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Cancers 2013, 5(3), 985-997; doi:10.3390/cancers5030985
Article

The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy

1, 1, 1,2, 3,4, 3,4, 1,2,3 and 1,2,3,*
1 School of Biological Sciences, Victoria University of Wellington, Kelburn Parade, Wellington 6140, New Zealand 2 Victoria University Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington, Wellington 6140, New Zealand 3 Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, University of Auckland, Auckland 1142, New Zealand 4 Auckland Cancer Society Research Centre, University of Auckland, Grafton, Auckland 1142, New Zealand
* Author to whom correspondence should be addressed.
Received: 31 May 2013 / Revised: 23 July 2013 / Accepted: 26 July 2013 / Published: 8 August 2013
(This article belongs to the Special Issue Cancers Gene Therapy)
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Abstract

Bacterial nitroreductase enzymes that can efficiently catalyse the oxygen-independent reduction of prodrugs originally developed to target tumour hypoxia offer great potential for expanding the therapeutic range of these molecules to aerobic tumour regions, via the emerging cancer strategy of gene-directed enzyme prodrug therapy (GDEPT). Two promising hypoxia prodrugs for GDEPT are the dinitrobenzamide mustard PR-104A, and the nitrochloromethylbenzindoline prodrug nitro-CBI-DEI. We describe here use of a nitro-quenched fluorogenic probe to identify MsuE from Pseudomonas aeruginosa as a novel nitroreductase candidate for GDEPT. In SOS and bacteria-delivered enzyme prodrug cytotoxicity assays MsuE was less effective at activating CB1954 (a first-generation GDEPT prodrug) than the “gold standard” nitroreductases NfsA and NfsB from Escherichia coli. However, MsuE exhibited comparable levels of activity with PR-104A and nitro-CBI-DEI, and is the first nitroreductase outside of the NfsA and NfsB enzyme families to do so. These in vitro findings suggest that MsuE is worthy of further evaluation in in vivo models of GDEPT.
Keywords: gene therapy; GDEPT; nitroaromatic prodrug; nitroreductase; CB1954; PR-104A; Nitro-CBI-DEI; SOS chromotest gene therapy; GDEPT; nitroaromatic prodrug; nitroreductase; CB1954; PR-104A; Nitro-CBI-DEI; SOS chromotest
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Green, L.K.; Storey, M.A.; Williams, E.M.; Patterson, A.V.; Smaill, J.B.; Copp, J.N.; Ackerley, D.F. The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy. Cancers 2013, 5, 985-997.

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