Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has previously been shown that the antiprotozoal drug pyrimethamine (PYR) in concentrations corresponding to those obtained in clinical practice temporarily suppressed the proliferation of phytohaemagglutinin (PHA-) stimulated human lymphocytes in vitro; 10-fold higher concentrations permanently suppressed PHA-stimulated cells, as indicated by decreased numbers of cells and DNA synthesis. In the present study, it was found that the 3H-deoxyuridine incorporation in PHA-stimulated lymphocytes was suppressed by PYR, and that PYR caused defective deoxyuridine suppression of 14C-thymidine incorporation. The effects of PYR were completely corrected by low concentrations of folinic acid and high concentrations of folic acid, indicating that the basic mechanism of action of PYR is competitive blocking of dihydrofolate reductase. However, the effect of PYR was poorly corrected by exogenous thymidine; therefore, reduced thymidylate synthesis cannot be the sole consequence of PYR exposure. It is suggested that an additional folate-dependent factor plays an important role in the antimitotic activity of PYR on lymphocytes.
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PMID:Pyrimethamine-induced alterations in human lymphocytes in vitro. Mechanisms and reversal of the effect. 405 Apr 44

MX-68 is a newly synthesized anti-folate, chemically designed not to undergo intracellular polyglutamation and to have increased affinity to dihydrofolate reductase (DHFR). In the present study, we examined the in vitro and in vivo biological activities of MX-68 compared with methotrexate (MTX) which forms several polyglutamates intracellularly. MX-68 dose-dependently inhibited the proliferation of PHA-, anti-CD3-, or PMA plus ionomycin-stimulated peripheral blood mononuclear cells (PBMC) and endothelial cells (EC) from normal subjects as well as IL-1 beta- or TNF alpha-stimulated synovial fibroblastic cells (SC) from rheumatoid arthritis (RA) patients. Coaddition of folinic acid completely reversed the anti-proliferative effects of both MX-68 and MTX. Although the anti-proliferative activities of MX-68 were almost comparable to those of MTX, the washout study clearly showed the characteristic nature of MX-68. When drugs were removed during culture, the suppressive effect of MX-68 completely disappeared, whereas suppression by MTX was merely weakened. MX-68 dramatically suppressed the onset of collagen-induced arthritis (CIA) in mice when the drug was orally administered three times a week. starting from the day of first immunization. In this model, 2 mg/kg of MX-68 was sufficient to completely suppress arthritis, whereas suppression by the same dose of MTX was partial. These lines of evidence suggest that polyglutamation is not always a prerequisite in the anti-rheumatic effects of anti-folate. In addition, since intracellular accumulation of polyglutamates is thought to have adverse effects, MX-68 may become a more potent and less toxic anti-rheumatic drug than MTX.
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PMID:In vitro and in vivo biological activities of a novel nonpolyglutamable anti-folate, MX-68. 891 93