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Leukemia Apr 2024Asparaginase is an essential component of acute lymphoblastic leukemia (ALL) therapy, yet its associated toxicities often lead to treatment discontinuation, increasing...
Asparaginase is an essential component of acute lymphoblastic leukemia (ALL) therapy, yet its associated toxicities often lead to treatment discontinuation, increasing the risk of relapse. Hypersensitivity reactions include clinical allergies, silent inactivation, or allergy-like responses. We hypothesized that even moderate increases in asparaginase clearance are related to later inactivation. We therefore explored mandatory monitoring of asparaginase enzyme activity (AEA) in patients with ALL aged 1-45 years treated according to the ALLTogether pilot protocol in the Nordic and Baltic countries to relate mean AEA to inactivation, to build a pharmacokinetic model to better characterize the pharmacokinetics of peg-asparaginase and assess whether an increased clearance relates to subsequent inactivation. The study analyzed 1631 real-time AEA samples from 253 patients, identifying inactivation in 18.2% of the patients. This inactivation presented as mild allergy (28.3%), severe allergy (50.0%), or silent inactivation (21.7%). A pharmacokinetic transit compartment model was used to describe AEA-time profiles, revealing that 93% of patients with inactivation exhibited prior increased clearance, whereas 86% of patients without hypersensitivity maintained stable clearance throughout asparaginase treatment. These findings enable prediction of inactivation and options for either dose increments or a shift to alternative asparaginase formulations to optimize ALL treatment strategies.
Topics: Humans; Asparaginase; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Polyethylene Glycols; Hypersensitivity; Antineoplastic Agents
PubMed: 38287133
DOI: 10.1038/s41375-024-02153-6 -
ACS Omega Jan 2024l-Asparaginase (E.C. 3.5.1.1) is an indispensable analeptic anticancer enzyme used as an amalgam with additional cancer medicines for the cure of acute lymphoblastic...
l-Asparaginase (E.C. 3.5.1.1) is an indispensable analeptic anticancer enzyme used as an amalgam with additional cancer medicines for the cure of acute lymphoblastic leukemia (ALL). The presence of lAparaginase in tomato was confirmed byWestern blotting and DNA sequencing. The l-Asparaginase gene from tomato has been deposited in the NCBI database with accession number: OR736141. Crude enzyme was extracted from the fruit pulp of and the activity was determined by the Nesslerization method. Further, the crude extract was subjected to purification, and kinetic parameters were studied. The percentage yield was calculated to be 6.457, and the purification fold was 0.086. The enzyme showed maximum activity at optimum pH 7.0, optimum temperature 37 °C, and incubation time of 05 min. The Michaelis constant "" and maximum velocity "" values were determined by the Lineweaver-Burk plot, which showed a low value of 0.66 and of 3.846 IU. Cytotoxic studies were carried out for crude and purified l-asparaginase. Purified l-Asparaginase has exhibited anticancer activity against the ALL model system, K-562 cell line, comparable to that of the anticancer compound vinblastine. Hence, l-Asparaginase from the fruit extract of tomato could be used as a nutraceutical to support cancer treatment in acute lymphoblastic leukemia.
PubMed: 38284052
DOI: 10.1021/acsomega.3c07633 -
Foods (Basel, Switzerland) Dec 2023Acrylamide is present in thermally processed foods, and it possesses toxic and carcinogenic properties. L-asparaginases could effectively regulate the formation of...
Acrylamide is present in thermally processed foods, and it possesses toxic and carcinogenic properties. L-asparaginases could effectively regulate the formation of acrylamide at the source. However, current L-asparaginases have drawbacks such as poor thermal stability, low catalytic activity, and poor substrate specificity, thereby restricting their utility in the food industry. To address this issue, this study employed consensus design to predict the crucial residues influencing the thermal stability of L-asparaginase (CgASNase). Subsequently, a combination of site-point saturating mutation and combinatorial mutation techniques was applied to generate the double-mutant enzyme L42T/S213N. Remarkably, L42T/S213N displayed significantly enhanced thermal stability without a substantial impact on its enzymatic activity. Notably, its half-life at 40 °C reached an impressive 13.29 ± 0.91 min, surpassing that of CgASNase (3.24 ± 0.23 min). Moreover, the enhanced thermal stability of L42T/S213N can be attributed to an increased positive surface charge and a more symmetrical positive potential, as revealed by three-dimensional structural simulations and structure comparison analyses. To assess the impact of L42T/S213N on acrylamide removal in biscuits, the optimal treatment conditions for acrylamide removal were determined through a combination of one-way and orthogonal tests, with an enzyme dosage of 300 IU/kg flour, an enzyme reaction temperature of 40 °C, and an enzyme reaction time of 30 min. Under these conditions, compared to the control (464.74 ± 6.68 µg/kg), the acrylamide reduction in double-mutant-enzyme-treated biscuits was 85.31%, while the reduction in wild-type-treated biscuits was 68.78%. These results suggest that L42T/S213N is a promising candidate for industrial applications of L-asparaginase.
