A case for the use of aminopterin in treatment of patients with leukemia based on metabolic studies of blasts in vitro

Angela Smith, Martina Hum, Naomi J. Winick, Barton A. Kamen

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Clinical and laboratory investigations during the past four decades have resulted in numerous schedules, doses, and routes of delivery for methotrexate (MTX). It remains as an important drug for the treatment of children with acute lymphoblastic leukemia (ALL). Aminopterin (AMT) was the initial antifolate showing promise as an anticancer drug. It is more potent than MTX and also is known to be accumulated more efficiently than MTX in model systems. Because Whitehead et al. (Blood, 76: 44-49, 1990) have shown that MTX accumulation by blasts at diagnosis is of prognostic significance in children with ALL, we reasoned that if accumulation of a 'stoichiometric inhibitor' of dihydrofolate reductase by leukemic blasts was of prognostic importance, then whether it was AMT or MTX may be relevant only with respect to the absolute dose. To compare MTX and AMT metabolism, we incubated lymphoblasts with 1 μM radiolabeled drug in vitro. MTX and AMT accumulation by ALL cells (n = 24) was 0.7 ± 0.7 and 1.47 ± 0.9 pmol/106 cells, respectively. Based on the data of Whitehead et al., this predicts pharmacological success in 59 and 84% of the MTX and AMT groups, respectively. Moreover, 5 of 10 patients considered poor risks based on MTX accumulation would be 'cures' based on AMT uptake. Even at only 0.1 μM AMT, a concentration at which there is little accumulation of MTX, 5 of 11 patients studied would be 'pharmacological cures' based on AMT uptake. Accumulation of AMT by blasts from 11 patients with T-cell-lineage ALL and 5 patients with acute myelogenous leukemia was also found to be twice the uptake of MTX. These data allow the suggestion that AMT, despite increased potential for toxicity, may be useful in children who are identified as poor risks with respect to MTX uptake.

Original languageEnglish (US)
Pages (from-to)69-73
Number of pages5
JournalClinical Cancer Research
Volume2
Issue number1
StatePublished - Jan 1996

Fingerprint

Aminopterin
Methotrexate
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Therapeutics
Folic Acid Antagonists
In Vitro Techniques
Pharmaceutical Preparations
Pharmacology
Cell Lineage
Acute Myeloid Leukemia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A case for the use of aminopterin in treatment of patients with leukemia based on metabolic studies of blasts in vitro. / Smith, Angela; Hum, Martina; Winick, Naomi J.; Kamen, Barton A.

In: Clinical Cancer Research, Vol. 2, No. 1, 01.1996, p. 69-73.

Research output: Contribution to journalArticle

@article{f16eeb2313234f8392b18e994734a36b,
title = "A case for the use of aminopterin in treatment of patients with leukemia based on metabolic studies of blasts in vitro",
abstract = "Clinical and laboratory investigations during the past four decades have resulted in numerous schedules, doses, and routes of delivery for methotrexate (MTX). It remains as an important drug for the treatment of children with acute lymphoblastic leukemia (ALL). Aminopterin (AMT) was the initial antifolate showing promise as an anticancer drug. It is more potent than MTX and also is known to be accumulated more efficiently than MTX in model systems. Because Whitehead et al. (Blood, 76: 44-49, 1990) have shown that MTX accumulation by blasts at diagnosis is of prognostic significance in children with ALL, we reasoned that if accumulation of a 'stoichiometric inhibitor' of dihydrofolate reductase by leukemic blasts was of prognostic importance, then whether it was AMT or MTX may be relevant only with respect to the absolute dose. To compare MTX and AMT metabolism, we incubated lymphoblasts with 1 μM radiolabeled drug in vitro. MTX and AMT accumulation by ALL cells (n = 24) was 0.7 ± 0.7 and 1.47 ± 0.9 pmol/106 cells, respectively. Based on the data of Whitehead et al., this predicts pharmacological success in 59 and 84{\%} of the MTX and AMT groups, respectively. Moreover, 5 of 10 patients considered poor risks based on MTX accumulation would be 'cures' based on AMT uptake. Even at only 0.1 μM AMT, a concentration at which there is little accumulation of MTX, 5 of 11 patients studied would be 'pharmacological cures' based on AMT uptake. Accumulation of AMT by blasts from 11 patients with T-cell-lineage ALL and 5 patients with acute myelogenous leukemia was also found to be twice the uptake of MTX. These data allow the suggestion that AMT, despite increased potential for toxicity, may be useful in children who are identified as poor risks with respect to MTX uptake.",
author = "Angela Smith and Martina Hum and Winick, {Naomi J.} and Kamen, {Barton A.}",
year = "1996",
month = "1",
language = "English (US)",
volume = "2",
pages = "69--73",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - A case for the use of aminopterin in treatment of patients with leukemia based on metabolic studies of blasts in vitro

AU - Smith, Angela

AU - Hum, Martina

AU - Winick, Naomi J.

