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Leukemia & Lymphoma Dec 2019
Topics: Asparaginase; Child; Humans; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 31558076
DOI: 10.1080/10428194.2019.1668941 -
Blood Reviews May 2022Acute lymphoblastic leukemia (ALL) is a malignancy of lymphoid progenitor cells occurring at an annual incidence rate of approximately 1.1 to 2.1 per 100,000... (Review)
Review
Acute lymphoblastic leukemia (ALL) is a malignancy of lymphoid progenitor cells occurring at an annual incidence rate of approximately 1.1 to 2.1 per 100,000 person-years globally. Approximately 40% of annual ALL cases occur in adults, yet estimated 5-year overall survival rates are about 40% to 50% in adults (and vary broadly by age) compared with 90% in children. Although the addition and/or intensification of asparaginase as a key treatment strategy for pediatric ALL is well recognized, further research is needed to clarify the benefit/risk ratio in adult patients with ALL. This review emphasizes the importance of efficient management of adverse events to increase asparaginase efficacy and explores novel strategies for optimizing asparaginase treatment, including new formulations of asparaginase, pharmacokinetic-based dosing, and pharmacogenetic profiling. Upcoming results of adult ALL trials should further clarify the role of asparaginase, building on the results of the large NOPHO 2008, CALGB 10403, GRAALL-2005, GMALL 07/2003, and UKALL14 trials.
Topics: Acute Disease; Adult; Antineoplastic Agents; Asparaginase; Humans; Incidence; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 35031177
DOI: 10.1016/j.blre.2021.100908 -
Andes Pediatrica : Revista Chilena de... Aug 2021
Topics: Asparaginase; Drug Hypersensitivity; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 34652385
DOI: 10.32641/andespediatr.v92i4.3825 -
Archives of Microbiology Jul 2020L-asparaginase (E.C.3.5.1.1) is an important enzyme that has been purified and characterized for over decades to study and evaluate its anti-carcinogenic activity... (Review)
Review
L-asparaginase (E.C.3.5.1.1) is an important enzyme that has been purified and characterized for over decades to study and evaluate its anti-carcinogenic activity against different lymphoproliferative disorders such as acute lymphoblastic leukemia (ALL) and Hodgkin's lymphoma. The ability of the enzyme to convert L-asparagine into aspartic acid and ammonia is the reason behind its anti-cancerous activity. Apart from its medicinal uses, it is widely used in food industry to tackle acrylamide, a probable human carcinogen and, production in carbohydrate-rich foods cooked at high temperatures. There are variety of organisms including microorganisms such as bacteria, fungi, algae, and plants that produce L-asparaginase. The enzyme obtained from different microbial and plant sources have different physiochemical properties and kinetic parameters. L-asparaginases have an optimum pH range between 6 and 10 and an optimum temperature between 37 and 85 °C. This article has reviewed the lowest molecular mass for L-asparaginase in Yersinia pseudotuberculosis Q66CJ2 which is 36.27 kDa, while the highest for Pseudomonas otitidis which has a molecular mass of 205 ± 3 kDa. This review is an attempt to summarize most of the available sources, their phylogenetic relationships, purification methods, data regarding different physiochemical and kinetic properties of L-asparaginase.
Topics: Ammonia; Asparaginase; Asparagine; Aspartic Acid; Bacteria; Fungi; Hodgkin Disease; Humans; Phylogeny; Plants; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 32052094
DOI: 10.1007/s00203-020-01814-1 -
Engineering and Expression Strategies for Optimization of L-Asparaginase Development and Production.International Journal of Molecular... Oct 2023Genetic engineering for heterologous expression has advanced in recent years. Model systems such as , and are often used as host microorganisms for the enzymatic... (Review)
Review
Genetic engineering for heterologous expression has advanced in recent years. Model systems such as , and are often used as host microorganisms for the enzymatic production of L-asparaginase, an enzyme widely used in the clinic for the treatment of leukemia and in bakeries for the reduction of acrylamide. Newly developed recombinant L-asparaginase (L-ASNase) may have a low affinity for asparagine, reduced catalytic activity, low stability, and increased glutaminase activity or immunogenicity. Some successful commercial preparations of L-ASNase are now available. Therefore, obtaining novel L-ASNases with improved properties suitable for food or clinical applications remains a challenge. The combination of rational design and/or directed evolution and heterologous expression has been used to create enzymes with desired characteristics. Computer design, combined with other methods, could make it possible to generate mutant libraries of novel L-ASNases without costly and time-consuming efforts. In this review, we summarize the strategies and approaches for obtaining and developing L-ASNase with improved properties.
