Evidence for negative feedback of extracellular methotrexate on blasts of acute lymphoblastic leukemia in vitro

Martina C. Hum, Angela K. Smith, Richard H. Lark, Naomi J. Winick, Barton A. Kamen

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Abstract

Study Objective. To explore the value of high-dose methotrexate (MTX). Subjects. Blast cells from 15 patients with acute lymphoblastic leukemia. Interventions. We compared uptake and polyglutamation of [3H]-MTX by freshly isolated leukemic blasts in vitro after 24-hour exposure to 1, 10, and 50 μM [3H]-MTX. Measurements and Main Results. Mean MTX uptake (pmol/106 cells) was 0.78 ± 0.19, 2.3 ± 0.54, and 5.9 ± 1.9, respectively, and mean polyglutamation was 82%, 66%, and 46%. Consequently, mean MTX polyglutamates were 0.68 ± 0.18, 1.5 ± 0.47, and 2.2 ± 0.67 pmol/106 cells. Three of 15 patient samples had no detectable polyglutamation of MTX at 50 μM but MTX polyglutamates were detectable at 1 μM. Two of these three had a decrease in MTX polyglutamates at 10 versus 1 μM. In eight precursor B cell samples there was a significant difference in median MTX polyglutamates at 1 versus 10 μM but not 10 versus 50 μM. Conclusion. Increasing extracellular MTX concentrations may be counterproductive for some patients with acute lymphoblastic leukemia. If MTX polyglutamates are important for efficacy, optimal delivery of MTX may have to be determined by individual metabolism rather than by targeting a specific drug concentration.

Original languageEnglish (US)
Pages (from-to)1260-1266
Number of pages7
JournalPharmacotherapy
Volume17
Issue number6
StatePublished - Nov 1997

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Methotrexate
B-Lymphoid Precursor Cells
In Vitro Techniques
methotrexate polyglutamate
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Evidence for negative feedback of extracellular methotrexate on blasts of acute lymphoblastic leukemia in vitro. / Hum, Martina C.; Smith, Angela K.; Lark, Richard H.; Winick, Naomi J.; Kamen, Barton A.

In: Pharmacotherapy, Vol. 17, No. 6, 11.1997, p. 1260-1266.

Research output: Contribution to journalArticle

Hum, Martina C. ; Smith, Angela K. ; Lark, Richard H. ; Winick, Naomi J. ; Kamen, Barton A. / Evidence for negative feedback of extracellular methotrexate on blasts of acute lymphoblastic leukemia in vitro. In: Pharmacotherapy. 1997 ; Vol. 17, No. 6. pp. 1260-1266.
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abstract = "Study Objective. To explore the value of high-dose methotrexate (MTX). Subjects. Blast cells from 15 patients with acute lymphoblastic leukemia. Interventions. We compared uptake and polyglutamation of [3H]-MTX by freshly isolated leukemic blasts in vitro after 24-hour exposure to 1, 10, and 50 μM [3H]-MTX. Measurements and Main Results. Mean MTX uptake (pmol/106 cells) was 0.78 ± 0.19, 2.3 ± 0.54, and 5.9 ± 1.9, respectively, and mean polyglutamation was 82{\%}, 66{\%}, and 46{\%}. Consequently, mean MTX polyglutamates were 0.68 ± 0.18, 1.5 ± 0.47, and 2.2 ± 0.67 pmol/106 cells. Three of 15 patient samples had no detectable polyglutamation of MTX at 50 μM but MTX polyglutamates were detectable at 1 μM. Two of these three had a decrease in MTX polyglutamates at 10 versus 1 μM. In eight precursor B cell samples there was a significant difference in median MTX polyglutamates at 1 versus 10 μM but not 10 versus 50 μM. Conclusion. Increasing extracellular MTX concentrations may be counterproductive for some patients with acute lymphoblastic leukemia. If MTX polyglutamates are important for efficacy, optimal delivery of MTX may have to be determined by individual metabolism rather than by targeting a specific drug concentration.",
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AB - Study Objective. To explore the value of high-dose methotrexate (MTX). Subjects. Blast cells from 15 patients with acute lymphoblastic leukemia. Interventions. We compared uptake and polyglutamation of [3H]-MTX by freshly isolated leukemic blasts in vitro after 24-hour exposure to 1, 10, and 50 μM [3H]-MTX. Measurements and Main Results. Mean MTX uptake (pmol/106 cells) was 0.78 ± 0.19, 2.3 ± 0.54, and 5.9 ± 1.9, respectively, and mean polyglutamation was 82%, 66%, and 46%. Consequently, mean MTX polyglutamates were 0.68 ± 0.18, 1.5 ± 0.47, and 2.2 ± 0.67 pmol/106 cells. Three of 15 patient samples had no detectable polyglutamation of MTX at 50 μM but MTX polyglutamates were detectable at 1 μM. Two of these three had a decrease in MTX polyglutamates at 10 versus 1 μM. In eight precursor B cell samples there was a significant difference in median MTX polyglutamates at 1 versus 10 μM but not 10 versus 50 μM. Conclusion. Increasing extracellular MTX concentrations may be counterproductive for some patients with acute lymphoblastic leukemia. If MTX polyglutamates are important for efficacy, optimal delivery of MTX may have to be determined by individual metabolism rather than by targeting a specific drug concentration.

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