Intrinsic and Acquired Resistance to Methotrexate in Acute Leukemia

Görlick, Richard; Göker, Erdem; Trippett, Tanya M.; Waltham, Mark; Banerjee, Debabrata; Bertino, Joseph R.

doi:10.1056/nejm199610033351408

Cited by 229 publications

(173 citation statements)

References 43 publications

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“…Decreased cellular uptake via the reduced folate carrier (RFC/SLC19A1) [3] or increased active efflux mediated by ABC transporters such as the multidrug resistance-associated proteins 1-5 (MRP 1-5), the breast cancer resistance protein (BCRP/ABCG2) [4,5] and P-glycoprotein (MDR or ABCB1) [6] can lead to resistance to hydrophilic and lipophilic antifolates. The ability of cells to accumulate long chain MTX polyglutamates (MTX-PGs) is highly dependent on the activities of folylpolyglutamate synthetase (FPGS) and folylpolyglutamate hydrolase (FPGH).…”

Section: Introductionmentioning

confidence: 99%

Gene expression profiling of leukemia T-cells resistant to methotrexate and 7-hydroxymethotrexate reveals alterations that preserve intracellular levels of folate and nucleotide biosynthesis

Fotoohi¹,

Assaraf²,

Moshfegh³

et al. 2009

Biochemical Pharmacology

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International audiencetreatment of human T-cell leukemia cells with 7-hydroxymethotrexate, the major metabolite of methotrexate resulted in acquired resistance as a result of the complete loss of folypolyglutamate synthetase (FPGS) activity. This was in contradistinction to the major modality of antifolate resistance of impaired drug transport in leukemia cells exposed to methotrexate.. To identify the genes associated with methotrexate and 7-hydroxymethotrexate resistance, we herein explored the patterns of genome-wide expression profiles in these antifolte-resistant leukemia sublines. mRNA levels of the reduced folate carrier, the primary influx transporter of folates and antifolates, were down-regulated >2-fold in methotrexate -resistant cells. The dramatic loss of FPGS activity in 7-hydroxymethotrexate - resistant cells was associated with alterations in the expression of various genes aimed at preserving reduced folates and/or enhancing purine nucleotide biosynthesis e.g. methylene tetrahydrofolate reductase, glycinamide ribonucleotide formyltransferase, adenosine deaminase, cystathionine β synthase, as well as the ATP-dependent folate exporters / and /. The observed changes in gene expression were generally not paralleled by acquired DNA copy numbers alterations, suggesting transcriptional regulatory mechanisms. Interestingly, gene expression of DNA/RNA metabolism and transport genes were more profoundly altered in methotrexate -resistant subline, whereas in 7-hydroxymethotrexate -resistant cells, the most profoundly affected groups of genes were those encoding for proteins involved in metabolism and cellular proliferation. Thus, the present investigation provides evidence that 7-hydroxymethotrexate induces gene expression alterations and an antifolate resistance modality that are distinct from its parent drug methotrexate

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Section: Introductionmentioning

confidence: 99%

Gene expression profiling of leukemia T-cells resistant to methotrexate and 7-hydroxymethotrexate reveals alterations that preserve intracellular levels of folate and nucleotide biosynthesis

Fotoohi¹,

Assaraf²,

Moshfegh³

et al. 2009

Biochemical Pharmacology

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“…In this study we present various lines of evidence for a novel site of interaction of SSZ with the reduced folate carrier (RFC) (28)(29)(30)(31)(32). RFC is the dominant cell membrane transporter for natural folates such as the main circulating folate 5-methyltetrahydrofolate, 5-formyltetrahydrofolate/leucovorin, and folic acid (29,32).…”

mentioning

confidence: 99%

“…Given their anionic nature, natural folates and MTX cannot traverse the plasma membrane; therefore, RFC-mediated cellular uptake should be regarded as the first critical step in any antiinflammatory/antiproliferative mode of action of MTX (33)(34)(35)(36). Consequently, diminished transport activity of RFC has been associated with loss of MTX efficacy and with folate deficiency (31,(37)(38)(39)(40).…”

