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,* email
Received: 31 May 2013; in revised form: 23 July 2013 / Accepted: 26 July 2013 / Published: 8 August 2013
(This article belongs to the Special Issue Cancers Gene Therapy)
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.
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
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MDPI and ACS Style

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.

AMA Style

Green LK, Storey MA, Williams EM, Patterson AV, Smaill JB, Copp JN, Ackerley DF. 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(3):985-997.

Chicago/Turabian Style

Green, Laura K.; Storey, Mathew A.; Williams, Elsie M.; Patterson, Adam V.; Smaill, Jeff B.; Copp, Janine N.; Ackerley, David F. 2013. "The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy." Cancers 5, no. 3: 985-997.

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