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Virus-directed enzyme prodrug therapy (VDEPT) utilising the bacterial enzyme nitroreductase delivered by a replication-defective adenovirus vector to activate the prodrug CB1954 is a promising strategy currently undergoing clinical trials in patients with a range of cancers. An understanding of the mechanism of tumour cell death induced by activated CB1954 will facilitate this clinical development. Here, we report that activated CB1954 kills cells predominantly by caspase-dependent apoptosis. This may have important implications for the generation of immune-mediated bystander effects. Further, the use of a replication-defective adenovirus vector to deliver nitroreductase may negatively affect cellular apoptotic pathways stimulated by activated CB1954. Finally, examination of nitroreductase/CB1954 in combination with conventional chemotherapy reveals a synergistic interaction with 5-fluorouracil. These data will facilitate the further development and future clinical trial design of this novel therapy.

Original publication

DOI

10.1038/sj.bjc.6601211

Type

Journal article

Journal

Br J Cancer

Publication Date

01/09/2003

Volume

89

Pages

944 - 950

Keywords

Adenoviridae, Antimetabolites, Antineoplastic, Apoptosis, Aziridines, Blotting, Western, Caspases, Drug Synergism, Enzyme Inhibitors, Female, Flow Cytometry, Fluorouracil, Gene Transfer Techniques, Genetic Therapy, Genetic Vectors, Humans, Nitroreductases, Ovarian Neoplasms, Prodrugs, Tumor Cells, Cultured