mentioning

confidence: 99%

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Jansen¹,

Heijden²,

Oerlemans³

et al. 2004

Arthritis & Rheumatism

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Objective. To investigate whether interactions of sulfasalazine (SSZ) with reduced folate carrier (RFC), the dominant cell membrane transporter for natural folates and methotrexate (MTX), may limit the efficacy of combination therapy with MTX and SSZ in patients with rheumatoid arthritis. Conclusion. At clinically relevant plasma concentrations, interactions of SSZ with RFC provide a biochemical rationale for 2 important clinical observations: 1) the onset of (sub)clinical folate deficiency during SSZ treatment, and 2) the lack of additivity/synergism of the combination of SSZ and MTX when these diseasemodifying antirheumatic drugs are administered simultaneously. Thus, when considering use of these drugs in combination therapies, the present results provide a rationale both for the use of folate supplementation and for spacing administration of these drugs over time.

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“…To hydrolyze the proteins in RBCs samples, forty microliter of protease solution (Qiagen protease, Qiagen, Methotrexate (MTX) is an antifolate that is widely used to treat the diseases such as rheumatoid arthritis (RA) and childhood acute lymphoblastic leukemia (Andersen et al 1985;Weinblatt et al 1985;Gorlick et al 1996;Evans et al 1998;Pui and Evans 1998;Pui et al 2001). RA is a chronic disease characterized by the painful inflammation of joints, uncontrolled proliferation of synovial tissue and multisystem comorbidities.…”

Section: Extraction Of Mtx and Mtx-pgs From Rbcmentioning

confidence: 99%

Application of Fluorescence Polarization Immunoassay for Determination of Methotrexate-Polyglutamates in Rheumatoid Arthritis Patients

Hayashi

Fujimaki

Tsuboi

et al. 2008

Tohoku J. Exp. Med.

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Rheumatoid arthritis (RA) is a chronic disease characterized by the painful joints, inflammation, uncontrolled proliferation of synovial tissue and multisystem comorbidities. Weekly low-dose methotrexate (MTX) has been established as effective treatment in RA patients. MTX is converted to γ -glutamyl polyglutamates, an active form of MTX, through the action of folylpolyglutamate synthetase in the cells. MTX-polyglutamates (MTX-PGs) in red blood cells (RBCs) may be useful as a therapeutic marker of RA. However, the previously reported methods for the quantification of MTX and MTX-PGs in RBCs are impractical for clinical use due to time-consuming, laborious and high cost. We attempted to apply a method with the commercially available fluorescence polarization immunoassay (FPIA) kit. We found that anti-MTX monoclonal antibody showed the reactivity to 4-amino-10-methylpteroylheptaglutamic acid (MTX-PG 7 ) as equal to MTX. Good agreement was observed in the concentration-response curves between MTX and MTX-PG 7 spiked samples. Accordingly, the anti-MTX monoclonal antibody for FPIA appeared to show the equal reactivity to MTX and MTX-PGs. The recoveries of MTX and MTX-PG 7 from RBCs were 99.0% and 94.1%, respectively. Furthermore, we determined total MTX-PGs concentrations in RBCs of 71 patients with RA treated with weekly pulse MTX. Total MTX-PGs concentrations in 70% of the patients were found to be more than 50 nM that is the lower limit of MTX-PGs concentration in RBCs for expected therapeutic outcome. The routine measurement of total MTX-PGs concentration in RBCs might be useful for prediction about therapeutic outcome of MTX in RA patients.methotrexate; methotrexate-polyglutamate; rheumatoid arthritis; therapeutic drug monitoring; fluorescence polarization immunoassay.Tohoku

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Intrinsic and Acquired Resistance to Methotrexate in Acute Leukemia

Cited by 229 publications

References 43 publications

Gene expression profiling of leukemia T-cells resistant to methotrexate and 7-hydroxymethotrexate reveals alterations that preserve intracellular levels of folate and nucleotide biosynthesis

Gene expression profiling of leukemia T-cells resistant to methotrexate and 7-hydroxymethotrexate reveals alterations that preserve intracellular levels of folate and nucleotide biosynthesis

Sulfasalazine is a potent inhibitor of the reduced folate carrier: Implications for combination therapies with methotrexate in rheumatoid arthritis

Application of Fluorescence Polarization Immunoassay for Determination of Methotrexate-Polyglutamates in Rheumatoid Arthritis Patients

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