AU - Kamen, Barton A.

PY - 1996/1

Y1 - 1996/1

N2 - Clinical and laboratory investigations during the past four decades have resulted in numerous schedules, doses, and routes of delivery for methotrexate (MTX). It remains as an important drug for the treatment of children with acute lymphoblastic leukemia (ALL). Aminopterin (AMT) was the initial antifolate showing promise as an anticancer drug. It is more potent than MTX and also is known to be accumulated more efficiently than MTX in model systems. Because Whitehead et al. (Blood, 76: 44-49, 1990) have shown that MTX accumulation by blasts at diagnosis is of prognostic significance in children with ALL, we reasoned that if accumulation of a 'stoichiometric inhibitor' of dihydrofolate reductase by leukemic blasts was of prognostic importance, then whether it was AMT or MTX may be relevant only with respect to the absolute dose. To compare MTX and AMT metabolism, we incubated lymphoblasts with 1 μM radiolabeled drug in vitro. MTX and AMT accumulation by ALL cells (n = 24) was 0.7 ± 0.7 and 1.47 ± 0.9 pmol/106 cells, respectively. Based on the data of Whitehead et al., this predicts pharmacological success in 59 and 84% of the MTX and AMT groups, respectively. Moreover, 5 of 10 patients considered poor risks based on MTX accumulation would be 'cures' based on AMT uptake. Even at only 0.1 μM AMT, a concentration at which there is little accumulation of MTX, 5 of 11 patients studied would be 'pharmacological cures' based on AMT uptake. Accumulation of AMT by blasts from 11 patients with T-cell-lineage ALL and 5 patients with acute myelogenous leukemia was also found to be twice the uptake of MTX. These data allow the suggestion that AMT, despite increased potential for toxicity, may be useful in children who are identified as poor risks with respect to MTX uptake.

AB - Clinical and laboratory investigations during the past four decades have resulted in numerous schedules, doses, and routes of delivery for methotrexate (MTX). It remains as an important drug for the treatment of children with acute lymphoblastic leukemia (ALL). Aminopterin (AMT) was the initial antifolate showing promise as an anticancer drug. It is more potent than MTX and also is known to be accumulated more efficiently than MTX in model systems. Because Whitehead et al. (Blood, 76: 44-49, 1990) have shown that MTX accumulation by blasts at diagnosis is of prognostic significance in children with ALL, we reasoned that if accumulation of a 'stoichiometric inhibitor' of dihydrofolate reductase by leukemic blasts was of prognostic importance, then whether it was AMT or MTX may be relevant only with respect to the absolute dose. To compare MTX and AMT metabolism, we incubated lymphoblasts with 1 μM radiolabeled drug in vitro. MTX and AMT accumulation by ALL cells (n = 24) was 0.7 ± 0.7 and 1.47 ± 0.9 pmol/106 cells, respectively. Based on the data of Whitehead et al., this predicts pharmacological success in 59 and 84% of the MTX and AMT groups, respectively. Moreover, 5 of 10 patients considered poor risks based on MTX accumulation would be 'cures' based on AMT uptake. Even at only 0.1 μM AMT, a concentration at which there is little accumulation of MTX, 5 of 11 patients studied would be 'pharmacological cures' based on AMT uptake. Accumulation of AMT by blasts from 11 patients with T-cell-lineage ALL and 5 patients with acute myelogenous leukemia was also found to be twice the uptake of MTX. These data allow the suggestion that AMT, despite increased potential for toxicity, may be useful in children who are identified as poor risks with respect to MTX uptake.

UR - http://www.scopus.com/inward/record.url?scp=0030054323&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030054323&partnerID=8YFLogxK

M3 - Article

C2 - 9816092

AN - SCOPUS:0030054323

VL - 2

SP - 69

EP - 73

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 1

ER -