Blast cell methotrexate-polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia.

Abstract

High-dose methotrexate (HDMTX) is a component of most treatment protocols for childhood acute lymphoblastic leukemia (ALL), yet recent studies of receptor-mediated transport and saturable polyglutamylation have questioned its rationale. To investigate this in vivo, methotrexate and its active polyglutamated metabolites (MTX-PG) were measured in bone marrow blasts obtained from 101 children randomized to single-agent therapy with either HDMTX (1 g/m2 per 24 h i.v., n = 47) or low-dose MTX (LDMTX, 30 mg/m2 by mouth every 6 h x 6, n = 54), before remission induction therapy. Blast concentrations of total MTX-PGs (median 460 vs 1380 pmol/10(9) cells) and of long-chain MTX-glu4-6 were both significantly higher after HDMTX (P < 0.001). With either treatment, MTX-PGs were significantly higher in B-lineage blasts than in T-lineage blasts (LDMTX P = 0.001, HDMTX P = 0.03). In a multiple regression analysis of B-lineage ALL, blast MTX-PG was significantly related to MTX dose (or plasma MTX concentration), lymphoblast ploidy (hyperdiploid > nonhyperdiploid), and percentage S-phase. This is the first evidence that HDMTX achieves higher MTX-PG concentrations in ALL blasts in vivo, establishing a rationale for HDMTX in the treatment of childhood ALL, especially T-lineage or nonhyperdiploid B-lineage ALL, disease characteristics associated with a poor prognosis on conventional therapy.

• Authors: T W Synold, M V Relling, J M Boyett, G K Rivera, J T Sandlund, H Mahmoud, W M Crist, C H Pui, W E Evans
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 94 Issue 5 Pg. 1996-2001 (Nov 1994) ISSN: 0021-9738 [Print] United States
• PMID: 7525652 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Polyglutamic Acid
• methotrexate polyglutamate
• Methotrexate

Topics

• Adolescent
• Child
• Child, Preschool
• Female
• Humans
• Infant
• Male
• Methotrexate (administration & dosage, analogs & derivatives, metabolism, pharmacokinetics)
• Ploidies
• Polyglutamic Acid (analogs & derivatives, metabolism)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism)