期刊论文详细信息
Cancers
The Flavin Reductase MsuE Is a Novel Nitroreductase that Can Efficiently Activate Two Promising Next-Generation Prodrugs for Gene-Directed Enzyme Prodrug Therapy
Laura K. Green1  Mathew A. Storey1  Elsie M. Williams1  Adam V. Patterson2  Jeff B. Smaill2  Janine N. Copp1 
[1] School of Biological Sciences, Victoria University of Wellington, Kelburn Parade, Wellington 6140, New Zealand;Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, University of Auckland, Auckland 1142, New Zealand
关键词: gene therapy;    GDEPT;    nitroaromatic prodrug;    nitroreductase;    CB1954;    PR-104A;    Nitro-CBI-DEI;    SOS chromotest;   
DOI  :  10.3390/cancers5030985
来源: mdpi
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【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.

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