Mechanism of cell death induced by the novel enzyme-prodrug combination, nitroreductase/CB1954, and identification of synergism with 5-fluorouracil

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...

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Autores principales: Palmer, D H, Milner, A E, Kerr, D J, Young, L S
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2003
Materias:
Experimental Therapeutics
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394473/
https://www.ncbi.nlm.nih.gov/pubmed/12942130
http://dx.doi.org/10.1038/sj.bjc.6601211
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author Palmer, D H
Milner, A E
Kerr, D J
Young, L S
author_facet Palmer, D H
Milner, A E
Kerr, D J
Young, L S
author_sort Palmer, D H
collection PubMed
description 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.
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spelling pubmed-23944732009-09-10 Mechanism of cell death induced by the novel enzyme-prodrug combination, nitroreductase/CB1954, and identification of synergism with 5-fluorouracil Palmer, D H Milner, A E Kerr, D J Young, L S Br J Cancer Experimental Therapeutics 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. Nature Publishing Group 2003-09-01 2003-08-26 /pmc/articles/PMC2394473/ /pubmed/12942130 http://dx.doi.org/10.1038/sj.bjc.6601211 Text en Copyright © 2003 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Experimental Therapeutics
Palmer, D H
Milner, A E
Kerr, D J
Young, L S
Mechanism of cell death induced by the novel enzyme-prodrug combination, nitroreductase/CB1954, and identification of synergism with 5-fluorouracil
title Mechanism of cell death induced by the novel enzyme-prodrug combination, nitroreductase/CB1954, and identification of synergism with 5-fluorouracil
title_full Mechanism of cell death induced by the novel enzyme-prodrug combination, nitroreductase/CB1954, and identification of synergism with 5-fluorouracil
title_fullStr Mechanism of cell death induced by the novel enzyme-prodrug combination, nitroreductase/CB1954, and identification of synergism with 5-fluorouracil
title_full_unstemmed Mechanism of cell death induced by the novel enzyme-prodrug combination, nitroreductase/CB1954, and identification of synergism with 5-fluorouracil
title_short Mechanism of cell death induced by the novel enzyme-prodrug combination, nitroreductase/CB1954, and identification of synergism with 5-fluorouracil
title_sort mechanism of cell death induced by the novel enzyme-prodrug combination, nitroreductase/cb1954, and identification of synergism with 5-fluorouracil
topic Experimental Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394473/
https://www.ncbi.nlm.nih.gov/pubmed/12942130
http://dx.doi.org/10.1038/sj.bjc.6601211
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