Topics: Humans; Asparaginase; Asparagine; Leukemia; Escherichia coli; Models, Biological; Antineoplastic Agents
PubMed: 37894901
DOI: 10.3390/ijms242015220 -
Biotechnology and Applied Biochemistry Oct 2022l-Asparaginase catalyzes the hydrolysis of asparagine into aspartic acid and ammonia. The present work elaborates the isolation and identification of a novel endophytic...
l-Asparaginase catalyzes the hydrolysis of asparagine into aspartic acid and ammonia. The present work elaborates the isolation and identification of a novel endophytic fungal isolate producing l-glutaminase and urease-free l-asparaginase. Cell growth and enzyme production were investigated for large production. The isolated endophytic fungi were identified at molecular levels and a phylogenetic tree was constructed. The enzyme synthesis was evaluated by cultivating the isolated microorganisms in potato dextrose agar medium. Out of 27 isolated endophytes, nine were producing "l-glutaminase and urease-free l-asparaginase." l-Asparaginase from Chaetomium sp. exhibited superior enzyme activity than from the other isolates. Observed optimal conditions for l-asparaginase activity were 25 min of incubation time, 0.5 mg of enzyme source, 40°C of temperature, and pH 7.0. l-Asparaginase from Chaetomium sp. exhibited anticancer activity on human blood cancer (MOLT-4) cells. The current study has demonstrated the production of contaminant-free l-asparaginase enzyme from endophytic fungal species. The results showed that: (a) maximum enzyme activity was observed for l-asparaginase from Chaetomium sp., (b) concentration of glucose in the medium as a carbon source suppressed the enzyme production. Chaetomium sp. is a novel source for "l-glutaminase and urease-free l-asparaginase," which may play a major role in pharmacotherapy.
Topics: Humans; Asparaginase; Glutaminase; Chaetomium; Endophytes; Urease; Phylogeny
PubMed: 34694636
DOI: 10.1002/bab.2276 -
Anti-cancer Agents in Medicinal... 2022Microbial L-asparaginase is the most effective first-line therapy used in the treatment protocols of paediatric and adult leukemia. Leukemic cells' auxotrophy for... (Review)
Review
Microbial L-asparaginase is the most effective first-line therapy used in the treatment protocols of paediatric and adult leukemia. Leukemic cells' auxotrophy for L-asparagine is exploited as a therapeutic strategy to mediate cell death through metabolic blockade of L-asparagine using L-asparaginase. Escherichia coli and Erwinia chrysanthemi serve as the major enzyme deriving sources accepted in clinical practice, and the enzyme has bestowed improvements in patient outcomes over the last 40 years. However, an array of side effects generated by the native enzymes due to glutamine co-catalysis and short serum stays augmenting frequent dosages intended a therapeutic switch towards developing bio better alternatives for the enzyme, including the formulations resulting in sustained local depletion of Lasparagine. In addition, the treatment with L-asparaginase in a few cancer types has proven to elicit drug-induced cytoprotective autophagy mechanisms and therefore warrants concern. Although the off-target glutamine hydrolysis has been viewed as contributing to the drug-induced secondary responses in cells deficient with asparagine synthetase machinery, the beneficial role of glutaminase-asparaginase in proliferative regulation of asparagine prototrophic cells has been looked forward. The current review provides an overview of the enzyme's clinical applications in leukemia and possible therapeutic implications in other solid tumours, recent advancements in drug formulations, and discusses the aspects of two-sided roles of glutaminase-asparaginases and drug-induced cytoprotective autophagy mechanisms.
Topics: Asparaginase; Asparagine; Child; Escherichia coli; Glutaminase; Glutamine; Humans; Leukemia
PubMed: 34994334
DOI: 10.2174/1871520622666220106103336 -
Molecular Genetics and Metabolism Jul 2023Hyperammonemia has been reported following asparaginase administration, consistent with the mechanisms of asparaginase, which catabolizes asparagine to aspartic acid and...
Hyperammonemia has been reported following asparaginase administration, consistent with the mechanisms of asparaginase, which catabolizes asparagine to aspartic acid and ammonia, and secondarily converts glutamine to glutamate and ammonia. However, there are only a few reports on the treatment of these patients, which varies widely from watchful waiting to treatment with lactulose, protein restriction, sodium benzoate, and phenylbutyrate to dialysis. While many patients with reported asparaginase-induced hyperammonemia (AIH) are asymptomatic, some have severe complications and even fatal outcomes despite medical intervention. Here, we present a cohort of five pediatric patients with symptomatic AIH, which occurred after switching patients from polyethylene glycolated (PEG)- asparaginase to recombinant Crisantaspase Pseudomonas fluorescens (4 patients) or Erwinia (1 patient) asparaginase, and discuss their subsequent management, metabolic workup, and genetic testing. We developed an institutional management plan, which gradually evolved based on our local experience and previous treatment modalities. Because of the significant reduction in glutamine levels after asparaginase administration, sodium benzoate should be used as a first-line ammonia scavenger for symptomatic AIH instead of sodium phenylacetate or phenylbutyrate. This approach facilitated continuation of asparaginase doses, which is known to improve cancer outcomes. We also discuss the potential contribution of genetic modifiers to AIH. Our data highlights the need for increased awareness of symptomatic AIH, especially when an asparaginase with higher glutaminase activity is used, and its prompt management. The utility and efficacy of this management approach should be systematically investigated in a larger cohort of patients.
