Personalized medicine in rheumatoid arthritis: methotrexate polyglutamylation revisited

Muller, Ittai B.; Hebing, Renske F.; Jansen, Gerrit; Nurmohamed, Michael T.; Lems, Willem F.; Peters, Godefridus J.; Jonge, Robert de

doi:10.1080/23808993.2018.1517025

Cited by 12 publications

(18 citation statements)

References 24 publications

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“…After their uptake inside the cell by the reduced folate carrier 35,36 , MTX and PTX undergo polyglutamylation by ATP-dependent folylpoly-γ-glutamate synthetase (FPGS), analogously to the folate species 37–40 . Polyglutamylation renders folates (or antifolates) polyanions that are not recognized by cellular efflux systems, and therefore accumulate in cellular compartments 41 .…”

Section: Discussionmentioning

confidence: 99%

Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models

Ruszkowski

Sekula

Ruszkowska

et al. 2019

Sci Rep

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Serine hydroxymethyltransferases (SHMTs) reversibly transform serine into glycine in a reaction accompanied with conversion of tetrahydrofolate (THF) into 5,10-methylene-THF (5,10-meTHF). In vivo, 5,10-meTHF is the main carrier of one-carbon (1C) units, which are utilized for nucleotide biosynthesis and other processes crucial for every living cell, but hyperactivated in overproliferating cells (e.g. cancer tissues). SHMTs are emerging as a promising target for development of new drugs because it appears possible to inhibit growth of cancer cells by cutting off the supply of 5,10-meTHF. Methotrexate (MTX) and pemetrexed (PTX) are two examples of antifolates that have cured many patients over the years but target different enzymes from the folate cycle (mainly dihydrofolate reductase and thymidylate synthase, respectively). Here we show crystal structures of MTX and PTX bound to plant SHMT isozymes from cytosol and mitochondria—human isozymes exist in the same subcellular compartments. We verify inhibition of the studied isozymes by a thorough kinetic analysis. We propose to further exploit antifolate scaffold in development of SHMT inhibitors because it seems likely that especially polyglutamylated PTX inhibits SHMTs in vivo. Structure-based optimization is expected to yield novel antifolates that could potentially be used as chemotherapeutics.

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Section: Discussionmentioning

confidence: 99%

Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models

Ruszkowski

Sekula

Ruszkowska

et al. 2019

Sci Rep

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“…MTX‐related toxicity may include hematologic, gastrointestinal disorders, hepatotoxicity, renal or cutaneous manifestations such as mucocutaneous damage, erythema multiforme, toxic epidermal necrolysis and cutaneous ulceration, among others 17 . The above has caused that 15%–30% of patients leave MTX treatment at early stage before 12 weeks on therapy or require discontinuation due to secondary failure, after the initial response at 24 weeks 3,16 . In such way, the EULAR recommends that monitoring should be frequent at the beginning of the disease and, if there is no improvement by 12 weeks after the start of treatment or the target has not been reached at 24 weeks, therapy should be modified 2 .…”

Section: Introductionmentioning

confidence: 99%

“…Rheumatoid arthritis (RA) is a complex public health problem, which requires a tight control and follow-up to attain a low disease activity or remission. [1][2][3] According to European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR), changes in the Disease Activity Score (DAS28) from the beginning of RA treatment allow to classify patients as good (ΔDAS28 > 1.2) and moderate responders (0.6 < ΔDAS28 ≤ 1.2) or non-responders (ΔDAS28 ≤ 0.6) considering as clinical remission when signs and symptoms of inflammatory disease depict a DAS28 < 2.4. 4 Current therapy strategies are focused on achieving remission or low disease activity in the early stages of the disease.…”

Section: Introductionmentioning

confidence: 99%

Disease activity and therapeutic drug monitoring of polyglutamates of methotrexate after daily or weekly administration of low‐dose methotrexate in patients recently diagnosed with rheumatoid arthritis

Rodríguez-Báez

Huerta-García

Medellín‐Garibay

et al. 2022

Basic Clin Pharma Tox

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Low‐dose methotrexate can be challenging to treat rheumatoid arthritis due to side effects, lack of adherence and risk of medication errors. The aim of this study was to explore the safety and efficacy of low‐dose methotrexate administered daily or weekly in patients with rheumatoid arthritis. Patients were randomized according to a total oral dose of 12.5 mg of methotrexate administered: (A) divided in 5 days/week and (B) once per week. Patients were assessed along 24 weeks after starting treatment. Polyglutamates of methotrexate were quantified by ultrahigh‐performance liquid chromatography coupled to tandem mass spectrometer. Patients from groups A and B showed a good response to methotrexate treatment in 29% and 25.5%, respectively, and a global frequency of adverse events of 37%. Methotrexate polyglutamate 3 concentrations were higher in normal weight (body mass index 18.5–24.9 kg/m2) than in obese (body mass index 30 kg/m2) patients with a median (interquartile range) of 28 (17.95–45.15) and 10.35 (5.22–30.88) nM without differences between dosage groups. Daily dosage regimen represents a therapeutic alternative without compromising the efficacy and safety of methotrexate treatment and with similar adherence patterns than weekly dosage regimen; further, methotrexate polyglutamate 3 concentrations could be a useful tool for therapeutic drug monitoring purposes.

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“…As such, future directions for MTX therapeutic drug monitoring and MTX-PG analyses warrant extension to relevant immune cells, which are analytically feasible by combined liquid chromatography and mass spectrometry technology with labeled internal standards. 24 Also, inclusion of a laboratory marker to better define the extent and duration of smoking, such as cotinine, 25 may be helpful for correlations with clinical response and laboratory variables. These studies may guide further improvement of current MTX nonresponse prediction models by inclusion of novel variables.…”

mentioning

confidence: 99%

Smoking and Methotrexate Inefficacy in Rheumatoid Arthritis: What About Underlying Molecular Mechanisms?

Jansen

Rotte²,

Jonge³

2021

J Rheumatol

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The study by Safy-Khan, et al in the current issue of The Journal of Rheumatology1 reports that in a methotrexate (MTX)-based treatment regimen for patients with early arthritis, current smoking was significantly associated with a smaller reduction of Disease Activity Score in 28 joints (DAS28) over time compared to noncurrent smoking. This negative effect of current smoking on DAS28 was dose-dependent: patients who smoked 10–19 cigarettes per day did worse than patients who smoked 1–9 cigarettes per day.

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Personalized medicine in rheumatoid arthritis: methotrexate polyglutamylation revisited

Cited by 12 publications

References 24 publications

Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models

Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models

Disease activity and therapeutic drug monitoring of polyglutamates of methotrexate after daily or weekly administration of low‐dose methotrexate in patients recently diagnosed with rheumatoid arthritis

Smoking and Methotrexate Inefficacy in Rheumatoid Arthritis: What About Underlying Molecular Mechanisms?

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