Late expression of p53 from a replicating adenovirus improves tumor cell killing and is more tumor cell specific than expression of the adenoviral death protein.
Gene transfer of p53 induces cell death in most cancer cells, and replication-defective adenoviral vectors expressing p53 are being evaluated in clinical trials. However, low transduction efficiency limits the efficacy of replication-defective vector systems for cancer therapy. The use of replication-competent vectors for gene delivery may have several advantages, holding the potential to multiply and spread the therapeutic agent after infection of only a few cells. However, expression of a transgene may adversely affect viral replication. We have constructed a replicating adenoviral vector (Adp53rc) that expresses high levels of p53 at a late time point in the viral life cycle and also contains a deletion of the adenoviral death protein (ADP). Adp53rc-infected cancer cells demonstrated high levels of p53 expression in parallel with the late expression pattern of the adenoviral fiber protein. p53 expression late in the viral life cycle did not impair effective virus propagation. Survival of several lung cancer cell lines was significantly diminished after infection with Adp53rc, compared with an identical p53-negative control virus. p53 expression also improved virus release and spread. Interestingly, p53 was more cytotoxic than the ADP in cancer cells but less cytotoxic than the ADP in normal cells. In conclusion, late expression of p53 from a replicating virus improves tumor cell killing and viral spread without impairing viral replication. In addition, in combination with a deletion of the ADP, specificity of tumor cell killing is improved.
Sauthoff
Harald
H
Division of Pulmonary and Critical Care Medicine, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
Pipiya
Teona
T
Heitner
Sheila
S
Chen
Shu
S
Norman
Robert G
RG
Rom
William N
WN
Hay
John G
JG
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D017503:Adenovirus E3 Proteins / Q000502:physiology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003588:Cytopathogenic Effect, Viral; D005347:Fibroblasts / Q000166:cytology; D015967:Gene Expression Regulation, Viral; D016158:Genes, p53; D005822:Genetic Vectors / Q000235:genetics* / Q000502:physiology; D008175:Lung Neoplasms / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000502:physiology*; D014779:Virus Replication
D017503:Adenovirus E3 Proteins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; C099609:adenovirus death protein, Adenovirus