Document Detail

Dihydrofolate reductase as a therapeutic target.
MedLine Citation:
PMID:  2185970     Owner:  NLM     Status:  MEDLINE    
The folate antagonists are an important class of therapeutic compounds, as evidenced by their use as antiinfective, antineoplastic, and antiinflammatory drugs. Thus far, all of the clinically useful drugs of this class have been inhibitors of dihydrofolate reductase (DHFR), a key enzyme in the synthesis of thymidylate, and therefore, of DNA. The basis of the antiinfective selectivity of these compounds is clear; the antifolates trimethoprim and pyrimethamine are potent inhibitors of bacterial and protozoal DHFRs, respectively, but are only weak inhibitors of mammalian DHFRs. These species-selective agents apparently exploit the differences in the active site regions of the parasite and host enzymes. Methotrexate is the DHFR inhibitor used most often in a clinical setting as an anticancer drug and as an antiinflammatory and immunosuppressive agent. Considerable progress has been made recently in understanding the biochemical basis for the selectivity of this drug and the biochemical mechanism (or mechanisms) responsible for the development of resistance to treatment with the drug. This understanding has led to a new generation of DHFR inhibitors that are now in clinical trials.
B I Schweitzer; A P Dicker; J R Bertino
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.; Review    
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  4     ISSN:  0892-6638     ISO Abbreviation:  FASEB J.     Publication Date:  1990 May 
Date Detail:
Created Date:  1990-06-12     Completed Date:  1990-06-12     Revised Date:  2012-02-15    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  2441-52     Citation Subset:  IM    
Laboratory of Molecular Pharmacology, Cornell University Graduate School of Medical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
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MeSH Terms
Amino Acids
Drug Resistance / genetics
Folic Acid Antagonists*
Methotrexate / therapeutic use
Models, Molecular
Molecular Structure
Protein Conformation
Species Specificity
Tetrahydrofolate Dehydrogenase / genetics,  metabolism
Grant Support
Reg. No./Substance:
0/Amino Acids; 0/Folic Acid Antagonists; 59-05-2/Methotrexate; EC Dehydrogenase

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