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Clinical Laboratory Feb 2022Asparaginase (ASP), a chemotherapy component in the acute lymphoblastic leukemia (ALL) treatment, could impair normal coagulation state. Usually, a decline in the levels...
BACKGROUND
Asparaginase (ASP), a chemotherapy component in the acute lymphoblastic leukemia (ALL) treatment, could impair normal coagulation state. Usually, a decline in the levels of several coagulation factors occurs which ultimately could lead to thrombotic events and abnormal coagulation tests. In this study, we aimed to compare the effects of two different subtypes of ASP, pegylated asparaginase (PEG-ASP) and L-asparaginase (L-ASP) on coagulation markers and test among 40 pediatric patients with ALL.
METHODS
In this cohort study a total of 40 pediatric patients with newly diagnosed ALL were enrolled and divided into two groups by simple randomization. In group A, 20 patients received PEG-ASP while in group B, 20 patients received L-ASP during the induction treatment. Coagulation markers included prothrombin time (PT), partial thrombin time (PTT), protein-C (Pr-C), protein-S (Pr-S), and antithrombin III (ATIII) and were assessed before start and after of induction chemotherapy.
RESULTS
Coagulation profile including PT, PTT, INR, Pr-C, Pr-S, and ATIII before start of treatment were not statistically significant between the two groups. Anticoagulant factors decreased significantly after consuming both drugs. Tests for PT and INR of those who took L-ASP decreased significantly. Overall, when comparing the changes of the six studied factors, ATIII and Pr-C were the significant factors which were different between groups.
CONCLUSIONS
ASP has a negative effect on anticoagulant factors including (ATIII, Pr-C, Pr-S). Additionally, the negative effect of L-ASP on anticoagulant factors was more prominent than PEG-ASP. Therefore, the risk of thrombosis probably was negligible in PEG-ASP in comparison with L-ASP.
Topics: Asparaginase; Child; Cohort Studies; Humans; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 35142188
DOI: 10.7754/Clin.Lab.2021.210502 -
Clinical Lymphoma, Myeloma & Leukemia Nov 2022The adoption of pediatric-inspired regimens in young adults with newly diagnosed acute lymphoblastic leukemia (ALL) has significantly improved their survival outcomes.... (Review)
Review
The adoption of pediatric-inspired regimens in young adults with newly diagnosed acute lymphoblastic leukemia (ALL) has significantly improved their survival outcomes. Pediatric-inspired regimens in ALL rely profoundly on delivering adequate dosing of non-myelosuppressive drugs of which asparaginase, a bacterial derived agent, is a key component. Asparaginase therapy is associated with a spectrum of unique toxicities that are observed more frequently in adult patients compared to children with ALL, and this observation has contributed to the reluctance of adult oncologists to administer the drug to their patients. Understanding the breadth of asparaginase toxicity and the associated risk factors may help in preventing severe manifestations and allow safer treatment for adults with ALL. In this review, we will discuss the different formulations of asparaginase and the appropriate dosing in adults with ALL. We will further discuss the frequency and risk factors for individual toxicities of asparaginase along with strategies for their prevention and management.
Topics: Child; Young Adult; Humans; Asparaginase; Antineoplastic Agents; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk Factors
PubMed: 36114134
DOI: 10.1016/j.clml.2022.08.009 -
Current Microbiology Jul 2023L-asparaginase is a tetrameric enzyme from the amidohydrolases family, that catalyzes the breakdown of L-asparagine into L-aspartic acid and ammonia. Since its discovery... (Review)
Review
L-asparaginase is a tetrameric enzyme from the amidohydrolases family, that catalyzes the breakdown of L-asparagine into L-aspartic acid and ammonia. Since its discovery as an anticancer drug, it is used as one of the prime chemotherapeutic agents to treat acute lymphoblastic leukemia. Apart from its use in the biopharmaceutical industry, it is also used to reduce the formation of a carcinogenic substance called acrylamide in fried, baked, and roasted foods. L-asparaginase is derived from many organisms including plants, bacteria, fungi, and actinomycetes. Currently, L-asparaginase preparations from Escherichia coli and Erwinia chrysanthemi are used in the clinical treatment of acute lymphoblastic leukemia. However, they are associated with low yield and immunogenicity problems. At this juncture, endophytic fungi from medicinal plants have gained much attention as they have several advantages over the available bacterial preparations. Many medicinal plants have been screened for L-asparaginase producing endophytic fungi and several studies have reported potent L-asparaginase producing strains. This review provides insights into fungal endophytes from medicinal plants and their significance as probable alternatives for bacterial L-asparaginase.
Topics: Asparaginase; Antineoplastic Agents; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Bacteria; Fungi
PubMed: 37450223
DOI: 10.1007/s00284-023-03392-z -
International Journal of Biological... Feb 2021L-asparaginase is an enzyme capable of hydrolyzing the asparagine to aspartic acid and ammonia. L-asparaginase is widely used in the treatment of acute lymphoblastic...
