Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. A rationale for high-dose methotrexate.

Masson, Éric; Relling, Mary V.; Synold, Timothy W.; Liu, Qing; Schuetz, John D.; Jt, Sandlund; Pui, Ching‐Hon; Evans, William E.

doi:10.1172/jci118409

Cited by 183 publications

(137 citation statements)

References 35 publications

(41 reference statements)

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“…12 Thus, the positive relationship between TGN levels and longchain MTX-PG concentrations we observed is consistent with their inhibition of de novo purine synthesis and increased PRPP formation.…”

Section: Resultssupporting

confidence: 84%

Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine

et al. 2002

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Methotrexate is widely administered with mercaptopurine, a prodrug requiring activation into thioguanine nucleotides (TGN) to exert antileukemic effects. In vitro, methotrexate enhances TGN formation, but in vivo, such enhancement has yet to be demonstrated. We investigated whether TGN concentrations were related to methotrexate concentrations in children with acute lymphoblastic leukemia who received a weekly intravenous methotrexate (

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Section: Resultssupporting

confidence: 84%

Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine

et al. 2002

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“…Hence, decreased MTX doses could reduce the antileukemic effect of MTX. 20,21 In addition, MTX dose reduction would limit penetration of MTX into the CNS, 22 which could increase the risk of CNS relapse. Supporting the clinical significance of high systemic MTX exposure, Evans et al 23 found that pharmacokinetically guided MTX dosage to achieve higher MTX concentration in patients with rapid clearance of the drug lead to a better outcome.…”

Section: Discussionmentioning

confidence: 99%

Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia

Nygaard

Schmiegelow

2003

Leukemia

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High-dose methotrexate (HDM) given concurrently with oral 6-mercaptopurine (6 MP) may be followed by myelotoxicity, which may necessitate treatment interruption and thus interfere with the efficacy of the treatment of childhood acute lymphoblastic leukemia (ALL). Through inhibition of purine de novo synthesis and enhancement of the bioavailability, HDM may increase the incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6 MP.A total of 26 children diagnosed 3/1996-4/2001 with ALL received five courses of HDM (5 g/m 2 /24 h with leucovorin rescue) at 8 weeks intervals during their first year of maintenance therapy with oral methotrexate (20 mg/m 2 /week) and 6MP (75 mg/m 2 /day). The dose of oral 6MP was reduced to a median of 51% (75% range: 39-62%, maximum 74%) of the standard dose from 2 weeks prior to until 2 weeks after HDM, because the previous HDM had led to a thrombocyte nadir p60 Â 10 9 /l and/or a neutrophil nadir p0.7 Â 10 9 /l. The 6MP dose reductions raised the median thrombocyte nadir following HDM from 46 Â 10 9 /l (range: 6-214) to 133 Â 10 9 /l (range: 21-305; Po0.001) and the median neutrophil nadir from 0.5 Â 10 9 /l (range: 0.0-1.4) to 0.9 Â 10 9 /l (range: 0.2-3.2; Po0.001). The effect of 6MP dose reductions was not significantly related to risk group, gender, age, or thiopurine methyltransferase genotype. With 6MP dose reductions, the median duration of treatment interruption following HDM was reduced from 8 to 0 days (Po0.001).The reduction of 6MP dosage during HDM can significantly reduce the risk of severe myelotoxicity and prevent treatment interruptions.

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“…8,9 The method for quantitating DNPS was modified to yield higher overall median values when compared with the method previously used to quantitate DNPS in ALL blasts. 7,9 However, the previously observed lineage differences in DNPS (T-ALL greater than B-lineage ALL) remained evident with the current DNPS assay.…”

Section: Measurement Of Purine Bases and Rate Of Dnps In Bone Marrow mentioning

confidence: 99%

Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis

Zaza

Yang

Kager

et al. 2004

Blood

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Because de novo purine synthesis (DNPS) is a target of widely used antileukemic agents (eg, methotrexate, mercaptopurine), we determined the rate of DNPS and the expression of genes involved in purine metabolism in different subtypes of acute lymphoblastic leukemia (ALL). Among 113 children with newly diagnosed ALL, lymphoblasts with the TEL-AML1 translocation had significantly lower DNPS than all other genetic subtypes of B-lineage ALL or T-lineage ALL (352 ؎ 57 versus 1001 ؎ 31 or versus 1315 ؎ 76 fmol/nmol/h, P < .0001). By assessing the expression of 82 genes involved in purine metabolism (KEGG pathway database) in ALL blasts from 38 patients with B-lineage ALL (14 with TEL-AML1, 24 without), we identified 16 genes that were differentially expressed in TEL-AML1-positive and TEL-AML1-negative ALL (P < .001, false discovery rate [FDR] ‫؍‬ 5%). The pattern of expression of these 16 genes discriminated TEL-AML1-positive ALL with a true accuracy of 84% in an independent test set (n ‫؍‬ 17, confidence interval 70% to 94%, P < .001). Western blots of selected genes documented corresponding levels of the proteins encoded. Differentially expressed genes included HPRT, IMPDH, PAICS, and GART, all of which were expressed at a significantly lower level in TEL-AML1 ALL. These findings have established that TEL-AML1 ALL has significantly lower de novo purine synthesis and differential expression of genes involved in purine metabolism. ( IntroductionPediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease comprising different immunophenotypes and various genetic subtypes caused by chromosomal translocations with aberrant gene fusions and inappropriate expression of oncogenes. These genetic abnormalities have important prognostic and therapeutic implications, but the underlying mechanisms are not fully understood. 1 De novo purine synthesis (DNPS) is higher in ALL cells compared with normal bone marrow cells and peripheral blood lymphocytes, and T-lineage ALL has higher DNPS than B-lineage ALL. 2,3 It is not known, however, whether DNPS differs among the genetic subtypes of B-lineage ALL.Nucleotides play a key role in many biochemical processes related to their importance as DNA and RNA precursors, energy carriers, coenzyme components, and metabolic regulators. 4 Cells obtain purine nucleotides through 2 separate metabolic pathways, de novo purine synthesis and salvage of extracellular purine bases and nucleotides. DNPS and several enzymes involved in the purine metabolism pathway are important targets for antimetabolites (eg, mercaptopurine and methotrexate) that are the cornerstone of continuation therapy for childhood ALL. 1 DNPS is a complex pathway in which nucleotides are synthesized from amino acids and tetrahydrofolate in a multienzymatic process, starting with phosphoribosyl pyrophosphate (PRPP), primarily formed from ribose-5-phosphate (from the pentose phosphate pathway) and adenosine triphosphate (ATP). 4 Previous studies have shown that the pattern of gene expression in ALL blasts differs among ...

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Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. A rationale for high-dose methotrexate.

Abstract: Methotrexate (MTX) is one of the most widely used drugs for the treatment of childhood acute lymphoblastic leukemia (ALL) and is commonly given in high doses. However, the rationale for high-dose MTX (HDMTX) has been challenged recently. To determine whether higher MTX polyglutamate (

Cited by 183 publications

References 35 publications

Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine

Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine

Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia

Acute lymphoblastic leukemia with TEL-AML1 fusion has lower expression of genes involved in purine metabolism and lower de novo purine synthesis

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