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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
2
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pubmed:dateCreated |
1984-4-25
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pubmed:abstractText |
The purpose of this study was to compare the pools of free FdUMP derived from 5-fluorouracil (FUra) and of dUMP synthesized de novo in Hep-2 and S-180 cells, their relationship to inhibition of thymidylate synthase (dTMP synthase; EC 2.1.1.45), and the effect of excess folinic acid (CF) on these parameters. These cells differ 50-fold in their sensitivity to FUra and, in the absence of thymidine, dTMP synthase is the growth-limiting site of action of FUra in S-180 cells, but in Hep-2 cells this site becomes growth-limiting only in the presence of excess folates. In both cells after a 3-hr incubation with varied concentrations of FUra, FdUMP comprised only 0.1-0.2% of the total acid-soluble pools derived from FUra. The changes in dUMP and FdUMP pools paralleled each other, dUMP being 1000-2000 times higher than FdUMP. The pools of dUMP increased only when dTMP synthase was significantly inhibited. This occurred in S-180 cells above 3 microM FUra and in Hep-2 cells above 30 microM, where the residual dTMP synthase was similar in both cells. Under these conditions, the dUMP and FdUMP pools in Hep-2 cells were 2 and 4 times higher, respectively, than in S-180 cells. After FUra removal, both pools continued to increase, dUMP and FdUMP pools in Hep-2 cells rising 6-fold and 10-fold higher, respectively, than in S-180 cells. The dTMP synthase inhibition and the high nucleotide pools in Hep-2 were short-lived, whereas in S-180 cells the inhibition and the pools were maintained longer. Excess CF retarded the recovery of dTMP synthase after FUra removal only in Hep-2 cells and led to a further increase in dUMP and FdUMP pools in these cells, while having no effect in S-180 cells. These data indicate that a high capacity of cells to accumulate free FdUMP does not alone guarantee that dTMP synthase inhibition will be growth-limiting. The relationship shown here between excess CF, dTMP synthase recovery, and the nucleotide pools suggests that some cell types, such as Hep-2, in spite of high levels of FdUMP, require in addition an excess of folates to retard dTMP synthase recovery and make it growth-limiting.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Deoxyuracil Nucleotides,
http://linkedlifedata.com/resource/pubmed/chemical/Fluorodeoxyuridylate,
http://linkedlifedata.com/resource/pubmed/chemical/Fluorouracil,
http://linkedlifedata.com/resource/pubmed/chemical/Leucovorin,
http://linkedlifedata.com/resource/pubmed/chemical/Methyltransferases,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidylate Synthase
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0026-895X
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:volume |
25
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
303-9
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:6608049-Animals,
pubmed-meshheading:6608049-Carcinoma,
pubmed-meshheading:6608049-Cell Line,
pubmed-meshheading:6608049-Deoxyuracil Nucleotides,
pubmed-meshheading:6608049-Fluorodeoxyuridylate,
pubmed-meshheading:6608049-Fluorouracil,
pubmed-meshheading:6608049-Humans,
pubmed-meshheading:6608049-Kinetics,
pubmed-meshheading:6608049-Leucovorin,
pubmed-meshheading:6608049-Methyltransferases,
pubmed-meshheading:6608049-Sarcoma, Experimental,
pubmed-meshheading:6608049-Thymidylate Synthase
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pubmed:year |
1984
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pubmed:articleTitle |
Relationship of dUMP and free FdUMP pools to inhibition of thymidylate synthase by 5-fluorouracil.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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