Linked Life Data

16180016

Source:http://linkedlifedata.com/resource/pubmed/id/16180016

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
6
pubmed:dateCreated
2006-4-10
pubmed:abstractText
4'-Thio-arabinofuranosylcytosine (T-araC) is a new cytosine analog, which exhibits excellent antitumor activity against various solid tumor xenografts in mice. T-araC is a structural analog of arabinofuranosylcytosine (araC), which is known to be marginally active against solid tumors. We have continued to study the biochemical pharmacology of T-araC in solid tumor cells to further characterize the mechanism of action of this new agent and to elucidate why these compounds show a profound difference in antitumor activity against solid tumors. AraC was a slightly more potent inhibitor of cell growth than T-araC when cells were continuously exposed to the drugs. However, T-araC was markedly more cytotoxic than araC when high concentrations of the compounds were given for short periods of time. Despite the fact that T-araC is a much poorer substrate, as compared to araC, for deoxycytidine kinase (the rate-limiting step in the formation of the triphosphates), similar intracellular concentrations of T-araC-5'-triphosphate (T-araCTP) and araCTP were formed in cells at these high, pharmacologically relevant concentrations due to similar Vmax's. The major difference in the metabolism of araC and T-araC was that the half-life of T-araCTP was tenfold longer than that of araCTP and much higher levels of T-araCTP were sustained in cells for long durations after exposure to T-araC. Inhibition of cytidine deaminase, deoxycytidylate deaminase, or DNA replication did not affect the half-life of either araCTP or T-araCTP. In addition, the rates of disappearance of the mono- and tri-phosphates of araC and T-araC in crude cell extracts were similar. These results indicated that these enzymes were not rate-limiting in the degradation of the respective triphosphates. However, the rate of phosphorylation of T-araC-5'-monophosphate (T-araCMP) in crude cell extracts was about tenfold greater than that of araCMP. The results of this work suggested that the longer intracellular retention of T-araCTP was responsible for the superior activity of T-araC against solid tumors in vivo, and that the greater activity of T-araCMP as a substrate of UMP/CMP kinase was responsible for the long intracellular half-life of T-araCTP.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0344-5704
pubmed:author
pubmed:issnType
Print
pubmed:volume
57
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
772-80
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
Long intracellular retention of 4'-thio-arabinofuranosylcytosine 5'-triphosphate as a critical factor for the anti-solid tumor activity of 4'-thio-arabinofuranosylcytosine.
pubmed:affiliation
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, N.I.H., Extramural