L-asparaginase is an enzyme capable of hydrolyzing the asparagine to aspartic acid and ammonia. L-asparaginase is widely used in the treatment of acute lymphoblastic leukemia (ALL) and other cancers. Here, for the first time, the effects of a novel yeast L-asparaginase from Yarrowia lipolytica were studied on human lung (A549) and breast cancer (MCF7) cell lines as the solid cancer cell lines in terms of cell growth and metastasis inhibition. Functional analysis showed the L-asparagine deprivation mediated anti-proliferation effects by apoptosis induction and changes in the expression of target genes involved in apoptosis and migration pathways. The qRT-PCR analysis showed the higher expression levels of pro-apoptosis genes, including Bax, P53, caspase 3, caspase 8, and down-regulation of Bcl-2 anti-apoptotic gene in treated cells. On the other hand, there was no increase in ROS production in the treated cells. However, L-asparaginase treatment was able to significantly induce autophagy activation in A549 cells. Besides, wound healing assay showed that L-asparaginase could considerably inhibit the migration of A549 and MCF7 cells. Taken together, our results suggested that Yarrowia lipolytica L-asparaginase might be considered for enzyme therapy against breast and lung cancers.
Topics: A549 Cells; Apoptosis; Asparaginase; Autophagy; Breast; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Lung; Lung Neoplasms; MCF-7 Cells; Reactive Oxygen Species; Yarrowia
PubMed: 33358949
DOI: 10.1016/j.ijbiomac.2020.12.141 -
Journal of Thrombosis and Haemostasis :... Feb 2020Venous thromboembolism is a common complication of asparaginase-based chemotherapy regimens for the treatment of acute lymphoblastic leukemia. Thrombosis associated with... (Review)
Review
Venous thromboembolism is a common complication of asparaginase-based chemotherapy regimens for the treatment of acute lymphoblastic leukemia. Thrombosis associated with asparaginase administration poses a number of specific and often clinically challenging management decisions. This review provides guidance on the prevention and treatment of thrombosis associated with asparaginase in adults including discussions on antithrombin repletion, pharmacologic thromboprophylaxis, cerebral venous thrombosis, and therapeutic anticoagulation.
Topics: Adult; Anticoagulants; Antithrombins; Asparaginase; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Venous Thromboembolism
PubMed: 31999063
DOI: 10.1111/jth.14671 -
Cell Death & Disease May 2023Extranodal NK/T-cell lymphoma (NKTL) is a rare and aggressive form of extranodal lymphoma with a poor prognosis. Currently, there are very limited treatment options for...
Extranodal NK/T-cell lymphoma (NKTL) is a rare and aggressive form of extranodal lymphoma with a poor prognosis. Currently, there are very limited treatment options for patients with advanced-stage disease or those with relapsed/recurrent disease. Here we show that Chiauranib, an orally small molecule inhibitor of select serine-threonine kinases (aurora B, VEGFRs, PDGFR, CSF1R, c-Kit), inhibited NKTL cell proliferation, induced cell cycle arrest, as well as suppressed the microvessel density in vitro and in vivo similar as in other types of cancer cells. Surprisingly, Chiauranib unfolded a new effect to induce apoptosis of NKTL cells by triggering AIF-dependent apoptosis other than the traditional cyt-c/caspase mitochondrial apoptosis pathway. The knockdown of AIF in vitro and in vivo dramatically blocked the efficacy of Chiauranib on NKTL. Mechanistically, the release of AIF from mitochondria is due to the upregulation of VDAC1 by the AKT-GSK3β pathway and activation of calcium-dependent m-calpain, which promotes the cleavage of VDAC1 and therefore permits the release of AIF. Notably, the low expression of Bax in both NKTL cells and patient tissues restrained the cyt-c release. It resulted in the inhibition of cyt-c/caspase mitochondrial pathway, suggesting that drugs targeting this traditional pathway may not be effective in NKTL. Furthermore, we found that L-asparaginase triggered CD95 (Fas/Apo-1)-caspase 8-caspase 3 apoptotic pathway in NKTL cells, and combination of Chiauranib and L-asparaginase exhibited a synergistic effect, suggesting a feasibility to combine these two drugs for effective treatment of NKTL. This study demonstrates Chiauranib's positive efficacy toward NKTL through the activation of the AIF-dependent apoptosis pathway for the first time. The novel and multi-targets of Chiauranib and the synergistic effect with L-asparaginase may provide a promising therapy for NKTL patients.
Topics: Humans; Asparaginase; Naphthalenes; Quinolines; Lymphoma, T-Cell
PubMed: 37160920
DOI: 10.1038/s41419-023-05833-w -
Journal of Agricultural and Food... Nov 2022l-Asparaginase has gained much attention for effectively treating acute lymphoblastic leukemia (ALL) and mitigating carcinogenic acrylamide in fried foods. Due to...
