Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many non-steroidal anti-inflammatory drugs (NSAIDs) (including sulphasalazine, sulindac, indomethacin, naproxen, salicylic acid, ibuprofen, piroxicam and mefenamic acid) were found to be competitive inhibitors (with respect to folate) of avian liver phosphoribosylaminoimidazolecarboxamide formyltransferase (AICAR transformylase, EC 2.1.2.3) and bovine liver dihydrofolate reductase (EC 1.5.1.3). In contrast, aspirin and the antipyretic-analgesic drugs acetaminophen and antipyrine were weak inhibitors of these enzymes. Structure-activity correlation suggests that an aromatic ring with a side chain containing a carboxylic acid is a requirement for competitive inhibition of the transformylase. The above-listed NSAIDs also inhibited the folate-coenzyme-mediated biosynthesis of serine from glycine and formate (i.e., the C1 index) by human blood mononuclear cells (BMCs) in experiments where the drug was added to a culture of BMCs. Acetaminophen had a weak inhibitory effect on the C1 index. Consistent with the results obtained in vitro is the observation that the C1 index of BMCs from rheumatoid-arthritis patients treated with drugs which possess little antifolate activity (e.g. acetaminophen) is higher than the C1 index of BMCs from rheumatoid-arthritis patients treated with NSAIDs possessing more potent antifolate activity (e.g. sulindac, sulphasalazine, naproxen and ibuprofen). The mean activity of the transformylase in BMCs taken from healthy humans was 1.98 nmol of product/h per 10(6) cells and the activity was positively correlated with BMC folate levels. These results are consistent with the hypothesis that (1) the antifolate activity of NSAIDs, and hence cytostatic consequences, are important factors in producing anti-inflammatory activity and (2) aspirin exerts its anti-inflammatory effects after its conversion into salicylic acid, which possesses greater antifolate activity than its parent compound.
 ...
PMID:Inhibition of folate-dependent enzymes by non-steroidal anti-inflammatory drugs. 154 Jan 35

The mode of action of low-dose methotrexate (MTX) in rheumatoid arthritis (RA) is unclear. The effects of MTX are mediated primarily through inhibition of dihydrofolate reductase, resulting in a dose-dependent inhibition of purine and pyrimidine synthesis. Other folate-dependent metabolic pathways might be secondarily affected. One such pathway is the regeneration of methionine from homocysteine, with subsequent formation of the methyl donor S-adenosylmethionine (SAM) and polyamines, which are important in cell-mediated immune reactions. To assess whether MTX inhibits SAM and polyamine synthesis in lymphocytes, pokeweed mitogen-stimulated mononuclear cells from healthy donors were incubated with MTX. This resulted in decreased proliferation and IgG, IgM, and IgM rheumatoid factor synthesis. However, addition of folinic acid, methionine, SAM, or spermidine resulted in reversal of the MTX-mediated inhibition. These data suggest that MTX inhibits the folate-dependent pathway of methionine regeneration, thereby inhibiting SAM and polyamine synthesis. Since RA lymphocytes have increased concentrations of polyamines, the beneficial effects of MTX in RA may be related to its potential ability to reduce polyamine synthesis.
Arthritis Rheum 1990 Jul
PMID:The in vitro effects of methotrexate on peripheral blood mononuclear cells. Modulation by methyl donors and spermidine. 197 54

Because of a previously observed plateau of clinical response after long-term methotrexate (MTX) therapy for rheumatoid arthritis (RA), we investigated whether such treatment might lead to acquired resistance to the drug. We studied the activity of dihydrofolate reductase (DHFR) (the target enzyme of MTX) in peripheral blood mononuclear cells of 11 RA patients who had been treated with MTX for a median of 43 months. The enzyme levels were markedly increased compared with levels found in the cells of 6 RA patients treated with other slow-acting drugs. Quantitative dot-blot analysis of DNA from 7 of these patients showed no evidence of DHFR gene amplification. No correlation was observed between increased levels of DHFR and either response to therapy or to the weekly MTX dosage. Phytohemagglutinin-stimulated peripheral blood lymphocytes from 6 patients with increased levels of DHFR showed no evidence of MTX resistance in vitro. The increased DHFR levels may result from binding of MTX to the enzyme, which may block the normal degradation pathways; they do not appear to be a marker of impending drug resistance.
Arthritis Rheum 1987 Apr
PMID:Increase of dihydrofolate reductase in peripheral blood lymphocytes of rheumatoid arthritis patients treated with low-dose oral methotrexate. 358 7

A number of studies show the efficacy of methotrexate (MTX) for rheumatoid arthritis (RA) in general. However, is there any reason to single this drug out for early RA? Mechanistically, it probably works differently in RA than in cancer, at least in part. Thus, in addition to dihydrofolate reductase-related effects, MTX inhibits aminoimidazocarboxamide transformylase, decreases leukotriene B4 production, and increases adenosine release at concentrations achieved with low-dose MTX regimens. Clinically, it is well tolerated over relatively long periods. Further, a recent meta-analysis of radiology studies shows that MTX compares favorably with intramuscular gold and is better than azathioprine. Toxicity remains a concern in treating early RA, particularly as pulmonary "hypersensitivity reactions" continue (1% to 7.6%), infections (both fungal and perioperative) are documented, and more cirrhosis is found. With all of the above in mind, the use of MTX seems reasonable but not necessarily uniformly appropriate and not yet proved for early RA. Studies of MTX in early RA, particularly in combination with other drugs, are only beginning.
Semin Arthritis Rheum 1994 Jun
PMID:Should methotrexate be used to treat early rheumatoid arthritis? 793 30

