Document Detail


Intrinsic resistance to methotrexate of cultured mammalian cells in relation to the inhibition kinetics of their dihydrololate reductases.
MedLine Citation:
PMID:  5189     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Four cultured mammalian cell lines, differing in intrinsic resistance to methotrexate over a 70-fold range, have been compared with respect to several biochemical factors that might influence response to the drug. Cellular activity of the enzymes dihydrofolate reductase and thymidylate synthetase and the total levels of folate cofactors did not vary by more than a factor of 2 among the cell lines. All the cell types were able to transport extracellular methotrexate efficiently across the cell membrane, and at comparable rates. A kinetic study of highly purified dihydrofolate reductases from the four sources revealed small differences in the Km values for dihydrofolate and reduced nicotinamide adenine dinucleotide phosphate. A study was made of the inhibition of the four dihydrofolate reductases by methotrexate, and Ki values were obtained by fitting the Zone B equation of Goldstein (Goldstein, A., J. Gen. Physiol., 27: 529-580, 1944) to the resulting data. Values Ki determined by this method correlated with intrinsic resistance of the cell lines and showed a 25-fold range from the most sensitive to the most resistant line. It is concluded that the response of a cell to methotrexate is significantly influenced by the dissociation constant of its dihydrofolate reductase-methotrexate complex.
Authors:
R C Jackson; L I Hart; K R Harrap
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Cancer research     Volume:  36     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  1976 Jun 
Date Detail:
Created Date:  1976-08-02     Completed Date:  1976-08-02     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1991-7     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Biological Transport
Cell Membrane / metabolism
Cells, Cultured
Drug Resistance
Folic Acid / analogs & derivatives,  analysis
Folic Acid Antagonists*
Kinetics
Methotrexate / metabolism,  pharmacology*
NADP / metabolism
Tetrahydrofolate Dehydrogenase / analysis,  metabolism
Thymidylate Synthase / analysis
Chemical
Reg. No./Substance:
0/Folic Acid Antagonists; 53-59-8/NADP; 59-05-2/Methotrexate; 59-30-3/Folic Acid; EC 1.5.1.3/Tetrahydrofolate Dehydrogenase; EC 2.1.1.45/Thymidylate Synthase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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