Stoichiometric inhibition of mammalian dihydrofolate reductase by the γ-glutamyl metabolite of methotrexate, 4-amino-4-deoxy-N10-methylpteroylglutamyl-γ-glutamate

Jacobs, Samuel A.; Adamson, Richard H.; Ba, Chabner; Derr, C.J.; Johns, D. G.

doi:10.1016/s0006-291x(75)80439-6

Cited by 77 publications

(13 citation statements)

References 9 publications

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“…As mentioned previously, DHFR is one of the few such enzymes that does not show a preference for polyglutamated folate substrates. MTX-Glu2 did not have greater inhibitory potency than the parent compound in initial studies with crude enzyme preparations (25) (Table I), including TS (26, 27) (Fig. 4), AICAR T'ase (28), and glycinamide ribonucleotide transformylase (GAR T'ase) (29).…”

Section: Pharmacologic Importance Ofpolyglutamationmentioning

confidence: 99%

Polyglutamation of methotrexate. Is methotrexate a prodrug?

Chabner¹,

Allegra²,

Curt³

et al. 1985

J. Clin. Invest.

426

258

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Section: Pharmacologic Importance Ofpolyglutamationmentioning

confidence: 99%

Polyglutamation of methotrexate. Is methotrexate a prodrug?

Chabner¹,

Allegra²,

Curt³

et al. 1985

J. Clin. Invest.

426

258

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“…MTX as well as its polyglutamated forms inhibit the enzyme dihydrofolate reductase (DHFR, see Fig. 1) [15,16] decreasing the level of the main folate form 5-methyl-tetrahydrofolate (5-methyl-THF). Repletion of the pool of reduced folates is possible by administration of calcium folinate, which is rapidly transformed into 5-methyl-THF (rescue).…”

Section: Introductionmentioning

confidence: 99%

Methotrexate‐associated alterations of the folate and methyl‐transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity

Vezmar

Schüsseler

Becker

et al. 2008

Pediatric Blood & Cancer

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BackgroundSevere neurotoxicity has been observed after systemic high‐dose and intrathecal methotrexate (MTX) treatment. The role of biochemical MTX‐induced alterations of the folate and methyl‐transfer pathway in the development of neurotoxic symptoms is not yet fully elucidated.ProcedureMTX, 5‐methyltetrahydrofolate, calcium folinate, S‐adenosylmethionine, and S‐adenosylhomocysteine were measured in the cerebrospinal fluid (CSF) of 29 patients with acute lymphoblastic leukemia (ALL) who were treated with high‐dose MTX (5 g/m2) followed by calcium folinate rescue (3 × 15 mg/m2) and/or intrathecal (8–12 mg) MTX. Two patients developed subacute MTX‐associated neurotoxicity. CSF was obtained by lumbal puncture 1–3 weeks after administration of MTX and shortly after the occurrence of neurotoxicity. The analytes were measured using HPLC assays with UV and/or fluorescence detection.ResultsIn non‐toxic patients, CSF concentrations of 5‐methyltetrahydrofolate and S‐adenosylmethionine were in the normal range 2 weeks after administration of high‐dose and intrathecal MTX followed by rescue. In contrast, when these patients received intrathecal MTX without rescue, 5‐methyltetrahydrofolate concentrations were significantly decreased 12 days after the first MTX administration. S‐adenosylmethionine concentrations were significantly decreased up to 45 days. The two patients suffering from neurotoxicity had decreased levels of 5‐methyltetrahydrofolate and S‐adenosylmethionine during or following toxicity. S‐adenosylhomocysteine was determined in all samples of neurotoxic patients but was below the limit of quantification in most samples of non‐toxic patients. Calcium folinate was not detected; MTX was present only in samples obtained during its infusion.ConclusionIntrathecal MTX without folinate rescue as well as MTX‐associated neurotoxicity are likely to be associated with specific alterations of the folate and methyl‐transfer pathway. Pediatr Blood Cancer 2009;52:26–32. © 2008 Wiley‐Liss, Inc.

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“…Following administration and absorption, MTX concentration in the serum decreases rapidly because of its structural similarity to folic acid and its cellular influx through the reduced folate carrier [131]. Intracellular MTX is rapidly converted by the enzyme folylpolyglutamate synthase, and MTX is retained as MTX-polyglutamate (MTX-PG), which is another inhibitor of dihydrofolate reductase, but it cannot be transported out of the cells again [132]. The accumulation of intracellular MTX-PGs allows for a prolonged intracellular presence with once-weekly administration [133].…”

Section: Methotrexate Metabolism and Folate Supplementationmentioning

confidence: 99%

Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease

et al. 2015

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Improving the efficacy and reducing the toxicity of thiopurines and methotrexate (MTX) have been areas of intense basic and clinical research. An increased knowledge on pharmacodynamics and pharmacokinetics of these immunomodulators has optimized treatment strategies in inflammatory bowel disease (IBD). This review focuses on the metabolism and mode of action of thiopurines and MTX, and provides an updated overview of individualized treatment strategies in which efficacy in IBD can be increased without compromising safety. The patient-based monitoring instruments adapted into clinical practice include pretreatment thiopurine S-methyltransferase testing, thiopurine metabolite monitoring, and blood count measurements that may help guiding the dosage to improve clinical outcome. Other approaches for optimizing thiopurine therapy in IBD include combination therapy with allopurinol, 5-aminosalicylates, and/or biologics. Similar strategies are yet to be proven effective in improving the outcome of MTX therapy. Important challenges for the management of IBD in the future relate to individualized dosing of immunomodulators for maximal efficacy with minimal risk of side effects. As low-cost conventional immunomodulators still remain a mainstay in pharmacotherapy of IBD, more research remains warranted, especially to substantiate these tailored management strategies in controlled clinical trials.

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Stoichiometric inhibition of mammalian dihydrofolate reductase by the γ-glutamyl metabolite of methotrexate, 4-amino-4-deoxy-N10-methylpteroylglutamyl-γ-glutamate

Cited by 77 publications

References 9 publications

Polyglutamation of methotrexate. Is methotrexate a prodrug?

Polyglutamation of methotrexate. Is methotrexate a prodrug?

Methotrexate‐associated alterations of the folate and methyl‐transfer pathway in the CSF of ALL patients with and without symptoms of neurotoxicity

Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease

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