Topics: Humans; Child; Asparaginase; Phenylbutyrates; Hyperammonemia; Sodium Benzoate; Glutamine; Ammonia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome; Antineoplastic Agents
PubMed: 37327713
DOI: 10.1016/j.ymgme.2023.107627 -
Molecules (Basel, Switzerland) Dec 2020l-asparaginase (ASNase, EC 3.5.1.1) is an aminohydrolase enzyme with important uses in the therapeutic/pharmaceutical and food industries. Its main applications are as... (Review)
Review
l-asparaginase (ASNase, EC 3.5.1.1) is an aminohydrolase enzyme with important uses in the therapeutic/pharmaceutical and food industries. Its main applications are as an anticancer drug, mostly for acute lymphoblastic leukaemia (ALL) treatment, and in acrylamide reduction when starch-rich foods are cooked at temperatures above 100 °C. Its use as a biosensor for asparagine in both industries has also been reported. However, there are certain challenges associated with ASNase applications. Depending on the ASNase source, the major challenges of its pharmaceutical application are the hypersensitivity reactions that it causes in ALL patients and its short half-life and fast plasma clearance in the blood system by native proteases. In addition, ASNase is generally unstable and it is a thermolabile enzyme, which also hinders its application in the food sector. These drawbacks have been overcome by the ASNase confinement in different (nano)materials through distinct techniques, such as physical adsorption, covalent attachment and entrapment. Overall, this review describes the most recent strategies reported for ASNase confinement in numerous (nano)materials, highlighting its improved properties, especially specificity, half-life enhancement and thermal and operational stability improvement, allowing its reuse, increased proteolysis resistance and immunogenicity elimination. The most recent applications of confined ASNase in nanomaterials are reviewed for the first time, simultaneously providing prospects in the described fields of application.
Topics: Asparaginase; Biosensing Techniques; Biotechnology; Drug Development; Food Industry; Humans; Nanotechnology; Protein Engineering; Structure-Activity Relationship
PubMed: 33321857
DOI: 10.3390/molecules25245827 -
Pediatric Blood & Cancer Aug 2019Asparaginase is a critical component of lymphoblastic leukemia therapy, with intravenous pegaspargase (PEG) as the current standard product. Acute adverse events (aAEs)...
BACKGROUND
Asparaginase is a critical component of lymphoblastic leukemia therapy, with intravenous pegaspargase (PEG) as the current standard product. Acute adverse events (aAEs) during PEG infusion are difficult to interpret, representing a mix of drug-inactivating hypersensitivity and noninactivating reactions. Asparaginase Erwinia chrysanthemi (ERW) is approved for PEG hypersensitivity, but is less convenient, more expensive, and yields lower serum asparaginase activity (SAA). We began a policy of universal premedication and SAA testing for PEG, hypothesizing this would reduce aAEs and unnecessary drug substitutions.
PROCEDURE
Retrospective chart review of patients receiving asparaginase before and after universal premedication before PEG was conducted, with SAA performed 1 week later. We excluded patients who had nonallergic asparaginase AEs. Primary end point was substitution to ERW. Secondary end points included aAEs, SAA testing, and cost.
RESULTS
We substituted to ERW in 21 of 122 (17.2%) patients pre-policy, and 5 of 68 (7.4%) post-policy (RR, 0.427; 95% CI, 0.27-0.69, P = 0.028). All completed doses of PEG yielded excellent SAA (mean, 0.90 units/mL), compared with ERW (mean, 0.15 units/mL). PEG inactivation post-policy was seen in 2 of 68 (2.9%), one silent and one with breakthrough aAE. The rate of aAEs pre/post-policy was 17.2% versus 5.9% (RR, 0.342; 95% CI, 0.20-0.58, P = 0.017). Grade 4 aAE rate pre/post-policy was 15% versus 0%. Cost analysis predicts $125 779 drug savings alone per substitution prevented ($12 402/premedicated patient).
CONCLUSIONS
Universal premedication reduced substitutions to ERW and aAE rate. SAA testing demonstrated low rates of silent inactivation, and higher SAA for PEG. A substantial savings was achieved. We propose universal premedication for PEG be standard of care.
Topics: Administration, Intravenous; Adolescent; Adult; Antineoplastic Agents; Asparaginase; Child; Child, Preschool; Drug Hypersensitivity; Drug Monitoring; Drug Substitution; Female; Follow-Up Studies; Hematologic Neoplasms; Humans; Infant; Male; Premedication; Prognosis; Retrospective Studies; Tissue Distribution; Young Adult
PubMed: 31099154
DOI: 10.1002/pbc.27797