Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs—from bench to bedside

Heijden, J.W. van der; Dijkmans, Ben A. C.; Scheper, Rik J.; Jansen, Gerrit

doi:10.1038/ncprheum0380

Cited by 108 publications

(96 citation statements)

References 50 publications

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“…This is the first detailed study investigating RA synovial tissue expression of a panel of multidrug transporter proteins from the family of ABC transporters, which are known to confer resistance to multiple anticancer drugs as well as DMARDs (9,26). Immunohistochemical detection of P-glycoprotein, MRP-2 through MRP-5, MRP-8, and MRP-9 in RA synovial tissue was not observed, in contrast to the drug transporters MRP-1 and BCRP, the latter being markedly expressed on RA synovial tissue macrophages in the intimal lining layer and the synovial sublining and on endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide

Heijden¹,

Oerlemans²,

Tak³

et al. 2009

Arthritis & Rheumatism

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Objective. To determine whether multidrugresistance efflux transporters are expressed on immune effector cells in synovial tissue from patients with rheumatoid arthritis (RA) and compromise the efficacy of methotrexate (MTX) and leflunomide (LEF).Methods. Synovial tissue biopsy samples obtained from RA patients before treatment and 4 months after starting treatment with MTX (n ‫؍‬ 17) or LEF (n ‫؍‬ 13) were examined by immunohistochemical staining and digital image analysis for the expression of the drug efflux transporters P-glycoprotein, multidrug resistance-associated protein 1 (MRP-1) through MRP-5, MRP-8, MRP-9, and breast cancer resistance protein (BCRP), and the relationship to clinical efficacy of MTX and LEF was assessed.Results. BCRP expression was observed in all RA synovial biopsy samples, both pretreatment and posttreatment, but not in control noninflammatory synovial tissue samples from orthopedic patients. BCRP expression was found both in the intimal lining layer and on macrophages and endothelial cells in the synovial sublining. Total numbers of macrophages in RA patients decreased upon treatment; in biopsy samples with persistently high macrophage counts, 2-fold higher BCRP expression was observed. Furthermore, median BCRP expression was significantly increased (3-fold) in nonresponders to disease-modifying antirheumatic drugs (DMARDs) compared with responders to DMARDs (P ‫؍‬ 0.048). Low expression of MRP-1 was found on synovial macrophages, along with moderate expression in T cell areas of synovial biopsy specimens from one-third of the RA patients.Conclusion. These findings show that the drug resistance-related proteins BCRP and MRP-1 are expressed on inflammatory cells in RA synovial tissue. Since MTX is a substrate for both BCRP and MRP-1, and LEF is a high-affinity substrate for BCRP, these transporters may contribute to reduced therapeutic efficacy of these DMARDs.

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Section: Discussionmentioning

confidence: 99%

Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide

Heijden¹,

Oerlemans²,

Tak³

et al. 2009

Arthritis & Rheumatism

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“…18 Moreover, the efficacy for bortezomib may differ between tumor types. 6,[19][20][21] Whether these observations are related to common mechanisms of drug resistance frequently seen for anticancer 22 or anti-inflammatory drugs 23 is largely unknown. However, their characterization is of key importance as it may pave the way for the overcoming of drug resistance, thereby enhancing the efficacy of this new class of proteasome-targeted drugs.…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of bortezomib resistance: proteasome subunit β5 (PSMB5) gene mutation and overexpression of PSMB5 protein

