Antifolate Polyglutamylation in Preclinical and Clinical Antifolate Resistance

McGuire, John J.

doi:10.1007/978-1-59259-725-3_16

Cited by 11 publications

(15 citation statements)

References 61 publications

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“…Antifolates have the advantage in that they utilise the same transport systems as folate to enter cells . Once inside the cell antifolates undergo polyglutamination by folylpolyglutamate synthetase (FPGS), which enhances their intracellular retention and increases their affinity towards their target enzymes . There are no protein sequence or structural similarities between hSHMT and the other enzymes involved in 1C‐metabolism which are targets of antifolates.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT2 by antifolate drugs

2019

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Serine hydroxymethyltransferase (SHMT) is the major source of 1‐carbon units required for nucleotide synthesis. Humans have cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms, which are upregulated in numerous cancers, making the enzyme an attractive drug target. Here, we show that the antifolates lometrexol and pemetrexed are inhibitors of SHMT2 and solve the first SHMT2‐antifolate structures. The antifolates display large differences in their hydrogen bond networks despite their similarity. Lometrexol was found to be the best hSHMT1/2 inhibitor from a panel antifolates. Comparison of apo hSHMT1 with antifolate bound hSHMT2 indicates a highly conserved active site architecture. This structural information offers insights as to how these compounds could be improved to produce more potent and specific inhibitors of this emerging anti‐cancer drug target.

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Section: Discussionmentioning

confidence: 99%

Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT2 by antifolate drugs

2019

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“…Resistance to MTX can occur via a number of mechanisms, reviewed in [36][37][38][39]. These include: 1.…”

Section: Clinical Resistance Mechanismsmentioning

confidence: 99%

“…This clinical difference along with the availability of clinical material has greatly aided the study of resistance mechanisms. The contrasting relative paucity of information on solid tumors is of course largely due to a number of technical and ethical issues associated with taking repeat biopsy samples [39].…”

Section: Clinical Resistance Mechanismsmentioning

confidence: 99%

From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates

2006

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“…1) by folylpolyglutamate synthetase can be limited by transport. Polyglutamyl antifolates are better retained and are often more potent inhibitors of their target enzyme than their respective monoglutamates (11); increased transport could enhance synthesis of these crucial metabolites. This may be especially critical in childhood acute lymphoblastic leukemia where clinical correlations show that the median difference in MTX polyglutamate accumulation between patients who respond to MTX-containing regimens and nonresponders is only about 3-fold (12,13).…”

Section: Introductionmentioning

confidence: 99%

5-Amino-4-Imidazolecarboxamide Riboside Potentiates Both Transport of Reduced Folates and Antifolates by the Human Reduced Folate Carrier and Their Subsequent Metabolism

2006

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Transport is required before reduced folates and anticancer antifolates [e.g., methotrexate (MTX)] exert their physiologic functions or cytotoxic effects. The folate/antifolate transporter with the widest tissue distribution and greatest activity is the reduced folate carrier (RFC). There is little evidence that RFCmediated influx is posttranscriptionally regulated. We show that [3 H]MTX influx in CCRF-CEM human childhood T-leukemia cells is potentiated up to 6-fold by exogenous 5-amino-4-imidazolecarboxamide riboside (AICAr) in a AICAr and MTX concentration-dependent manner. Metabolism to more biologically active polyglutamate forms is also potentiated for MTX and other antifolates. That potentiation of influx by AICAr is mediated by effects on the RFC is supported by analyses FAICAr showing (a) similarity and magnitude of kinetic constants for [ 3 H]MTX influx; (b) similarity of inhibitory potency of known RFC substrates; (c) lack of potentiation in a CCRF-CEM subline that does not express the RFC; and (d) similarity of time and temperature dependence. Potentiation occurs rapidly and does not require new protein synthesis. Effects of specific inhibitors of folate metabolism and the time and sequence of AICAr incubation with cells suggest that both dihydrofolate reductase inhibition and metabolism of AICAr are essential for potentiation. Acute folate deficiency or incubation of CCRF-CEM with AICArrelated metabolites (e.g., adenosine) does not initiate potentiation. AICAr increases growth inhibitory potency of MTX and aminopterin against CCRF-CEM cells when both AICAr and antifolate are present for the first 24 hours of a 120-hour growth period. AICAr is the first small molecule that regulates RFC activity. (Cancer Res 2006; 66(7): 3836-44)

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Antifolate Polyglutamylation in Preclinical and Clinical Antifolate Resistance

Cited by 11 publications

References 61 publications

Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT2 by antifolate drugs

Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT2 by antifolate drugs

From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates

5-Amino-4-Imidazolecarboxamide Riboside Potentiates Both Transport of Reduced Folates and Antifolates by the Human Reduced Folate Carrier and Their Subsequent Metabolism

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