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E. coli NfsA: an alternative nitroreductase for prodrug activation gene therapy in combination with CB1954
Prodrug activation gene therapy is a developing approach to cancer treatment, whereby prodrug-activating enzymes are expressed in tumour cells. After administration of a non-toxic prodrug, its conversion to cytotoxic metabolites directly kills tumour cells expressing the activating enzyme, whereas t...
Autores principales: | , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Nature Publishing Group
2009
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690450/ https://www.ncbi.nlm.nih.gov/pubmed/19455141 http://dx.doi.org/10.1038/sj.bjc.6605094 |
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author | Vass, S O Jarrom, D Wilson, W R Hyde, E I Searle, P F |
author_facet | Vass, S O Jarrom, D Wilson, W R Hyde, E I Searle, P F |
author_sort | Vass, S O |
collection | PubMed |
description | Prodrug activation gene therapy is a developing approach to cancer treatment, whereby prodrug-activating enzymes are expressed in tumour cells. After administration of a non-toxic prodrug, its conversion to cytotoxic metabolites directly kills tumour cells expressing the activating enzyme, whereas the local spread of activated metabolites can kill nearby cells lacking the enzyme (bystander cell killing). One promising combination that has entered clinical trials uses the nitroreductase NfsB from Escherichia coli to activate the prodrug, CB1954, to a potent bifunctional alkylating agent. NfsA, the major E. coli nitroreductase, has greater activity with nitrofuran antibiotics, but it has not been compared in the past with NfsB for the activation of CB1954. We show superior in vitro kinetics of CB1954 activation by NfsA using the NADPH cofactor, and show that the expression of NfsA in bacterial or human cells results in a 3.5- to 8-fold greater sensitivity to CB1954, relative to NfsB. Although NfsB reduces either the 2-NO(2) or 4-NO(2) positions of CB1954 in an equimolar ratio, we show that NfsA preferentially reduces the 2-NO(2) group, which leads to a greater bystander effect with cells expressing NfsA than with NfsB. NfsA is also more effective than NfsB for cell sensitisation to nitrofurans and to a selection of alternative, dinitrobenzamide mustard (DNBM) prodrugs. |
format | Text |
id | pubmed-2690450 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-26904502009-09-21 E. coli NfsA: an alternative nitroreductase for prodrug activation gene therapy in combination with CB1954 Vass, S O Jarrom, D Wilson, W R Hyde, E I Searle, P F Br J Cancer Translational Therapeutics Prodrug activation gene therapy is a developing approach to cancer treatment, whereby prodrug-activating enzymes are expressed in tumour cells. After administration of a non-toxic prodrug, its conversion to cytotoxic metabolites directly kills tumour cells expressing the activating enzyme, whereas the local spread of activated metabolites can kill nearby cells lacking the enzyme (bystander cell killing). One promising combination that has entered clinical trials uses the nitroreductase NfsB from Escherichia coli to activate the prodrug, CB1954, to a potent bifunctional alkylating agent. NfsA, the major E. coli nitroreductase, has greater activity with nitrofuran antibiotics, but it has not been compared in the past with NfsB for the activation of CB1954. We show superior in vitro kinetics of CB1954 activation by NfsA using the NADPH cofactor, and show that the expression of NfsA in bacterial or human cells results in a 3.5- to 8-fold greater sensitivity to CB1954, relative to NfsB. Although NfsB reduces either the 2-NO(2) or 4-NO(2) positions of CB1954 in an equimolar ratio, we show that NfsA preferentially reduces the 2-NO(2) group, which leads to a greater bystander effect with cells expressing NfsA than with NfsB. NfsA is also more effective than NfsB for cell sensitisation to nitrofurans and to a selection of alternative, dinitrobenzamide mustard (DNBM) prodrugs. Nature Publishing Group 2009-06-16 2009-05-19 /pmc/articles/PMC2690450/ /pubmed/19455141 http://dx.doi.org/10.1038/sj.bjc.6605094 Text en Copyright © 2009 Cancer Research UK https://creativecommons.org/licenses/by-nc-sa/3.0/This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/. |
spellingShingle | Translational Therapeutics Vass, S O Jarrom, D Wilson, W R Hyde, E I Searle, P F E. coli NfsA: an alternative nitroreductase for prodrug activation gene therapy in combination with CB1954 |
title | E. coli NfsA: an alternative nitroreductase for prodrug activation gene therapy in combination with CB1954 |
title_full | E. coli NfsA: an alternative nitroreductase for prodrug activation gene therapy in combination with CB1954 |
title_fullStr | E. coli NfsA: an alternative nitroreductase for prodrug activation gene therapy in combination with CB1954 |
title_full_unstemmed | E. coli NfsA: an alternative nitroreductase for prodrug activation gene therapy in combination with CB1954 |
title_short | E. coli NfsA: an alternative nitroreductase for prodrug activation gene therapy in combination with CB1954 |
title_sort | e. coli nfsa: an alternative nitroreductase for prodrug activation gene therapy in combination with cb1954 |
topic | Translational Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690450/ https://www.ncbi.nlm.nih.gov/pubmed/19455141 http://dx.doi.org/10.1038/sj.bjc.6605094 |
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