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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 -
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 -
Cancers Nov 2023This report presents the results of the assessment of MRD response by multicolor flow cytometry (MFC) with regard to the randomized use of pegylated asparaginase (PEG)....
UNLABELLED
This report presents the results of the assessment of MRD response by multicolor flow cytometry (MFC) with regard to the randomized use of pegylated asparaginase (PEG). In this study, PEG was randomly administered at a dose of 1000 U/m on day 3 of induction therapy in children with B-lineage ALL.
METHODS
Conventional induction therapy consisted of dexamethasone, vincristine, and daunorubicin. MRD data was available in 502 patients who were randomized at the start of induction therapy, standard-risk (SR) patients into three (conventional induction without PEG, induction with additional PEG and with PEG but without daunorubicin) and intermediate-risk (ImR) patients into two groups (with additional PEG and without PEG).
RESULTS
The single administration of PEG resulted in a significantly higher proportion of rapid responders, in SR patients even when no anthracyclines were used for induction. In the SR group, the event-free survival of the MFC-MRD fast responders was similar in the PEG- and PEG+ arms (92.0 ± 3.1% vs. 96.2 ± 1.5%, respectively), and the same unfavorable trend was observed for MFC-MRD slow responders (57.5 ± 12.3% vs. 66.7 ± 15.7%, respectively). Results were similar in ImR patients: (94.3 ± 3.2% vs. 95.1 ± 2.4%, for fast responders and 63.3 ± 7.6% vs. 78.1 ± 7.9%, for slow responders in PEG- and PEG+ arms, respectively). However, there is a large difference between the proportion of MFC-MRD slow responders in the PEG- and PEG+ groups (18.3% vs. 5.2% for the SR group and 44.2% vs. 25.0% for the ImR group).
CONCLUSIONS
Therefore, early use of PEG-ASP not only leads to an accelerated reduction of blasts, but also to an excellent outcome in a significantly larger proportion of patients in both risk groups.
PubMed: 38067249
DOI: 10.3390/cancers15235547 -
Frontiers in Pharmacology 2023In Uruguay, the pediatric acute lymphoblastic leukemia (ALL) cure rate is 82.2%, similar to those reported in developed countries. However, many patients suffer adverse...
In Uruguay, the pediatric acute lymphoblastic leukemia (ALL) cure rate is 82.2%, similar to those reported in developed countries. However, many patients suffer adverse effects that could be attributed, in part, to genetic variability. This study aims to identify genetic variants related to drugs administered during the induction phase and analyze their contribution to adverse effects, considering individual genetic ancestry. Ten polymorphisms in five genes (, , , , and ) related to prednisone, vincristine, and L-asparaginase were genotyped in 200 patients. Ancestry was determined using 45 ancestry informative markers (AIMs). The sample ancestry was 69.2% European, 20.1% Native American, and 10.7% African, but with high heterogeneity. Mucositis, Cushing syndrome, and neurotoxicity were the only adverse effects linked with genetic variants and ancestry. Mucositis was significantly associated with (rs3832526; 3R/3R vs. 2R carriers; OR: = 6.88 [1.88-25.14], = ) and (non-expressors vs. expressors; OR: 4.55 [1.01-20.15], = ) genes. Regarding Cushing syndrome, patients with the TA genotype (rs1049674, ) had a higher risk of developing Cushing syndrome than those with the TT genotype (OR: 2.60 [1.23-5.51], = ). Neurotoxicity was significantly associated with (rs9282564; TC vs. TT; OR: 4.25 [1.47-12.29], = ). Moreover, patients with <20% Native American ancestry had a lower risk of developing neurotoxicity than those with ≥20% (OR: 0.312 [0.120-0.812], = ). This study shows the importance of knowing individual genetics to improve the efficacy and safety of acute lymphoblastic leukemia.
PubMed: 38044950
DOI: 10.3389/fphar.2023.1278769