Asparaginase‐induced derangements of glutamine metabolism: the pathogenetic basis for some drug‐related side‐effects

Abstract

Abstract. Several side-effects of asparaginase therapy have been said to be a consequence of the glutaminase activity of Escherichia coli asparaginase, especially the deleterious influence on the liver function. We report here the drug-induced impairments of asparagine and glutamine metabolism in correlation to concentrations changes of plasma proteins, synthesized in the liver, in patients with acute lymphatic leukaemia. One hour after asparaginase application, plasma glutamine decreased to 5% (0-39%: median, range) of the initial values, with a subsequent rise to concentrations slightly lower than those prior to therapy. During the 14 days of drug application the fasting plasma concentrations of glutamine fell to a median of 63% of the pre-therapeutic levels, indicating a depletion of the glutamine pools. Two days after the end of asparaginase application, in one patient the glutamine concentrations increased to the pre-therapeutic range. Plasma concentrations of fibrinogen and antithrombin I11 decreased to 46% and 56%, respectively, of the initial values, with a slight increase 2 days after the end of therapy. The changes of plasma protein concentrations followed the course of plasma glutamine and asparagine. From that we deduce that the hepatic synthesis of the plasma proteins might be influenced by asparagine and glutamine depletion as a consequence of the therapy with E. coli asparaginase.

Pharmacokinetic, pharmacodynamic and intracellular effects of PEG-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia: results from a single agent window study

“…9 The administration of L-asparaginase results in the deamination of asparagine into aspartic acid leading to a rapid and complete depletion of serum asparagine, which ultimately affects the intracellular asparagine levels. 10,11 L-asparaginase also has 3-4% glutaminase activity leading to serum glutamine depletion. 12 L-asparaginase enzymatic activity should be 4100 IU/l to sufficiently diminish the asparagine serum levels required to induce leukemic cell kill.…”

Purification and Biochemical Characterization of Native and Pegylated Form of L-Asparaginase from <i>Aspergillus terreus</i> and Evaluation of Its Antiproliferative Activity

“…According to Panosyan et al [16] the effective deamination of glutamine by L-asparaginase appears to contribute to the decrease of asparagine depletion by depriving the asparagine synthetase of glutamine, the precursor asparagine biosynthesis. Bacterial L-asparaginase, used in therapeutic protocols, has low glutaminase activity but toxicity reactions are attributed to this activity [17,18]. Herein L-glutaminase activity was not detected in crude enzyme (concentrated or not) produced by A. terreus (PC-1.7.A) even after 60 min of the reaction.…”

“…It is important to know that the half-lives of E. coli asparaginase linked to PEG are longer than the native enzyme [3,17]. Herein the pegylated-L-asparaginase was resistant to trypsin, a cysteine protease, and was more thermostable than the native enzyme, as well maintained 93% of the original activity.…”

One‐step purification and kinetic properties of the recombinant l‐asparaginase from Erwinia carotovora

“…It is thought that one of the main reasons of Lasparaginase toxicity is its L-glutaminase activity [12]. L-Gln is the main form of nitrogen transportation in blood, and prolonged depletion of this amino acid during asparaginase therapy causes serious biochemical disorders in the body, particularly in liver.…”