title: A mathematical model of in vivo methotrexate accumulation in acute lymphoblastic leukemia.
abstract: Methotrexate (MTX) is one of the most widely used drugs for the treatment of childhood acute lymphoblastic leukemia (ALL). Interindividual differences in lymphoblast accumulation of MTX and its active metabolites, methotrexate polyglutamates (MTXPG), may contribute to the effectiveness of treatment among ALL subtypes. To better understand these differences in MTXPG accumulation, we developed a model to characterize the cellular influx and efflux of MTX, formation of MTXPG by the addition of glutamyl residues catalyzed by FPGS (folylpolyglutamate synthetase), and cleavage of glutamyl residues from MTXPG by GGH (gamma-glutamyl hydrolase). The model was fitted to in vivo intracellular MTXPG concentrations measured serially in leukemic blasts from 20 newly diagnosed patients with ALL treated with 24-h intravenous infusions of MTX. The observed median concentrations of total MTXPG at 44 h was higher in B-lineage than in T-cell ALL (1706 vs 518 pmol/10(9) cells, P<0.025), consistent with the higher estimated Vmax for FPGS activity in B-lineage vs T-lineage blasts (414 vs 93 pmol/10(9) cells/h, P<0.008). Simulations based on the model-estimated parameters indicated greater accumulation of MTX, MTXPGs (MTXPG(2-7)) and total MTX (MTXPG(1-7)) with longer MTX infusions and with higher MTX doses, with the highest concentrations in hyperdiploid B-lineage, intermediate in non-hyperdiploid B-lineage, and lowest in T-cell ALL. These differences provide mechanistic and treatment insights for lineage and ploidy differences in MTXPG accumulation in human leukemia cells in vivo.
authors.affiliation: St. Jude Children's Research Hospital, 332 North Lauderdale St., Memphis, TN 38105-2794, USA.
authors.forename: John Carl
authors.initials: JC
authors.lastname: Panetta
authors.forename: Yuri
authors.initials: Y
authors.lastname: Yanishevski
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: John T
authors.initials: JT
authors.lastname: Sandlund
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rubnitz
authors.forename: Gaston K
authors.initials: GK
authors.lastname: Rivera
authors.forename: Raul
authors.initials: R
authors.lastname: Ribeiro
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000782:Aneuploidy; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D001402:B-Lymphocytes / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D019070:Cell Lineage; D002648:Child; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011099:Polyglutamic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D011355:Prodrugs / Q000493:pharmacokinetics*; D013601:T-Lymphocytes / Q000378:metabolism; D011623:gamma-Glutamyl Hydrolase / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D002352:Carrier Proteins; D009363:Neoplasm Proteins; D011355:Prodrugs; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate