Skip to main content
Journal cover image

Insight into the mechanism of asparaginase-induced depletion of antithrombin III in treatment of childhood acute lymphoblastic leukemia.

Publication ,  Journal Article
Bushman, JE; Palmieri, D; Whinna, HC; Church, FC
Published in: Leuk Res
July 2000

Asparaginase (ASNase) is a widely used and successful agent against childhood acute lymphoblastic leukemia (ALL). Asparaginase cleaves asparagine (Asn) to give aspartic acid and ammonia, thereby depleting free Asn in the blood. However, treatment with ASNase has been implicated in significant reduction of plasma levels of the coagulation serine protease inhibitor (serpin) antithrombin III (AT3), predisposing patients to thromboembolic complications. Our investigation was designed to delineate the biochemical mechanism of AT3 depletion that can occur in the plasma of ALL patients undergoing ASNase therapy. SDS-PAGE showed no cleavage of purified AT3 following treatment with ASNase. Furthermore, purified AT3 treated with ASNase demonstrated no decrease in inhibitory activity. Human plasma and whole blood treated with approximate therapeutic concentrations of ASNase showed no loss of AT3 activity as detected by a plasma-based factor Xa inhibition assay. Treatment of a confluent monolayer of HepG2 (hepatocarcinoma) cells with ASNase showed no gross loss in AT3 message levels detected by rtPCR. However, a decrease of cell viability was observed in cultures treated with ASNase. Interestingly, medium from HepG2 cells treated with ASNase showed a marked decrease in secretion of AT3 and another serpin, heparin cofactor II. Collectively, these data show that ASNase has no direct effect on AT3 in blood or plasma, but that ASNase may affect plasma levels of AT3 by interfering with translation and/or secretion of the protein in liver cells.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Leuk Res

DOI

ISSN

0145-2126

Publication Date

July 2000

Volume

24

Issue

7

Start / End Page

559 / 565

Location

England

Related Subject Headings

  • Tumor Cells, Cultured
  • Serpins
  • RNA, Messenger
  • Protein Biosynthesis
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Plasma
  • Immunology
  • Humans
  • Cell Survival
  • Asparaginase
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Bushman, J. E., Palmieri, D., Whinna, H. C., & Church, F. C. (2000). Insight into the mechanism of asparaginase-induced depletion of antithrombin III in treatment of childhood acute lymphoblastic leukemia. Leuk Res, 24(7), 559–565. https://doi.org/10.1016/s0145-2126(00)00017-5
Bushman, J. E., D. Palmieri, H. C. Whinna, and F. C. Church. “Insight into the mechanism of asparaginase-induced depletion of antithrombin III in treatment of childhood acute lymphoblastic leukemia.Leuk Res 24, no. 7 (July 2000): 559–65. https://doi.org/10.1016/s0145-2126(00)00017-5.
Bushman, J. E., et al. “Insight into the mechanism of asparaginase-induced depletion of antithrombin III in treatment of childhood acute lymphoblastic leukemia.Leuk Res, vol. 24, no. 7, July 2000, pp. 559–65. Pubmed, doi:10.1016/s0145-2126(00)00017-5.
Journal cover image

Published In

Leuk Res

DOI

ISSN

0145-2126

Publication Date

July 2000

Volume

24

Issue

7

Start / End Page

559 / 565

Location

England

Related Subject Headings

  • Tumor Cells, Cultured
  • Serpins
  • RNA, Messenger
  • Protein Biosynthesis
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Plasma
  • Immunology
  • Humans
  • Cell Survival
  • Asparaginase