Linked Life Data

18600257

Source:http://linkedlifedata.com/resource/pubmed/id/18600257

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2008-10-8
pubmed:abstractText
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 IC(50) 16-fold from 0.61 to 0.04 microM. 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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1476-5500
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
15
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
758-64
pubmed:meshHeading
pubmed-meshheading:18600257-Analysis of Variance, pubmed-meshheading:18600257-Antineoplastic Agents, pubmed-meshheading:18600257-Arylamine N-Acetyltransferase, pubmed-meshheading:18600257-Aziridines, pubmed-meshheading:18600257-Blotting, Western, pubmed-meshheading:18600257-Cell Line, Tumor, pubmed-meshheading:18600257-Cell Survival, pubmed-meshheading:18600257-DNA Primers, pubmed-meshheading:18600257-Drug Therapy, pubmed-meshheading:18600257-Escherichia coli, pubmed-meshheading:18600257-Female, pubmed-meshheading:18600257-Flow Cytometry, pubmed-meshheading:18600257-Humans, pubmed-meshheading:18600257-Hydroxylamines, pubmed-meshheading:18600257-Inhibitory Concentration 50, pubmed-meshheading:18600257-Nitroreductases, pubmed-meshheading:18600257-Ovarian Neoplasms, pubmed-meshheading:18600257-Plasmids, pubmed-meshheading:18600257-Prodrugs, pubmed-meshheading:18600257-Sulfotransferases
pubmed:year
2008
pubmed:articleTitle
E. coli nitroreductase/CB1954 gene-directed enzyme prodrug therapy: role of arylamine N-acetlytransferase 2.
pubmed:affiliation
School of Biomedical Sciences, University of Queensland, St Lucia, Queensland, Australia.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't