PubMed: 38231880
DOI: 10.3390/foods12234364 -
Anales de Pediatria Jan 2024
Topics: Humans; Asparaginase; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Agents
PubMed: 38177039
DOI: 10.1016/j.anpede.2023.09.016 -
Cureus Dec 2023L-asparaginase (L-Asp) is a useful antileukemic agent for acute lymphoblastic leukemia (ALL); however, it often causes severe liver injury with marked fatty liver. Here,...
L-asparaginase (L-Asp) is a useful antileukemic agent for acute lymphoblastic leukemia (ALL); however, it often causes severe liver injury with marked fatty liver. Here, we present a case of L-Asp-induced fatty liver disease in a 21-year-old female patient with ALL. Serum cholinesterase levels, which are usually elevated in fatty liver, decrease at the onset of liver injury. After treatment with L-carnitine and vitamin B complex, the liver injury rapidly improved, resulting in the patient being able to continue subsequent chemotherapy.
PubMed: 38161559
DOI: 10.7759/cureus.49787 -
South Asian Journal of Cancer Oct 2023Dhaarani Jayaraman Acute lymphoblastic leukemia (ALL) is a common type of leukemia in children. The innovator pegylated L-asparaginase has several advantages over...
Dhaarani Jayaraman Acute lymphoblastic leukemia (ALL) is a common type of leukemia in children. The innovator pegylated L-asparaginase has several advantages over native L-asparaginase; however, its use in India is limited due to availability and cost. Therefore, a generic pegylated L-asparaginase can be considered as an alternative to the innovator molecule. A retrospective study was conducted to assess the outcome (minimal residual disease [MRD]) and toxicity of a generic pegylated L-asparaginase (Hamsyl) at the end of induction therapy. Eighty-eight (80.7%) and 21 (19.3%) patients had received generic pegylated L-asparaginase and conventional asparaginase, respectively, as a part of their treatment protocol. Nearly 82% of patients had B-type ALL. Eight-one percent of children had a white blood cell count of fewer than 50,000/mm . At the end of induction, 80.7% (88) of children were minimal residual disease (MRD)-negative, and at the end of augmented consolidation therapy, 20.2% were MRD-negative. Ten percent of patients exhibited allergic reactions. Two children had pancreatitis, and one child had central venous thrombosis. The generic pegylated L-asparaginase (Hamsyl) was effective and safe for use in pediatric ALL.
PubMed: 38130281
DOI: 10.1055/s-0042-1759785 -
Leukemia Research Reports 2023[This corrects the article DOI: 10.1016/j.lrr.2022.100357.].
[This corrects the article DOI: 10.1016/j.lrr.2022.100357.].
PubMed: 38098958
DOI: 10.1016/j.lrr.2023.100375 -
Science Advances Dec 2023Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is...
Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is no consensus on the characteristics for identifying this disease type because of its rarity and lack of defined distinctive molecular characteristics. In this study, multiomics analysis revealed that MNKPL is distinct from acute myeloid leukemia, T cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia (MPAL), and and activation and down-regulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, the results of our single-cell analysis using MNKPL cells suggest that NK cells and myeloid cells share common progenitor cells. Treatment outcomes for MNKPL are unsatisfactory, even when hematopoietic cell transplantation is performed. Multiomics analysis and in vitro drug sensitivity assays revealed increased sensitivity to l-asparaginase and reduced levels of asparagine synthetase (ASNS), supporting the clinically observed effectiveness of l-asparaginase.
Topics: Humans; Asparaginase; Leukemia, Myeloid, Acute; Acute Disease; Killer Cells, Natural; Treatment Outcome; Repressor Proteins; Tumor Suppressor Proteins
PubMed: 38091391
DOI: 10.1126/sciadv.adj4407