Asparaginase: an old drug with new questions

Cecconello, D; Magalhães, Mariana Rodrigues; Werlang, Isabel Cristina Ribas; Lee, Maria Lúcia de Martino; Michalowski, Mariana Bohns; Daudt, Liane Esteves

doi:10.1016/j.htct.2019.07.010

Cited by 25 publications

(27 citation statements)

References 40 publications

(106 reference statements)

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“…Whereas ASNase has been used very successfully for over 40 years, that therapy is not free of pitfalls. Recorded side effects include pancreatitis, hypercoagulability, liver dysfunction, allergic reactions, and general ASNase resistance [27][28][29]. Thus, much of the current effort is focused on the development of variants with improved toxicity profiles [30][31][32].…”

Section: Utilization Of Asnases For Anticancer Therapy and Food Manufacturingmentioning

confidence: 99%

Structural and biochemical properties of L‐asparaginase

Łubkowski

Wlodawer

2021

The FEBS Journal

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L-asparaginase (a hydrolase converting L-asparagine to L-aspartic acid) was the first enzyme to be used in clinical practice as an anticancer agent after its approval in 1978 as a component of a treatment protocol for childhood acute lymphoblastic leukemia (ALL). Structural and biochemical properties of L-asparaginases have been extensively investigated during the last half century, providing an accurate structural description of the enzyme isolated from a variety of sources, as well as clarifying the mechanism of its activity. This review provides a critical assessment of the current state of knowledge of primarily structural, but also selected biochemical properties of "bacterial-type" L-asparaginases from different organisms. The most extensively studied members of this enzyme family are L-asparaginases highly homologous to one of the two enzymes from Escherichia coli (usually referred to as EcAI and EcAII). Members of this enzyme family, although often called bacterial-type L-asparaginases, have been also identified in such divergent organisms as archaea or eukarya. Over 100 structural models of L-asparaginases have been deposited in the Protein Data Bank during the last 30 years. One of the prime achievements of structure-centered approaches was the elucidation of the details of the mechanism of enzymatic action of this unique hydrolase that utilizes a side chain of threonine as the primary nucleophile. The molecular basis of other important properties of these enzymes, such as their substrate specificity, are still being evaluated. Results of structural and mechanistic studies of L-asparaginases are being utilized in efforts to improve the clinical properties of this important anticancer drug.

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Section: Utilization Of Asnases For Anticancer Therapy and Food Manufacturingmentioning

confidence: 99%

Structural and biochemical properties of L‐asparaginase

Łubkowski

Wlodawer

2021

The FEBS Journal

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“…The development of anti-ASNase antibodies is mostly observed with native E. coli ASNase, generally ranging 10–30% but can be up to 75% of ALL patients, depending upon ASNase preparations and treatment [ 121 ]. Patients who encountered hypersensitivity to one preparation may cause the rapid inactivation of ASNase, leading to worse prognosis or so-called “silent inactivation” [ 122 ]. The availability of multiple ASNase preparations allows patients to switch to alternative ASNases.…”

Section: Mechanisms Of Drug Resistancementioning

confidence: 99%

Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy

et al. 2021

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Proline, glutamine, asparagine, and arginine are conditionally non-essential amino acids that can be produced in our body. However, they are essential for the growth of highly proliferative cells such as cancers. Many cancers express reduced levels of these amino acids and thus require import from the environment. Meanwhile, the biosynthesis of these amino acids is inter-connected but can be intervened individually through the inhibition of key enzymes of the biosynthesis of these amino acids, resulting in amino acid starvation and cell death. Amino acid starvation strategies have been in various stages of clinical applications. Targeting asparagine using asparaginase has been approved for treating acute lymphoblastic leukemia. Targeting glutamine and arginine starvations are in various stages of clinical trials, and targeting proline starvation is in preclinical development. The most important obstacle of these therapies is drug resistance, which is mostly due to reactivation of the key enzymes involved in biosynthesis of the targeted amino acids and reprogramming of compensatory survival pathways via transcriptional, epigenetic, and post-translational mechanisms. Here, we review the interactive regulatory mechanisms that control cellular levels of these amino acids for amino acid starvation therapy and how drug resistance is evolved underlying treatment failure.

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“…The cost of TDM is an obstacle (US$105), which limits the use in real-world of some developing countries, like Brazil. [2][3][4] On the other hand, the costs of ammonia dosage at the study site were US$1,50. 5 We did not propose the use of ammonia level for silent inactivation, only in the context of an infusion reaction.…”

Section: Response To Comment On Ammonia Level As a Proxy Of Asparaginase Inactivation In Children: A Strategy For Classification Of Infusmentioning

confidence: 99%

Response to comment on Ammonia level as a proxy of asparaginase inactivation in children: A strategy for classification of infusion reactions

Santos

Land

Lima

2021

J Oncol Pharm Pract

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effect. The characteristic points different from the patient treated by Pamp ın-Sa´nchez et al. were: 1) an EGFR mutation-positive patient, 2) relapse after the long-term control, and 3) re-response to EGFR-TKI. Although the efficacy of immune checkpoint inhibitors in EGFR mutation-positive patients has been limited, 2 our patient responded to nivolumab. We evaluated that it is desirable to refrain from high-dose corticosteroid administration in order to sustain the effects of immune checkpoint inhibitors. We do agree with the conclusion by Pamp ın-Sa´nchez et al. 1 that suspension of treatment with close monitoring of these patients until progression may be an alternative, since immune-related toxicities could be related to a greater clinical benefit and a durable response to nivolumab.

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Asparaginase: an old drug with new questions

Cited by 25 publications

References 40 publications

Structural and biochemical properties of L‐asparaginase

Structural and biochemical properties of L‐asparaginase

Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy

Response to comment on Ammonia level as a proxy of asparaginase inactivation in children: A strategy for classification of infusion reactions

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