Oerlemans

Franke

Assaraf

et al. 2008

Blood

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The proteasome inhibitor bortezomib is a novel anticancer drug that has shown promise in the treatment of refractory multiple myeloma. However, its clinical efficacy has been hampered by the emergence of drug-resistance phenomena, the molecular basis of which remains elusive. Toward this end, we here developed high levels (45-to 129-fold) of acquired resistance to bortezomib in human myelomonocytic THP1 cells by exposure to stepwise increasing (2.5-200 nM) concentrations of bortezomib. Study of the molecular mechanism of bortezomib resistance in these cells revealed (1) an Ala49Thr mutation residing in a highly conserved bortezomib-binding pocket in the proteasome ␤5-subunit (PSMB5) protein, (2) a dramatic overexpression (up to 60-fold) of PSMB5 protein but not of other proteasome subunits including PSMB6, PSMB7, and PSMA7, (3) high levels of cross-resistance to ␤5 subunit-targeted cytotoxic peptides 4A6, MG132, MG262, and ALLN, but not to a broad spectrum of chemotherapeutic drugs, (4) no marked changes in chymotrypsin-like proteasome activity, and (5) IntroductionThe ubiquitin proteasome system (UPS) facilitates the degradation of ubiquitin-tagged intracellular proteins, many of which play a regulatory role in cell proliferation, cell survival, and signaling processes. [1][2][3] As such, proteasome inhibitors have been recognized as a new generation of chemotherapeutic agents and antiinflammatory drugs. [4][5][6][7][8][9][10][11][12][13] The boronic dipeptide bortezomib (PS341, Velcade) is the first proteasome inhibitor that has been approved for the treatment of refractory multiple myeloma. 6,14 Bortezomib is a reversible inhibitor that targets primarily the ␤5-subunit (PSMB5) subunit/chymotrypsin-like activity of the 26S proteasome and to a somewhat lesser extent also caspase-like activity harbored by the ␤1 (PSMB6) proteasome subunit. At higher concentrations, bortezomib inhibits trypsin-like proteolytic activity facilitated by ␤2 (PSMB7) proteasome subunits. [15][16][17] Despite promising clinical activity, some patients with multiple myeloma failed to respond to bortezomib therapy. 18 Moreover, the efficacy for bortezomib may differ between tumor types. 6,[19][20][21] Whether these observations are related to common mechanisms of drug resistance frequently seen for anticancer 22 or anti-inflammatory drugs 23 is largely unknown. However, their characterization is of key importance as it may pave the way for the overcoming of drug resistance, thereby enhancing the efficacy of this new class of proteasome-targeted drugs.One mode of primary resistance to bortezomib is conveyed by constitutively high levels of heat shock protein 27. 24 In the context of acquired resistance, studies aimed at delineating the mechanism of acquired resistance to the tripeptidyl aldehyde proteasome inhibitor ALLN (N-acetyl-leucyl-leucyl-norleucinal) revealed 2 possible molecular mechanisms: (a) enhanced cellular efflux via the multidrug resistance (MDR) transporter P-glycoprotein (Pgp; ABCC1) 25 or multidrug resistance-related pro...

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“…Over the past years, several treatment strategies with multiple DMARD's [8], step-up, step-down, saw tooth and parallel treatment have emerged [9]. However, once remission is achieved with DMARDs, there are no clear guidelines for maintenance therapy, although strategies are described in situations requiring drug withdrawal/dose modiWcation at the occurrence of adverse drug reactions (ADR), lack of eYcacy and development of resistance [5,[10][11][12][13][14][15]. Also, pharmacogenetic variations in the pattern of rheumatoid arthritis in diVerent populations [16], and genetic diVerences in eYcacy and safety to drugs [17][18][19][20][21], demand studies to be conducted in diVerent populations separately.…”

Section: Introductionmentioning

confidence: 99%

Causes of DMARD withdrawal following ADR within 6 months of initiation among Indian rheumatoid arthritis patients

et al. 2010

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The present study was conducted in Indian rheumatoid arthritis (RA) patients prescribed disease-modifying anti-rheumatic drugs (DMARDs) to determine the incidence and type of adverse drug reactions (ADRs) leading to their withdrawal in the initial 6 months of therapy. This was considered important as pharmacogenetic variations in the pattern of RA in different populations and genetic differences in efficacy and safety to drugs demand separate studies to be conducted in different populations. Hospital records were used to identify 1,000 consecutive patients with RA fulfilling the American College of Rheumatology criteria and having at least 6-month follow-up. Age, gender, duration of arthritis, drug usage and ADR-related drug withdrawal were recorded from the charts. Most of the patients were put on single DMARD. Combined use of DMARD was less frequent and non-use of DMARD was common; however, disease control was good. The commonest DMARD used in our hospital was hydroxychloroquine 444 (44%) and the commonest combination used was methotrexate with hydroxychloroquine by 55 (6%). Sulphasalazine use showed preference to young and males. Supportive drugs used were NSAIDs by 883 (88%), corticosteroids by 646 (65%), paracetamol by 594 (59%) and amitriptyline by 88 (9%). Incidence of ADR-related DMARD withdrawal was maximum with leflunomide 2/15 (13.33%) followed by methotrexate 9/116 (7.76%), sulphasalazine 6/185 (3.24%), chloroquine 3/131 (2.29%) and hydroxychloroquine 8/444 (1.8%). Severity and symptomatology of disease, genetic pattern of patients, financial status, previous experience of the clinicians and patients, availability of drugs, patient expectations and compliance were the main factors that lead to a difference in pattern of therapy in our patients compared to other population.

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Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs—from bench to bedside

Cited by 108 publications

References 50 publications

Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide

Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide

Molecular basis of bortezomib resistance: proteasome subunit β5 (PSMB5) gene mutation and overexpression of PSMB5 protein

Causes of DMARD withdrawal following ADR within 6 months of initiation among Indian rheumatoid arthritis patients

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