Dihydrofolate reductase as a therapeutic target Journal Article
| Authors: | Schweitzer, B. I.; Dicker, A. P.; Bertino, J. R. |
| Article Title: | Dihydrofolate reductase as a therapeutic target |
| Abstract: | 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. |
| Keywords: | review; nonhuman; methotrexate; protein conformation; animal; mammalia; drug resistance; enzyme activity; bacteria (microorganisms); species specificity; kinetics; models, molecular; molecular structure; amino acids; dihydrofolate reductase; thymidylate synthase; folic acid antagonists; tetrahydrofolate dehydrogenase; biochemistry; trimethoprim; trimetrexate; cooperativity; human; priority journal; support, non-u.s. gov't; support, u.s. gov't, p.h.s.; pyrimethamine; dihydrofolate; s- phase; tetrahydrofolate |
| Journal Title: | FASEB Journal |
| Volume: | 4 |
| Issue: | 8 |
| ISSN: | 0892-6638 |
| Publisher: | Federation of American Societies for Experimental Biology |
| Date Published: | 1990-05-01 |
| Start Page: | 2441 |
| End Page: | 2452 |
| Language: | English |
| PUBMED: | 2185970 |
| PROVIDER: | scopus |
| DOI: | 10.1096/fasebj.4.8.2185970 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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22Schweitzer
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