Trial reportPLoS computational biology2010
Modeling mechanisms of in vivo variability in methotrexate accumulation and folate pathway inhibition in acute lymphoblastic leukemia cells.
Trial report in PLoS computational biology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT00137111 (Total XV - Total Therapy Study XV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia), which is not on this map. Cited by 26 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Total XV - Total Therapy Study XV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
Who cites it
26 citing papers in PubMed, 2 syntheses or guidelines pooled it, 49 citations in OpenAlex.
- Influence of FPGS rs1544105 and GGH rs3758149 Gene Polymorphisms on Methotrexate Pharmacogenetics.Biochemical genetics · 2026Pooled it
- Systematic review: genetic polymorphisms in the pharmacokinetics of high-dose methotrexate in pediatric acute lymphoblastic leukemia patients.Cancer chemotherapy and pharmacology · 2024Pooled it
- Trial
- Shortening infusion time for high-dose methotrexate alters antileukemic effects: a randomized prospective clinical trial.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2011Trial
- Cellular pharmacokinetic of methotrexate and its modulation by folylpolyglutamate synthetase and γ-glutamyl hydrolase in tumor cells.PloS one · 2024Article
- Pharmacokinetic-pharmacodynamic modeling of maintenance therapy for childhood acute lymphoblastic leukemia.Scientific reports · 2023Article
- Pharmacogenomics of intracellular methotrexate polyglutamates in patients' leukemia cells in vivo.The Journal of clinical investigation · 2020Article
- MTXPK.org: A Clinical Decision Support Tool Evaluating High-Dose Methotrexate Pharmacokinetics to Inform Post-Infusion Care and Use of Glucarpidase.Clinical pharmacology and therapeutics · 2020Article
- Association ofGenes · 2020Article
- Polymorphisms of SLC19A1 80 G>A, MTHFR 677 C>T, and Tandem TS Repeats Influence Pharmacokinetics, Acute Liver Toxicity, and Vomiting in Children With Acute Lymphoblastic Leukemia Treated With High Doses of Methotrexate.Frontiers in pediatrics · 2020Article
- Model-Based Simulation of Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia.Frontiers in physiology · 2020Article
- A study on the predictability of acute lymphoblastic leukaemia response to treatment using a hybrid oncosimulator.Interface focus · 2018Article
- Effect of the Polymorphism of Folylpolyglutamate Synthetase on Treatment of High-Dose Methotrexate in Pediatric Patients with Acute Lymphocytic Leukemia.Medical science monitor : international medical journal of experimental and clinical research · 2016Article
- Linking gene expression to phenotypes via pathway information.Journal of biomedical semantics · 2015Article
- A Review of Mathematical Models for Leukemia and Lymphoma.Drug discovery today. Disease models · 2015Article
- A General Network Pharmacodynamic Model-Based Design Pipeline for Customized Cancer Therapy Applied to the VEGFR Pathway.CPT: pharmacometrics & systems pharmacology · 2014Article
- FPGS rs1544105 polymorphism is associated with treatment outcome in pediatric B-cell precursor acute lymphoblastic leukemia.Cancer cell international · 2013Article
- A health-care system perspective on implementing genomic medicine: pediatric acute lymphoblastic leukemia as a paradigm.Clinical pharmacology and therapeutics · 2013Review
- Optimizing drug development of anti-cancer drugs in children using modelling and simulation.British journal of clinical pharmacology · 2013Review
- Center of cancer systems biology second annual workshop--tumor metronomics: timing and dose level dynamics.Cancer research · 2013Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Methotrexate (MTX) is widely used for the treatment of childhood acute lymphoblastic leukemia (ALL). The accumulation of MTX and its active metabolites, methotrexate polyglutamates (MTXPG), in ALL cells is an important determinant of its antileukemic effects. We studied 194 of 356 patients enrolled on St. Jude Total XV protocol for newly diagnosed ALL with the goal of characterizing the intracellular pharmacokinetics of MTXPG in leukemia cells; relating these pharmacokinetics to ALL lineage, ploidy and molecular subtype; and using a folate pathway model to simulate optimal treatment strategies. Serial MTX concentrations were measured in plasma and intracellular MTXPG concentrations were measured in circulating leukemia cells. A pharmacokinetic model was developed which accounted for the plasma disposition of MTX along with the transport and metabolism of MTXPG. In addition, a folate pathway model was adapted to simulate the effects of treatment strategies on the inhibition of de novo purine synthesis (DNPS). The intracellular MTXPG pharmacokinetic model parameters differed significantly by lineage, ploidy, and molecular subtypes of ALL. Folylpolyglutamate synthetase (FPGS) activity was higher in B vs T lineage ALL (p<0.005), MTX influx and FPGS activity were higher in hyperdiploid vs non-hyperdiploid ALL (p<0.03), MTX influx and FPGS activity were lower in the t(12;21) (ETV6-RUNX1) subtype (p<0.05), and the ratio of FPGS to γ-glutamyl hydrolase (GGH) activity was lower in the t(1;19) (TCF3-PBX1) subtype (p<0.03) than other genetic subtypes. In addition, the folate pathway model showed differential inhibition of DNPS relative to MTXPG accumulation, MTX dose, and schedule. This study has provided new insights into the intracellular disposition of MTX in leukemia cells and how it affects treatment efficacy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.