Linked Life Data

11849051

Source:http://linkedlifedata.com/resource/pubmed/id/11849051

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2002-2-18
pubmed:abstractText
The antitumor agent sulofenur (LY186641), which has shown promising activity against a wide range of cancers, causes hemolytic anemia and methemoglobinemia at dose-limiting toxicities. The antitumor and toxicological mechanism(s) of action of the drug is (are) not well understood, but unlike other antineoplastic agents, sulofenur does not interfere with DNA, RNA, or protein synthesis, or with polynucleotide function. In the present study, we evaluated the hypothesis that sulofenur undergoes bioactivation in vivo to generate p-chlorophenyl isocyanate (CPIC), which could carbamoylate biological macromolecules directly or form a conjugate with glutathione (GSH) which would serve as a latent form of CPIC. The objectives of this study, therefore, were to determine if the GSH and N-acetylcysteine conjugates of CPIC were excreted into bile and urine, respectively, after an i.p. dose of sulofenur to rats. In addition, the chemical stability and thiol exchange properties of these S-linked conjugates were determined. The results of this study indicate that sulofenur does undergo metabolism in vivo to yield the GSH conjugate of CPIC, and that this conjugation reaction is reversible and subject to thiol exchange in buffered aqueous solution (pH 7.4, 37 degrees C). In contrast, sulofenur itself was stable under these same conditions, even in the presence of GSH and glutathione-S-transferase (GST), thus raising the possibility that bioactivation of sulofenur is necessary for liberation of CPIC. These findings suggest that the generation of this isocyanate in vivo and subsequent carbamoylation of biological macromolecules may play a role in the toxicity and/or antitumor activity of sulofenur and related diarylsulfonylureas.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0893-228X
pubmed:author
pubmed:issnType
Print
pubmed:volume
15
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
240-8
pubmed:dateRevised
2003-11-14
pubmed:meshHeading
pubmed:year
2002
pubmed:articleTitle
Glutathione-dependent metabolism of the antitumor agent sulofenur. Evidence for the formation of p-chlorophenyl isocyanate as a reactive intermediate.
pubmed:affiliation
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, Washington 98195, USA.
pubmed:publicationType
Journal Article