Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer---Children's Leukemia Group phase 3 trial

Duval, Manon

doi:10.1182/blood.v99.8.2734

Cited by 383 publications

(261 citation statements)

References 28 publications

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“…These data are consistent with the notion that the risk of thrombosis may be higher in those with highest exposure to active asparaginase. 26,27 These data support our practice to substitute Erwinia asparaginase in patients who develop clinical hypersensitivity to native E. coli, asparaginase, and raise the concern of using PEG asparaginase (at the currently recommended dose) in this situation. It remains uncertain whether patients with subclinical hypersensitivity should receive an alternative asparaginase preparation even in the absence of clinical allergy.…”

Section: Discussionmentioning

confidence: 50%

Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia

Chen

et al. 2004

Leukemia

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Polyethylene glycol-conjugated (PEG) asparaginase is approved for use in patients who develop allergy to other forms of asparaginase, although its ability to deplete asparagine systemically in patients with hypersensitivity has not been well elucidated. In 53 children with newly diagnosed acute lymphoblastic leukemia, we serially assessed asparagine concentrations in cerebrospinal fluid (CSF) and plasma as well as serum anti-asparaginase antibodies. All patients received native Escherichia coli (Elspar) asparaginase during induction therapy; patients received PEG asparaginase during reinductions when available, and those who developed allergy received Erwinia asparaginase. All eight patients who developed clinical evidence of allergy to asparaginase had anti-asparaginase antibodies. Among patients who had no antibodies, those who received E. coli had lower mean (7s.d.) CSF asparagine (0.2970.63, n ¼ 9) than those who received PEG (0.7770.82, n ¼ 4) (P ¼ 0.007). Results were similar for plasma asparagine. There was no situation where asparagine concentrations were more effectively depleted by PEG than by other preparations. None of the five patients who developed thrombosis had an allergy or antibodies to asparaginase at the time of the thrombosis. We conclude that asparagine concentrations were less effectively depleted by PEG than by E. coli asparaginase at the doses commonly used. The risk of thrombosis may be affected by the intensity of asparaginase exposure.

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Section: Discussionmentioning

confidence: 50%

Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia

Chen

et al. 2004

Leukemia

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“…Escherichia coli L-ASNase has been used extensively as a therapeutic enzyme in the frontline treatment of lymphoblastic malignancies, such as acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma [3,4], since the 1960s. In light of the significance of L-ASNase as a therapeutic protein, various methods have been developed for measuring the enzyme's activity.…”

Section: Leukemia L-aspartate Oxidase Coupled Enzyme Assay Amplex Redmentioning

confidence: 99%

An Amplex Red-based fluorometric and spectrophotometric assay for l-asparaginase using its natural substrate

Karamitros

Lim

Konrad

2014

Analytical Biochemistry

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Leukemia L-Aspartate oxidase Coupled enzyme assay Amplex Red a b s t r a c tWe report on the development of a sensitive real-time assay for monitoring the activity of L-asparaginase that hydrolyzes L-asparagine to L-aspartate and ammonia. In this method, L-aspartate is oxidized by Laspartate oxidase to iminoaspartate and hydrogen peroxide (H 2 O 2 ), and in the detection step horseradish peroxidase uses H 2 O 2 to convert the colorless, nonfluorescent reagent Amplex Red to the red-colored and highly fluorescent product resorufin. The assay was validated in both the absorbance and the fluorescence modes. We show that, due to its high sensitivity and substrate selectivity, this assay can be used to measure enzymatic activity in human serum containing L-asparaginase.Ó 2013 Elsevier Inc. All rights reserved.The enzyme L-asparaginase (EC 3.5.1.1, L-asparagine amidohydrolase, L-ASNase), 1 which predominantly occurs in microorganisms and plants, catalyzes the hydrolysis of L-asparagine (L-Asn) to L-aspartic acid (L-Asp) and ammonia [1,2]. Escherichia coli L-ASNase has been used extensively as a therapeutic enzyme in the frontline treatment of lymphoblastic malignancies, such as acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma [3,4], since the 1960s. In light of the significance of L-ASNase as a therapeutic protein, various methods have been developed for measuring the enzyme's activity. Those assays can be used in either absorbance mode [5][6][7][8][9][10] or fluorescence mode [11,12]. However, these assays suffer from certain disadvantages that are primarily related to the use of substrate analogs instead of the natural substrate L-Asn [6,7,11,12]. Such assays are not suitable for in vitro evolution of L-asparaginases that aims to select variants showing improved catalytic efficiency and selectivity for the physiological substrate. Moreover, the limited sensitivity of absorption-based spectrophotometric assays [5][6][7]9,10] is a major handicap to significantly reducing reaction volumes. A noteworthy example of such a case is droplet-based microfluidics, which has emerged as a powerful tool for high-throughput screening in directed protein evolution [13,14]. In these experimental setups, the assay volume is minimized to 1 nl, to 1 fl, scaling down light path lengths to 1 lm.Here, we report on the development of a novel L-ASNase assay that can be used in either the fluorescence or absorbance mode and relies solely on the use of the physiological substrate L-Asn. In this three-step coupled enzyme system (Fig. 1), L-Asp, which is one of the two products of the L-ASNase reaction, is oxidized by L-aspartate oxidase (L-AspOx), resulting in the formation of iminoaspartate and hydrogen peroxide (H 2 O 2 ); the latter product is used by horseradish peroxidase (HRP) to oxidize the nonfluorescent compound Amplex Red (AR) to resorufin, which exhibits excellent fluorescence as well as absorbance properties.For establishing and quantitatively evaluating the assay, we cloned and recombinantly produced E. coli L-AspOx [15]...

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“…chrysanthemi (ErA), are used in the chemotherapy of acute leukaemia and lymphoand reticuloblastomas, due to their lowest toxicity among the large variety of similar enzymes with known antitumour activities [10]. Various side-effects, such as immunosuppresion, hepato-and neurotoxicity, acute pancreatitis and thromboembolisis, limit the therapeutic use of bacterial asparaginases [11].…”

Section: Introductionmentioning

confidence: 99%

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

Krasotkina

Borisova

Gervaziev

et al. 2004

Biotech and App Biochem

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ECAR-LANS, the recombinant L-asparaginase fromErwinia carotovora, is a prospective therapeutic enzyme for leukaemia treatment. An efficient and economical scheme was developed for the purification, cloning and expression in Eschericha coli of ECAR-LANS. More than 90 % purity, complemented with 72 % active enzyme recovery, was achieved with a single chromatographic purification step. The activity of purified L-asparaginase was 630 i.u./mg. The ECAR-LANS K m value was 98 × 10 −6 M for the main physiological substrate L-Asn and 3400 × 10 −6 M for L-Gln. ECAR-LANS was found to have low relative glutaminase activity (1.2 %) at physiological concentrations of L-Asn and L-Gln in blood. Kinetic studies of ECAR-LANS showed that the recombinant asparaginase combined the main advantages of Erw. chrysanthemi and E. coli L-asparaginases II, currently used in the treatment of acute lymphoblastic leukaemia.

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Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer---Children's Leukemia Group phase 3 trial

Cited by 383 publications

References 28 publications

Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia

Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia

An Amplex Red-based fluorometric and spectrophotometric assay for l-asparaginase using its natural substrate

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

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