transplantation; D015183:Restriction Mapping; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics; D014055:Tomography, Emission-Computed; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir