Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.5.1.3 (dihydrofolate reductase)
5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many combinations of methotrexate and folic or folinic acid have been used to limit the side effects of methotrexate therapy in psoriasis or psoriatic arthropathy. Methotrexate inhibits the enzyme dihydrofolate reductase and prevents the formation of DNA and RNA. Folinic acid, the 5-formyl derivative of tetrahydrofolic acid, is the active form of folic acid. We have confirmed in 5 patients that continuous administration of folinic acid with weekly oral methotrexate prevents improvement of psoriasis. When folinic acid was ceased on the day of methotrexate in these patients their psoriasis improved. Five other patients with previous sensitivity to methotrexate, forcing cessation of therapy, were given weekly oral methotrexate and folinic acid every day except the day of methotrexate. Marked improvement of psoriasis or arthropathy occurred in each case without side effects. This method precisely limits the exposure to methotrexate, allowing a therapeutic effect without complication even in those patients who exhibit methotrexate sensitivity.
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PMID:Folinic acid rescue used routinely in psoriatic patients with known methotrexate "sensitivity". 136 37

Studies of the time course of methotrexate-derived antifolate activity (methotrexate activity) in plasma and skin of rats have been carried out to evaluate the hypothesis that the formation of therapeutically active poly-gamma-glutamyl conjugates of methotrexate in skin after systemic administration of the drug will result in the prolongation of methotrexate effects in skin. Such a finding may eventually bear on the use of the drug in the treatment of psoriasis. Three groups of 4 rats received a single i.v. dose of methotrexate, 5, 20, or 40 mg/kg, respectively. Serial skin and plasma samples were obtained over 48 h from each rat and analyzed for methotrexate activity by a dihydrofolate reductase enzyme inhibition assay. The values of pharmacokinetic parameters describing the disposition of the drug were calculated from plasma data using standard methods. Skin to plasma ratio of methotrexate activity was also calculated each time a skin sample was obtained. Pharmacokinetic parameter values and skin to plasma ratios were not significantly different between doses. Methotrexate activity declined biexponentially in plasma and skin. The terminal half-life in plasma (mean +/- SD) was 20.3 +/- 9.2 h. At early times, methotrexate activity in skin was less than plasma, but at later times activity in skin was an order of magnitude greater than that in plasma. In a preliminary study to determine whether the persistent activity in skin is associated with the presence of poly-gamma-glutamyl conjugates of methotrexate, a rat was dosed with tritiated methotrexate, 0.18 mg/kg, i.v., and skin was obtained 24 h later. Skin homogenate was treated with papain and applied to an anion-exchange column for cleanup prior to injection on a reversed-phase high-pressure liquid chromatography system. Methotrexate poly-gamma-glutamates were identified by elution with authentic standards and specific hydrolysis with carboxypeptidase G1.
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PMID:Persistence of antifolate activity in skin of rats following systemic administration of methotrexate. 669 Jun 31

To analyze if methotrexate (MTX) resistance arises from gene amplification in a patient treated clinically with MTX, the cytogenetic and drug sensitivity profile of the tumor colony forming units (TCFUs) from a 58-year-old woman with stage III well-differentiated ovarian serous adenocarcinoma was studied. This patient had not received treatment directed against her tumor for nine months before this study, but had received oral-dose MTX (2.5 mg, twice weekly) for three years for the treatment of psoriasis. Analysis of TCFUs grown in nucleoside-free media demonstrated MTX resistance at concentrations of up to 100 micrograms/mL (2.2 X 10(-4)M). Cytologic evidence for dihydrofolate reductase (DHFR) gene amplification in TCFUs was determined by in situ hybridization, using radiolabeled cDNA to DHFR mRNA. Results localized the DHFR sequences to an abnormally staining region present on chromosome 4q. This study supports the notion that alterations in gene dosage (that is, gene amplification) play a role in the development of drug resistance in spontaneous human cancers.
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PMID:Cytologic evidence for gene amplification in methotrexate-resistant cells obtained from a patient with ovarian adenocarcinoma. 669 60

An open, 12-week, multicentre study was conducted to assess the efficacy of piritrexim isethionate in the treatment of severe psoriasis. Piritrexim isethionate is a lipid-soluble dihydrofolate reductase inhibitor which cannot form polyglutamates, and may be as effective as methotrexate in the treatment of psoriasis. If, as is suspected, but as yet unproven, methotrexate polyglutamates are responsible for the hepatotoxicity of methotrexate, piritrexim should be less hepatotoxic, and may offer an alternative to methotrexate therapy. Fifty-five patients were enrolled, of whom 41 completed the study. Patients were allocated to receive either 150, 225, 300, or 450 mg of piritrexim weekly, in divided doses over 72 h (low-dose groups, 150 and 225 mg), or over 36 h (300 and 450 mg groups). Twenty-four of the 41 patients who completed the study had a greater than 50% improvement in the severity of their psoriasis, as demonstrated by a reduction in the Psoriasis Severity Score, a measure analogous to the PASI scoring system. Adverse events were common, but mild, and were controlled by dose reduction. Piritrexim appears to be an effective therapy for severe psoriasis at doses of 300 and 450 mg weekly, in three divided doses over 36 h.
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PMID:A multicentre 12-week open study of a lipid-soluble folate antagonist, piritrexim in severe psoriasis. 825 56

Methotrexate is a chemotherapy antimetabolite, folic acid antagonist, that inhibits the enzyme dihydrofolate reductase resulting in decreased levels of tetrahydrofolate in the cells. This in turn blocks synthesis of thymidylate, a nucleotide necessary for DNA synthesis. It is readily absorbed from the gastrointestinal tract. Toxicity from overdose can affect multiple organ systems including bone marrow, liver, intestinal tract, kidneys, lungs, skin, and blood vessels, resulting in death in severe cases. Methotrexate is widely used to treat neoplastic disease, dermatologic disorders (psoriasis), and rheumatologic disorders (severe rheumatoid arthritis). As its indications for use increase, more accidental overdoses can be expected. We present the treatment and clinical course of one such case, that of a 2-year-old who accidentally took her grandmother's arthritis pills. Her initial serum level was 10 times greater than that needed to cause toxicity. She was treated with gastric lavage, activated charcoal, leucovorin rescue, and ICU admission. Her clinical course was unremarkable, and the only evidence of toxicity was a mild elevation in a liver-associated enzyme that resolved without any clinical sequela. Leucovorin at a dose equal to or greater than the possible ingestion should be given as soon as possible in methotrexate overdoses.
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PMID:Pediatric case of accidental oral overdose of methotrexate. 1038 2

Methotrexate (MTX) inhibits DNA synthesis by competition with dihydrofolate reductase. Adverse cutaneous reactions to MTX are usually dose-related and have been mainly reported in patients receiving extremely large doses of chemotherapy. Painful erosion of psoriatic plaques has been often reported as an early sign of MTX toxicity, but cutaneous ulceration as a sign of MTX toxicity in patients without psoriasis has only been described in one case. We report a patient with rheumatoid arthritis and without psoriasis who developed cutaneous ulceration on the knuckles as a sign of MTX toxicity. Cutaneous ulceration by MTX toxicity is an exclusion diagnosis and its pathogenic mechanism may be multifactorial, including direct toxicity of the drug in addition to local factors.
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PMID:Cutaneous ulceration as a sign of methotrexate toxicity. 1152 55

Derivatives of the vitamin folic acid function in the body for the synthesis of thymidylate, purines and amino acids and are necessary for normal metabolism and growth. Methotrexate (MTX), an inhibitor of dihydrofolate reductase (DHFR) is the outstanding example of an antitumor antifolate. MTX is clinically useful in the treatment of childhood leukemia, choriocarcinoma and psoriasis, where it corrects abnormal growth, and in rheumatoid arthritis and other autoimmune diseases where it corrects abnormal immune function. Since 1949, when the chemical synthesis of MTX was reported by workers at the Lederle Laboratories of the American Cyanamid Company, much has been learned about the basis of antifolate cytotoxicity and selectivity. This review will focus on deaza antifolates which are: 1). presently under clinical development and 2). less developed compounds which represent novel approaches. Compounds will be grouped according to their enzyme targets; DHFR, thymidylate synthase (TS) and glycinamide ribonucleotide formyltransferase (GARFT). In addition to inhibition of target enzymes, antifolate membrane transport into cells and conversion to poly-L-gamma-glutamate forms are important considerations in drug design along with the reverse processes, cellular hydrolysis of antifolate poly-L-gamma-glutamates to monoglutamates and the extrusion of the monoglutamates through the cell membrane. These processes can be modulated by competition with folates.
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PMID:Deaza analogs of folic acid as antitumor agents. 1452 45

A naturally occurring gallated polyphenol isolated from green tea leaves, (-)-epigallocatechin gallate (EGCG), has been shown to be an inhibitor of dihydrofolate reductase (DHFR) activity in vitro at concentrations found in the serum and tissues of green tea drinkers (0.1-1.0 micromol/L). These data provide the first evidence that the prophylactic effect of green tea drinking on certain forms of cancer, suggested by epidemiologic studies, is due to the inhibition of DHFR by EGCG and could also explain why tea extracts have been traditionally used in "alternative medicine" as anticarcinogenic/antibiotic agents or in the treatment of conditions such as psoriasis. EGCG exhibited kinetics characteristic of a slow, tight-binding inhibitor of 7,8-dihydrofolate reduction with bovine liver DHFR (K(I) = 0.109 micromol/L), but of a classic, reversible, competitive inhibitor with chicken liver DHFR (K(I) = 10.3 micromol/L). Structural modeling showed that EGCG can bind to human DHFR at the same site and in a similar orientation to that observed for some structurally characterized DHFR inhibitor complexes. The responses of lymphoma cells to EGCG and known antifolates were similar, that is, a dose-dependent inhibition of cell growth (IC50 = 20 micromol/L for EGCG), G0-G1 phase arrest of the cell cycle, and induction of apoptosis. Folate depletion increased the sensitivity of these cell lines to antifolates and EGCG. These effects were attenuated by growing the cells in a medium containing hypoxanthine-thymidine, consistent with DHFR being the site of action for EGCG.
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PMID:The antifolate activity of tea catechins. 1616 39

Methotrexate (MTX) is an anti-metabolite widely used in the treatment of neoplastic disorders, rheumatoid arthritis and psoriasis. The basis for its therapeutic efficacy is the inhibition of dihydrofolate reductase (DHFR), a key enzyme in the folic acid (FA) metabolism. FA is a water-soluble vitamin which is involved in the synthesis of purines and pyrimidines, the essential precursors of DNA. Folinic acid (FNA) is the reduced form of FA that circumvents the inhibition of DHFR. Folate supplementation during MTX therapy for psoriasis and inflammatory arthritis reduces both toxicity and side effects without compromising the efficacy. Further, FNA supplementation reduces the common side effects of MTX in the treatment of juvenile idiopathic arthritis. FA and FNA are reported to have protective effects on MTX-induced genotoxicity in the somatic cells; however their protective effects on the germ cells have not been much explored. Previously, we evaluated the cytotoxic and genotoxic effects of MTX in the germ cells of mice. In the present study, we have intervened FA and FNA for the protection of germ cell toxicity induced by MTX in male swiss mice. The animals were pre-treated with FA at the doses of 50, 100 and 200 microg/kg for 4 consecutive days per week and on day five; MTX was administered at the dose of 20mg/kg once. FNA was administered at the doses of 2.5, 5 and 10 mg/kg, 6 h (h) after single administration of MTX at the dose of 20 mg/kg. The dosing regimen was continued up to 10 weeks. The germ cell toxicity was evaluated using testes weight (wt), sperm count, sperm head morphology, sperm comet assay, histology, TUNEL and halo assay in testis. The results clearly demonstrate that prior administration of FA and post-treatment with FNA reduces the germ cell toxicity induced by MTX as evident from the decreased sperm head abnormalities, seminiferous tubule damage, sperm DNA damage, TUNEL positive cells and increased sperm counts. In the present study, we report that FA and FNA ameliorate the germ cell toxicity of MTX in mice.
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PMID:Methotrexate-induced cytotoxicity and genotoxicity in germ cells of mice: intervention of folic and folinic acid. 1911 71

Methotrexate (MTX) is an antimetabolite and antifolate drug used in the treatment of cancer and autoimmune diseases. MTX inhibits DNA synthesis by competitive inhibition of dihydrofolate reductase in immunologically active cells. It also decreases inflammation by other mechanisms. Cutaneous toxicity is usually dose-related and generally occurs when recommended guidelines are ignored or there is a decrease in renal excretion. Self-medication is a problem with unknown prevalence. Signs of MTX toxicity include bone marrow suppression, hepatotoxicity, and mucocutaneous toxicity. Painful erosions of psoriatic plaques and, less commonly, erosions in patients without psoriasis have been reported as an early sign of MTX toxicity. To our knowledge, this is the first case of skin toxicity related to MTX that affected the normal skin and spared the psoriatic plaques.
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PMID:Focal skin toxicity related to methotrexate sparing psoriatic plaques. 2057 71


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