Methotrexate analogues display enhanced inhibition of TNF-α production in whole blood from RA patients

Heijden, J.W. van der; Assaraf, Yehuda G.; Gerards, A.; Oerlemans, Ruud; Lems, Willem F.; Scheper, R.J.; Dijkmans, Ben A. C.; Jansen, Gerrit

doi:10.3109/03009742.2013.797490

Cited by 9 publications

(9 citation statements)

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“…Thus, MTX targeting with respect to polarization of macrophages and the role of FRβ therein warrant further investigations. Given the fact that beyond MTX several other second-generation anti-folates have been developed which have demonstrated potential pre-clinical anti-arthritic activity [7, 9, 38–40], [ 18 F]fluoro-PEG - folate PET imaging may be useful for monitoring their efficacy.…”

Section: Discussionmentioning

confidence: 99%

In-vivo monitoring of anti-folate therapy in arthritic rats using [18F]fluoro-PEG-folate and positron emission tomography

et al. 2017

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BackgroundFolate receptor β (FRβ) is involved in facilitating cellular uptake of folates and anti-folates (such as methotrexate (MTX)). In rheumatoid arthritis, FRβ is expressed on synovial macrophages and recently has been explored as a biomarker for imaging in arthritic rats using the folate-based positron emission tomography (PET) tracer [18F]fluoro-PEG-folate. The purpose of this study was to examine whether this folate tracer can also be used to monitor therapeutic efficacy of MTX in arthritic rats.MethodsArthritic rats received either no treatment or MTX therapy (1 mg/kg, either 2× or 4×). Healthy rats did not receive any arthritic induction or therapy. [18F]fluoro-PEG-folate PET-CT scans (60 min) were performed before and after MTX therapy. Following PET, the ex-vivo tissue distribution of radioactivity was determined in excised knees and multiple tissues. Synovial macrophage infiltration in knee sections was quantified by immunohistochemistry using ED1 and ED2 antibodies.ResultsPET scans clearly visualized increased uptake of [18F]fluoro-PEG-folate in arthritic knees compared with contralateral knees. Significantly lower standard uptake values (1.5-fold, p < 0.01) were observed in arthritic knees of both MTX-treated groups after therapy, approximating the levels seen in healthy rats. Consistently, ex-vivo tissue distribution demonstrated a 2–4-fold lower tracer uptake in the arthritic knee of 2× and 4× MTX-treated rats, respectively, compared with control rats. These results were corroborated with significantly reduced (2–4-fold, p < 0.01) ED1-positive and ED2-positive synovial macrophages in arthritic knees of the MTX-treated rats compared with those of the control rats.ConclusionThis study in arthritic rats underscores the potential and usefulness of [18F]fluoro-PEG-folate PET as a therapeutic monitoring tool of MTX therapy and potentially other anti-folate treatment of arthritis.

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Section: Discussionmentioning

confidence: 99%

In-vivo monitoring of anti-folate therapy in arthritic rats using [18F]fluoro-PEG-folate and positron emission tomography

et al. 2017

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“…Given the fact that RFC is constitutively expressed on immune cells [ 87 , 88 ], including macrophages [ 86 , 89 ], and exhibits a much greater folate transport capacity than FRβ [ 68 , 81 ], it is still an unresolved issue whether the primary function of FRβ in macrophages is folate transport rather than other homeostatic or immune-regulatory functions. In rapidly proliferating cancer cells, folate transporters (Table 2 ) facilitate folate uptake to promote DNA synthesis [ 66 – 68 ].…”

Section: Folate Receptors (General Properties)mentioning

confidence: 99%

The folate receptor β as a macrophage-mediated imaging and therapeutic target in rheumatoid arthritis

Chandrupatla

Molthoff

Lammertsma

et al. 2018

Drug Deliv. and Transl. Res.

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Macrophages play a key role in the pathophysiology of rheumatoid arthritis (RA). Notably, positive correlations have been reported between synovial macrophage infiltration and disease activity as well as therapy outcome in RA patients. Hence, macrophages can serve as an important target for both imaging disease activity and drug delivery in RA. Folate receptor β (FRβ) is a glycosylphosphatidyl (GPI)-anchored plasma membrane protein being expressed on myeloid cells and activated macrophages. FRβ harbors a nanomolar binding affinity for folic acid allowing this receptor to be exploited for RA disease imaging (e.g., folate-conjugated PET tracers) and therapeutic targeting (e.g., folate antagonists and folate-conjugated drugs). This review provides an overview of these emerging applications in RA by summarizing and discussing properties of FRβ, expression of FRβ in relation to macrophage polarization, FRβ-targeted in vivo imaging modalities, and FRβ-directed drug targeting.

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“…101(2):311–317 (2006) [ 109 ] Raltitrexed van der Heijden et al Scand J Rheumatol. 43(1):9–16 (2014) [ 100 ] Balsalazide Carter et al Gut. 53(Suppl 5):V1-V16 (2004) [ 110 ] BIRB 796 Page et al Arthritis Rheum.…”

Section: Resultsmentioning

confidence: 99%

DrugGenEx-Net: a novel computational platform for systems pharmacology and gene expression-based drug repurposing

et al. 2016

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BackgroundThe targeting of disease-related proteins is important for drug discovery, and yet target-based discovery has not been fruitful. Contextualizing overall biological processes is critical to formulating successful drug-disease hypotheses. Network pharmacology helps to overcome target-based bottlenecks through systems biology analytics, such as protein-protein interaction (PPI) networks and pathway regulation.ResultsWe present a systems polypharmacology platform entitled DrugGenEx-Net (DGE-NET). DGE-NET predicts empirical drug-target (DT) interactions, integrates interaction pairs into a multi-tiered network analysis, and ultimately predicts disease-specific drug polypharmacology through systems-based gene expression analysis. Incorporation of established biological network annotations for protein target-disease, −signaling pathway, −molecular function, and protein-protein interactions enhances predicted DT effects on disease pathophysiology. Over 50 drug-disease and 100 drug-pathway predictions are validated. For example, the predicted systems pharmacology of the cholesterol-lowering agent ezetimibe corroborates its potential carcinogenicity.When disease-specific gene expression analysis is integrated, DGE-NET prioritizes known therapeutics/experimental drugs as well as their contra-indications. Proof-of-concept is established for immune-related rheumatoid arthritis and inflammatory bowel disease, as well as neuro-degenerative Alzheimer’s and Parkinson’s diseases.ConclusionsDGE-NET is a novel computational method that predicting drug therapeutic and counter-therapeutic indications by uniquely integrating systems pharmacology with gene expression analysis. DGE-NET correctly predicts various drug-disease indications by linking the biological activity of drugs and diseases at multiple tiers of biological action, and is therefore a useful approach to identifying drug candidates for re-purposing.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-1065-y) contains supplementary material, which is available to authorized users.

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Methotrexate analogues display enhanced inhibition of TNF-α production in whole blood from RA patients

Cited by 9 publications

References 42 publications

In-vivo monitoring of anti-folate therapy in arthritic rats using [18F]fluoro-PEG-folate and positron emission tomography

In-vivo monitoring of anti-folate therapy in arthritic rats using [18F]fluoro-PEG-folate and positron emission tomography

The folate receptor β as a macrophage-mediated imaging and therapeutic target in rheumatoid arthritis

DrugGenEx-Net: a novel computational platform for systems pharmacology and gene expression-based drug repurposing

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