lometrexol has been researched along with Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma* in 4 studies
4 other study(ies) available for lometrexol and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma
| Article | Year |
|---|---|
Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL.
Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Among chemotherapeutics, thiopurines are key drugs in ALL combination therapy. Using whole-exome sequencing, we identified relapse-specific mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes a rate-limiting purine biosynthesis enzyme, in 24/358 (6.7%) relapsed childhood B cell ALL (B-ALL) cases. All individuals who harbored PRPS1 mutations relapsed early during treatment, and mutated ALL clones expanded exponentially before clinical relapse. Our functional analyses of PRPS1 mutants uncovered a new chemotherapy-resistance mechanism involving reduced feedback inhibition of de novo purine biosynthesis and competitive inhibition of thiopurine activation. Notably, the de novo purine synthesis inhibitor lometrexol effectively abrogated PRPS1 mutant-driven drug resistance. These results highlight the importance of constitutive activation of the de novo purine synthesis pathway in thiopurine resistance, and they offer therapeutic strategies for the treatment of relapsed and thiopurine-resistant ALL. Topics: Adolescent; Child; Child, Preschool; Exome; Feedback, Physiological; Female; High-Throughput Nucleotide Sequencing; Humans; Infant; Leukemia, B-Cell; Male; Mercaptopurine; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines; Recurrence; Ribose-Phosphate Pyrophosphokinase; Tetrahydrofolates | 2015 |
Design, synthesis, and biological evaluation of fluoronitrophenyl substituted folate analogues as potential inhibitors of GAR transformylase and AICAR transformylase.
The examination results of a novel series of potential inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide transformylase (AICAR Tfase) are reported. These agents incorporate an electrophilic fluoronitrophenyl group that can potentially react with an active site nucleophile or the substrate GAR/AICAR amine via nucleophilic aromatic substitution. Topics: Animals; Biological Assay; Combinatorial Chemistry Techniques; Drug Design; Enzyme Inhibitors; Fluorine; Folic Acid; Hydroxymethyl and Formyl Transferases; Molecular Structure; Nitro Compounds; Phosphoribosylglycinamide Formyltransferase; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines; Ribonucleotides; Tumor Cells, Cultured | 2000 |
Altered transport of folic acid and antifolates through the carrier mediated reduced folate transport system in a human leukemia cell line resistant to (6R) 5,10-dideazatetrahydrofolic acid (DDATHF).
Topics: Binding Sites; Biological Transport; Carrier Proteins; Cell Line; Drug Resistance; Folate Receptors, GPI-Anchored; Folic Acid; Folic Acid Antagonists; Humans; Kinetics; Methotrexate; Peptide Synthases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Cell Surface; Tetrahydrofolates; Tumor Cells, Cultured | 1993 |
Determinants of the disparate antitumor effects of (6R)5,10-dideaza-5,6,7,8- tetrahydrofolate and methotrexate toward methotrexate resistant CCRF-CEM cells, characterized by severely impaired antifolate membrane transport.
Topics: Antineoplastic Agents; Carrier Proteins; Cell Line; Drug Resistance; Folate Receptors, GPI-Anchored; Folic Acid Antagonists; Humans; Kinetics; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Cell Surface; Tetrahydrofolates; Tumor Cells, Cultured | 1993 |