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.
 ...
PMID:In vitro and in vivo biological activities of a novel nonpolyglutamable anti-folate, MX-68. 891 93

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.
 ...
PMID:Pediatric case of accidental oral overdose of methotrexate. 1038 2

The mechanism of action for the anti-arthritic effect of methotrexate (MTX) was investigated in rats with antigen-induced arthritis (AIA). Arthritis intensity was quantified as area under the curve (AUC) for the joint swelling. The response to MTX was in several respects similar to what is seen in the clinic. The drug reduced the AUC in a dose-dependent manner after oral weekly (2-4 mg/kg/week) or daily (0.3 mg/kg/day) dosing. This effect was not affected by supplementation with an equal dose of folate. The model thus seemed suitable for this type of study. Supplementation with folate in excess abolished the effect of MTX. A structurally similar antifolate, aminopterin, also reduced the arthritis. The effect thus seemed to be due to folate antagonism although a complete inhibition of dihydrofolate reductase (DHFR) might not be essential. Hence, it could be that the main target is a process downstream of DHFR. It has been proposed that inhibition of AICAR-transformylase induce the release of adenosine with anti-inflammatory properties. Here the adenosine antagonist R-PIA reduced the arthritis but when MTX was combined with adenosine antagonists no attenuation of the anti-arthritic effect was seen. On the contrary, three adenosine agonists (8-p-sulphophenyltheophyllamine 30 mg/kg i.p. twice daily; 3,7-dimethyl-1-propargylxanthine, p.o. 3 mg/kg/day and 8-cyclopentyl-1,3-dipropylxanthine, 1.5 mg/kg/day p.o.) potentiated MTX. The specific thymidylate synthase inhibitor 5-fluourouracil (0. 3-3.0 mg/kg/day) had no anti-arthritic effect. Neither did our data support the hypotheses that syntheses of polyamines or cytokines were primary targets. It is thus possible that the mechanism of action is inhibition of a process downstream of DHFR but the release of adenosine seems not to be important.
 ...
PMID:Anti-arthritic effect of methotrexate: is it really mediated by adenosine? 1066 73

N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]-carbonyl]-L-homoglutamic acid (MX-68), a derivative of methotrexate, was chemically designed to resist polyglutamation and to have a high affinity for dihydrofolate reductase, in an attempt to reduce the side effects of methotrexate. We confirmed that MX-68 did not undergo polyglutamation and investigated the pharmacological activities of MX-68 compared with methotrexate. (1) In vitro: MX-68 inhibited the activity of dihydrofolate reductase to the same degree as methotrexate-tetraglutamate. MX-68 treatment produced a similar anti-proliferative effect to that of methotrexate. However, the intracellular concentration of MX-68 was much lower than the sum of the levels of methotrexate and its polyglutamate, and the effects of MX-68 disappeared when it was removed from the culture medium. (2) In vivo: Oral administration of MX-68 suppressed the development of collagen-induced arthritis in mice and adjuvant-induced arthritis in rats, in a similar fashion to that of methotrexate. These results indicate that polyglutamation is not essential for the anti-arthritic effect of antifolates.
 ...
PMID:Polyglutamation of a novel antifolate, MX-68, is not necessary for its anti-arthritic effect. 1182 Oct 32

Much attention has focused on the development of protein kinases as drug targets to treat a variety of human diseases including diabetes, cancer, hypertension and arthritis. To date, Gleevec is one example of a drug targeting protein that has successfully treated human cancer. Several other protein kinase inhibitors are in clinical development. However, protein kinases are in fact part of a larger collection of some 2000 distinct proteins expressed by the genome that like the protein kinases also bind purines (the purinome), either to be utilized as substrates or as co-factors in the form of NAD, NADP and co-enzyme A. The solution structures of many representative gene family members within the purinome show these proteins bind purines in a similar orientations to that observed in all protein kinases. Several non-protein kinase purine utilizing proteins are established drug targets such as HMG CoA reductase, dihydrofolate reductase, phosphodiesterase and HSP90. Searches of OMIM identifies many purine utilizing enzymes that are associated with inborn errors in metabolism. Inhibition of any one of which by a drug could lead to an undesirable side effect. The purinome is therefore somewhat of a drug discovery mixed blessing. It is a rich source of therapeutic targets, but also contains a large collection of diverse proteins whose inhibition could result in an adverse outcome. Drug discovery within the purinome should therefore encompass strategies that enable broad assessment of selectivity across the entire purinome at the earliest stages of the discovery process. In this article we review the purinome within the context of drug discovery and discuss approaches for avoiding off target binding during the discovery/lead optimization process with particular emphasis on use of proteome mining technology.
 ...
PMID:The purinome, a complex mix of drug and toxicity targets. 1684 50

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.
 ...
PMID:Methotrexate-induced cytotoxicity and genotoxicity in germ cells of mice: intervention of folic and folinic acid. 1911 71


1 2 Next >>