E. coli nitroreductase/CB1954 gene-directed enzyme prodrug therapy: role of arylamine N-acetlytransferase 2

Mitchell, D. J. and Minchin, R. F. (2008) E. coli nitroreductase/CB1954 gene-directed enzyme prodrug therapy: role of arylamine N-acetlytransferase 2. Cancer Gene Therapy, 15 11: 758-764. doi:10.1038/cgt.2008.47


Author Mitchell, D. J.
Minchin, R. F.
Title E. coli nitroreductase/CB1954 gene-directed enzyme prodrug therapy: role of arylamine N-acetlytransferase 2
Journal name Cancer Gene Therapy   Check publisher's open access policy
ISSN 0929-1903
Publication date 2008-01-01
Year available 2008
Sub-type Article (original research)
DOI 10.1038/cgt.2008.47
Open Access Status
Volume 15
Issue 11
Start page 758
End page 764
Total pages 7
Editor Scanlon, K. J
Sobol, R. E
Place of publication United Kingdom
Publisher Nature Publishing Group
Language eng
Subject C1
111201 Cancer Cell Biology
920102 Cancer and Related Disorders
Abstract Gene-directed enzyme prodrug therapy is a promising approach to the local management of cancer and a number of gene prodrug combinations have entered clinical trials. The antitumor activity of Escherichia coli nitroreductase (NTR) in combination with the prodrug CB1954 relies on the reduction of the nitro groups to reactive N-hydroxylamine intermediates that are toxic in proliferating and nonproliferating cells. We examined whether secondary metabolic activation of the N-hydroxylamines by sulfotransferases or acetyltransferases altered cell responsiveness to the drug. We evaluated the coexpression of NTR with the human cytosolic sulfotransferases SULT1A1, 1A2, 1A3, 1E1 and 2A1, or the human arylamine N-acetyltransferases NAT1 and NAT2 on SKOV3 cell survival. Only NAT2 significantly altered the toxicity of CB1954, decreasing the IC50 16-fold from 0.61 to 0.04 mM. These results suggest that one or more of the N-hydroxyl metabolites are a substrate for O-acetylation by NAT2. We also examined the bystander effect of SKOV3 cells expressing NTR or NTR plus NAT2. Addition of the acetyltransferase resulted in a significant decreased bystander effect (P>0.01), possibly due to a lower concentration of reactive metabolites in the culture medium. These results suggest that a combination of bacterial NTR and NAT2 may provide a greater clinical response at therapeutic concentrations of CB1954 provided the reduction in bystander effect is not clinically significant. Moreover, endogenous NAT2, which is localized predominantly in the liver and gut, may be involved in the dose-limiting hepatic toxicity and gastrointestinal side effects seen in patients treated with the higher doses of CB1954.
Keyword CB1954
nitroreductase
sulfotransferase
N-acetyltransferase
ESCHERICHIA-COLI
5-(AZIRIDIN-1-YL)-2,4-DINITROBENZAMIDE CB1954
ACETYLATION
CB-1954
BIOACTIVATION
ACTIVATION
CANCER
ACETYLTRANSFERASES
SULFOTRANSFERASES
METABOLISM
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
School of Biomedical Sciences Publications
 
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Created: Wed, 18 Mar 2009, 22:06:06 EST