Linked Life Data

2521299

Source:http://linkedlifedata.com/resource/pubmed/id/2521299

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
1989-2-23
pubmed:abstractText
Fluorodeoxyuridine (FdUrd) is a cytotoxic analogue of thymidine which requires activation by thymidine kinase to FdUMP. FdUMP inhibits thymidylate synthetase and, thus, the synthesis of dTTP. 5'-Aminothymidine (5'-AdThd) can antagonize the feedback inhibition exerted by dTTP on thymidine kinase activity and thereby stimulate FdUrd phosphorylation. This provided a novel approach to assess the degree to which end product inhibition regulates the phosphorylation of FdUrd. We used 5'-AdThd to investigate the effects of dThd and IdUrd on the regulation of FdUrd uptake in intact 647V cells, a human bladder cancer cell line. Contributions from catabolic processes were found not to be important in our system. We detected no nucleoside phosphorylase activity in the 647V cells or any effect of 5'-AdThd on the breakdown of 5-fluorodeoxyuridine monophosphate to FdUrd by crude preparations from these cells. Thus, phosphorylation by thymidine kinase determined FdUrd uptake (phosphorylation). In the absence of added nucleosides the rate of FdUrd uptake increased in a time dependent fashion. Diminished feedback inhibition of thymidine kinase appeared to be an important factor, as evidenced by a decrease in intracellular dTTP pools and a time dependent loss in the ability of 5'-AdThd to stimulate FdUrd uptake. Thymidine and iododeoxyuridine inhibited FdUrd phosphorylation (uptake) by two mechanisms: competition for the active site of thymidine kinase and increased feedback inhibition. Increased feedback inhibition was indicated by stimulation of FdUrd uptake by 5'-AdThd. The effects of IdUrd on FdUrd uptake were also time dependent, presumably reflecting accumulation of iododeoxyuridine triphosphate and dTTP pools. FdUrd cytotoxicity was modulated by dThd, IdUrd, and 5'-AdThd in parallel to their perturbation of FdUrd uptake. Individually they reduced the growth inhibitory properties of FdUrd. These results show that the regulation of FdUrd uptake is critically dependent on the presence of dThd and IdUrd and emphasize the potential importance of circulating levels of these nucleosides in mediating FdUrd activation and cytotoxicity.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
49
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
618-24
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1989
pubmed:articleTitle
Regulation of the activation of fluorodeoxyuridine by substrate competition and feedback inhibition in 647V cells.
pubmed:affiliation
Department of Human Oncology, University of Wisconsin Clinical Cancer Center, University of Wisconsin School of Medicine, Madison 53792.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.