Linked Life Data

7945405

Source:http://linkedlifedata.com/resource/pubmed/id/7945405

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
1994-11-10
pubmed:abstractText
A new dimeric fluoropyrimidine molecule (5-fluoro-2'-deoxyuridilyl-(5'-->3')-5-fluoro-2'-deoxy-5'-uridylic acid, Compound 1) was chemically synthesized from two separately deblocked 5-fluoro-2'-deoxyuridine mononucleotide moieties. Other structurally related nucleotides, 5-fluoro-2'-deoxyuridine-5'-diphosphate (FdUDP), 5-fluoro-2'-deoxyuridine-5'-triphosphate (FdUTP) and 5-fluoro-2'-deoxyuridine-3',5'-bisphosphate were also synthesized. The structures of all synthesized molecules were verified by mass spectrometric analyses and were consistent with expected molecular mass values. The metabolic patterns of conversion of Compound 1 were investigated both in human erythrocyte lysates and in intact erythrocytes previously loaded with this molecule according to a highly conservative encapsulation procedure. In hemolysates, Compound 1 was transformed to 5-fluoro-2'-deoxyuridine (FUdR) and to 5-fluorouracil (FU) through the intermediate formation of 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP). In intact red cells, Compound 1 still generated FUdR (and to a lesser extent FU), that was then released outside. The conversion pathway involves a phosphodiesterase-catalysed hydrolysis of Compound 1 into two FdUMP molecules, followed by further dephosphorylation to FUdR and by partial conversion to FU. Unlike hemolysates, Compound 1-loaded intact erythrocytes featured transient formation of FdUDP and FdUTP, both metabolites representing storage compounds for the final and sustained production of FUdR and FU. Therefore, human erythrocytes can behave as bioreactors ensuring the time-controlled production and delivery of the two powerful antitumor drugs FUdR and FU from encapsulated Compound 1. This new molecule and other compounds as well (e.g. FdUDP and FdUTP) can be viewed as useful pre-prodrugs, exploitable for intraerythrocytic bioconversion reactions.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0006-2952
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
48
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1121-8
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1994
pubmed:articleTitle
A novel dimeric fluoropyrimidine molecule behaves as a remote precursor of 5-fluoro-2'-deoxyuridine in human erythrocytes.
pubmed:affiliation
Institute of Biological Chemistry, University of Genova, Italy.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't