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WIREs Syst Biol Med
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Mathematical modeling of folate metabolism

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Folate metabolism is a complex biological process that is influenced by many variables including transporters, cofactors, and enzymes. Mathematical models provide a useful tool to evaluate this complex system and to elucidate hypotheses that would be otherwise untenable to test in vitro or in vivo. Forty years of model development and refinement along with enhancements in technology have led to systematic improvement in our biological understanding of these models. However, increased complexity does not always lead to increased understanding, and a balanced approach to modeling the system is often advantageous. This approach should address questions about sensitivity of the model to variation and incorporate genomic data. The folate model is a useful platform for investigating the effects of antifolates on the folate pathway. The utility of the model is demonstrated through interrogation of drug resistance, drug‐drug interactions, drug selectivity, and drug doses and schedules. Mathematics can be used to create models with the ability to design and improve rationale therapeutic interventions. WIREs Syst Biol Med 2013, 5:603–613. doi: 10.1002/wsbm.1227 This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Biological Mechanisms > Metabolism Translational, Genomic, and Systems Medicine > Therapeutic Methods

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Folate metabolism pathway also depicting the inhibitory effects of methotrexate. The abbreviations are described in Table . (Courtesy of PharmGKB and Stanford University.)
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Simulations of the effects of ALL lineage and MTX dosage on model‐estimated DNPS activity. The curves represent the median and the shaded regions represent the quartiles of the results from the respective simulated patient populations. (a) Simulated percent change in DNPS versus time after a 1 g/m2 dose of MTX. Solid curve and red shading: B‐lineage hyperdiploid; dashed curve and blue shading: T‐lineage. (b) Simulated percent change in DNPS at 42 h versus dose. Solid curve and red shading: 24 h MTX infusion; Dashed curve and blue shading: 4 h MTX infusion. (Reprinted with permission from Ref . PLoS Computational Biology Copyright 2010.)
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Box plot of intracellular concentration of total methotrexate polyglutamates (MTXPG2–7) according to ALL subtypes, following in vivo treatment with 1 g/m2 MTX infused over 24 h. MTXPG accumulation (picomoles per 109 bone marrow ALL cells) is shown for hyperdiploid B‐lineage ALL (BHD, n = 19), nonhyperdiploid B‐lineage ALL without defined molecular genetic abnormalities (BNHD, n = 39), ALL with E2A‐PBX1 fusion (E2A‐PBX1, n = 5), T‐ALL (n = 14), and ALL with TEL‐AML1 fusion (TEL‐AML1, n = 24). Medians, quartiles, and ranges excluding outliers (circles) are depicted. P values are from pairwise comparisons using the Wilcoxon rank sum test after adjustment for multiple testing. (Reprinted with permission from Ref . Copyright 2005 American Society for Clinical Investigation)
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Gene expression of FPGS and three transporters with known MTX transport capacity in ALL subtypes. Box plots with medians, quartiles, and ranges excluding outliers (circles) of log mRNA expression are depicted for folylpolyglutamate synthetase (FPGS) (a), reduced folate carrier (RFC, or SLC19A1) (b), multidrug resistance‐associated protein 1 (MRP1, or ABCC1) (c), and breast cancer resistance protein (BCRP, or ABCG2) (d). Data from 197 patients were plotted (BHD, n = 42; BNHD, n = 58; E2A‐PBX1, n = 21; T‐ALL, n = 35; TEL‐AML1, n = 41). P values were determined by the Kruskal–Wallis test. The red boxes indicate subtypes in which gene expression was significantly higher, whereas the green boxes indicate subtypes with significantly lower expression of the gene depicted. (Reprinted with permission from Ref . Copyright 2005 American Society for Clinical Investigation)
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Models of Systems Properties and Processes > Mechanistic Models
Biological Mechanisms > Metabolism
Translational, Genomic, and Systems Medicine > Therapeutic Methods

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