Linked Life Data

6865913

Source:http://linkedlifedata.com/resource/pubmed/id/6865913

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
1983-8-11
pubmed:abstractText
In HeLa and Vero cells the antiproliferative effects of iododeoxyuridine (IdUrd) were modulated in a biphasic manner by 5'-amino-5'-deoxythymidine (5'-AdThd). Low concentrations of 5'-AdThd increased the cytotoxicity of IdUrd whereas high concentrations of 5'-AdThd were antagonistic. Opposing effects on two enzymes, thymidine kinase (EC 2.7.1.21) and thymidylate kinase (EC 2.7.4.9), account for this unusual biphasic interaction. In the case of thymidine kinase, 5'-AdThd was found to antagonize the feedback inhibition which is normally exerted by the 5'-triphosphates of thymidine and IdUrd. Consequently, 5'-AdThd increased the rate of IdUrd phosphorylation. This stimulation (deinhibition) of enzyme activity was demonstrable in cell-free extracts and with a purified preparation of thymidine kinase provided that the 5'-triphosphates of IdUrd or thymidine were present. In their absence only enzyme inhibition was detected. In intact cells this stimulatory effect of 5'-AdThd was seen as a rapidly apparent, sustained increase in the steady-state levels of the phosphorylated IdUrd metabolites. As a result, IdUrd cytotoxicity was increased. Under these conditions, 5'-AdThd did not alter the relative abundance of the mono-, di-, and triphosphates of IdUrd. However, as the concentration of 5'-AdThd was raised, the percentage of IdUrd nucleotides present as iododeoxyuridylate increased dramatically. Corresponding reductions in the incorporation of IdUrd into cellular DNA and the associated cytotoxic effects were seen. These data suggested a second site of interaction, thymidylate kinase, the enzyme responsible for the conversion of iododeoxyuridylate to the diphosphate. In experiments measuring thymidylate kinase activity in cell-free extracts, 5'-AdThd effectively inhibited the phosphorylation of iododeoxyuridylate but not that of thymidylate. Additionally, 5'-AdThd did not produce an accumulation of thymidylate in intact cells. Thus, the ability of high concentrations of 5'-AdThd to antagonize the cytotoxicity produced by IdUrd without concomitantly inhibiting the phosphorylation of thymidylate and, thereby, reducing DNA synthesis was explained. Although the modulation of IdUrd metabolism produced by 5'-AdThd was qualitatively similar in Vero and HeLa cells, key quantitative differences were evident. Thus, 100 microM 5'-AdThd stimulated the uptake of 3 microM IdUrd in Vero cells but it was inhibitory in HeLa cells. Perturbation of nucleoside metabolism by agents such as 5'-AdThd may provide an important new way to achieve selective toxicity in cancer chemotherapy.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0026-895X
pubmed:author
pubmed:issnType
Print
pubmed:volume
23
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
709-16
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1983
pubmed:articleTitle
Modulation of the metabolism and cytotoxicity of iododeoxyuridine by 5'-amino-5'-deoxythymidine.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't