title: Shortening infusion time for high-dose methotrexate alters antileukemic effects: a randomized prospective clinical trial.
abstract: OBJECTIVE
  To determine whether shortening the infusion duration of high-dose methotrexate (HDMTX; 1 g/m(2)) affects the in vivo accumulation of active methotrexate polyglutamates (MTXPG(1-7)) in leukemia cells and whether this differs among major acute lymphoblastic leukemia (ALL) subtypes.
  
  
  METHODS
  From June 2000 through October 2007, 356 children with ALL were randomly assigned to receive initial single-agent treatment with HDMTX (1 g/m(2)) as either a 24-hour infusion or a 4-hour infusion at two pediatric hospitals in the United States. The primary outcome measures were the accumulation of MTXPG(1-7) in leukemia cells and the antileukemic effects (eg, inhibition of de novo purine synthesis in bone marrow ALL cells, and decrease in circulating ALL cells).
  
  
  RESULTS
  The 24-hour infusion resulted in significantly higher amounts of MTXPG(1-7) in bone marrow leukemia cells (median: 1,695 v 1,150 pmol/10(9) cells, P = .0059), and better antileukemic effects. The 24-hour infusion had the greatest effect on MTXPG(1-7) accumulation in hyperdiploid ALL (median: 3,919 v 2,417 pmol/10(9) cells, P = .0038); T-cell ALL exhibited smaller differences in MTXPG(1-7) but greater antileukemic effects with the longer infusion (median decrease in leukemia cells: 88.4% v 51.8%, P = .0075). In contrast, infusion duration had no significant impact on MTXPG(1-7) accumulation or antileukemic effects in ALL with the t(12;21)/(ETV6-RUNX1) chromosomal translocation.
  
  
  CONCLUSIONS
  Shortening the infusion time of HDMTX reduces accumulation of active methotrexate in leukemia cells and decreases antileukemic effects, with differing consequences among major ALL subtypes.
authors: St Jude Children's Research Hospital, 262 Danny Thomas Pl, Memphis, TN 38105, USA.
authors: Torben S
authors: TS
authors: Mikkelsen
authors: Alex
authors: A
authors: Sparreboom
authors: Cheng
authors: C
authors: Cheng
authors: Yinmei
authors: Y
authors: Zhou
authors: James M
authors: JM
authors: Boyett
authors: Susana C
authors: SC
authors: Raimondi
authors: John C
authors: JC
authors: Panetta
authors: W Paul
authors: WP
authors: Bowman
authors: John T
authors: JT
authors: Sandlund
authors: Ching-Hon
authors: CH
authors: Pui
authors: Mary V
authors: MV
authors: Relling
authors: William E
authors: WE
authors: Evans
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002675:Child, Preschool; D004334:Drug Administration Schedule; D006801:Humans; D007223:Infant; D008727:Methotrexate / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D011099:Polyglutamic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D011687:Purines / Q000096:biosynthesis
chemical_list: D000964:Antimetabolites, Antineoplastic; D011687:Purines; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; C030985:purine; D008727:Methotrexate