Deletion of the adenoviral E1b-19kD gene enhances tumor cell killing of a replicating adenoviral vector.
Replicating adenoviral vectors are a promising new modality for cancer treatment and clinical trials with such vectors are ongoing. Targeting these vectors to cancer cells has been the focus of research. However, even if perfect targeting were to be achieved, a vector still must effectively kill cancer cells and spread throughout the bulk of the tumor. The adenoviral E1b-19kD protein is a potent inhibitor of apoptosis and may therefore compromise the therapeutic efficacy of an adenoviral vector. In this study we have investigated if an E1b-19kD gene deletion could improve the ability of a replicating adenoviral vector to spread through and kill cancer cells. In several lung cancer cell lines an E1b-19kD-deleted virus (Ad337) induced substantially more apoptosis than did a wild-type virus (Ad309), and tumor cell survival was significantly reduced in three of four cell lines. In addition, the apoptotic effects of cisplatin or paclitaxel were augmented by Ad337, but inhibited by wild-type virus. The number of infectious virus particles in the supernatant of infected cells was increased with Ad337 compared with wild-type virus, indicating enhanced early viral release. Ad337, in contrast to Ad309, induced significantly larger plaques after infection of A549 cells. This well-described large plaque phenotype of an E1b-19kD mutant virus is likely the result of early viral release and enhanced cell-to-cell viral spread. Loss of E1b-19kD function caused only minor cell line-specific increase or decrease in viral yield. We conclude that deletion of the E1b-19kD gene may enhance the tumoricidal effects of a replicating adenoviral vector.
Sauthoff
H
H
Department of Medicine, New York University School of Medicine, NY 10016, USA.
Heitner
S
S
Rom
W N
WN
Hay
J G
JG
D000256:Adenoviridae / Q000235:genetics*; D017501:Adenovirus E1B Proteins / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D002945:Cisplatin / Q000494:pharmacology; D017353:Gene Deletion; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D010948:Viral Plaque Assay; D014779:Virus Replication
D017501:Adenovirus E1B Proteins; D000970:Antineoplastic Agents; D017239:Paclitaxel; D002945:Cisplatin