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 trea tment and clinical trials with such vectors are ongoing, Targeting these ve ctors to cancer cells has been the focus of research. However, even if perf ect targeting were to be achieved, a vector still must effectively kill can cer cells and spread throughout the bulk of the tumor, The adenoviral E1b-1 9kD protein is a potent inhibitor of apoptosis and may therefore compromise the therapeutic efficacy of an adenoviral vector. In this study we have in vestigated if an E1b-19kD gene deletion could improve the ability of a repl icating adenoviral vector to spread through and kill cancer cells. In sever al lung cancer cell lines an E1b-19kD-deleted virus (Ad337) induced substan tially more apoptosis than did a wild-type virus (Ad309), and tumor cell su rvival was significantly reduced in three of four cell lines. In addition, the apoptotic effects of cisplatin or paclitaxel were augmented by Ad337, b ut inhibited by wild-type virus. The number of infectious virus particles i n the supernatant of infected cells was increased with Ad337 compared with wild-type virus, indicating enhanced early viral release. Ad337, in contras t to Ad309, induced significantly larger plaques after infection of A549 ce lls. 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 vira l spread. Loss of E1b-19kD function caused only minor cell line-specific in crease or decrease in viral yield. We conclude that deletion of the Elb-19k D gene may enhance the tumoricidal effects of a replicating adenoviral vect or.