l-Asparaginase has gained much attention for effectively treating acute lymphoblastic leukemia (ALL) and mitigating carcinogenic acrylamide in fried foods. Due to high-dose dependence for clinical treatment and low mitigation efficiency for thermal food processes caused by poor thermal stability, a method to achieve thermostable l-asparaginase has become a critical bottleneck. In this study, a rational design including free energy combined with structural and conservative analyses was applied to engineer the thermostability of l-asparaginase from (BlAsnase). Two enhanced thermostability mutants D172W and E207A were screened out by site-directed saturation mutagenesis. The double mutant D172W/E207A exhibited highly remarkable thermostability with a 65.8-fold longer half-life at 55 °C and 5 °C higher optimum reaction temperature and melting temperature () than those of wild-type BlAsnase. Further, secondary structure, sequence, molecular dynamics (MD), and 3D-structure analysis revealed that the excellent thermostability of the mutant D172W/E207A was on account of increased hydrophobicity and decreased flexibility, highly rigid structure, hydrophobic interactions, and favorable electrostatic potential. As the first report of rationally designing l-asparaginase with improved thermostability from , this study offers a facile and efficient process to improve the thermostability of l-asparaginase for industrial applications.
Topics: Asparaginase; Bacillus licheniformis; Enzyme Stability; Mutagenesis, Site-Directed; Temperature
PubMed: 36341695
DOI: 10.1021/acs.jafc.2c05712 -
Journal of Biomolecular Structure &... Jun 2022In the present study, a new bacterial strain, OHEM18 was significantly found to produce extracellular L-asparaginase. L-asparaginase was purified using ammonium sulfate...
In the present study, a new bacterial strain, OHEM18 was significantly found to produce extracellular L-asparaginase. L-asparaginase was purified using ammonium sulfate precipitation and QFF column to 3.84-fold with specific activity of 215.33 U/mg and its molecular mass was assessed to be 41.5 kDa. Maximum enzyme activity was determined at pH 8.2 and 40 °C and with retaining 70% of its activity after incubation for 1 h at 50 °C. Km and Vmax values were determined to be 0.0047 M and 92.74, respectively. Cytotoxicity test indicated a significant safety of L-asparaginase on Vero cells with selectivity against leukemia, breast cancer and hepatoma cells. NFS-60 cells was the most sensitive tumor cells to L-asparaginase with IC of 10.29 µg/ml and selectivity index of 30.61. This selectivity was recognized to be an apoptosis-dependent mechanism proven cell cycle arrest in sub-G1 phase and fragmentation of genomic DNA. L-asparaginase showed antioxidant activity against both DPPH and ABTS radicals with IC values of 64.07 and 177.1 mg/ml, respectively. These competitive advantage of bacterial L-asparaginase over than other sources is that it might be produced in large amounts through production in large-scale biofermenters, which decreases costs, besides having a sustainable bacterial source. Our findings established that the potent cytotoxic effect of L-asparaginase isolated from OHEM18 may be a promise candidate for further medicinal applications as an antioxidant and antitumor drug.Communicated by Ramaswamy H. Sarma.
Topics: Animals; Antineoplastic Agents; Antioxidants; Asparaginase; Bacillus; Chlorocebus aethiops; Enzyme Stability; Vero Cells
PubMed: 33228468
DOI: 10.1080/07391102.2020.1851300 -
Applied Biochemistry and Biotechnology Aug 2020In this presented work, magnetic poly(HEMA-GMA) nanoparticles were synthesized, characterized, and used for immobilization of an anti-leukemic enzyme L-asparaginase. The...
In this presented work, magnetic poly(HEMA-GMA) nanoparticles were synthesized, characterized, and used for immobilization of an anti-leukemic enzyme L-asparaginase. The average particle size of the synthesized magnetic nanoparticles was found to be as 117.5 nm. L-asparaginase was successfully immobilized onto the synthesized magnetic nanoparticles, and attached amount of L-asparaginase was found to be as 66.43 mg/g nanoparticle. The effects of the medium pH, temperature, and substrate concentration on the L-asparaginase activity were also tested. Optimum pH of the free and immobilized L-asparaginase was found to be as 7.5 and 6.5, respectively. Optimum temperature of the free L-asparaginase was 45 °C, while optimum temperature was shifted to 55 °C after immobilization onto the magnetic nanoparticles. Also, k value of free L-asparaginase (47,356 min) was calculated to be higher than that of immobilized L-asparaginase (497 min). Thermal stability of both asparaginase preparation was followed for 10 h, and at the end of the incubation time, free asparaginase almost lost its activity, while immobilized asparaginase protected 50% of its initial activity. Storage stabilities of free and immobilized asparaginase were also tested, and at the end of the 40 days storage, free asparaginase lost all of its activity, while immobilized asparaginase still showed 30% activity. Operational stability of immobilized asparaginase was tested for 8 successive usage, and immobilized asparaginase lost only 15% of its initial activity. In present study, activities of free and immobilized L-asparaginase were tested in artificial human serum medium, to foresee the in vivo efficiency, and it was demonstrated here that immobilized L-asparaginase protected its 74.74% of its initial activity in artificial serum medium.
Topics: Asparaginase; Catalysis; Enzyme Stability; Enzymes, Immobilized; Humans; Hydrogen-Ion Concentration; Hydrolysis; Kinetics; Magnetite Nanoparticles; Neoplasms; Particle Size; Temperature
PubMed: 32103470
DOI: 10.1007/s12010-020-03276-z -
Journal of Microbiological Methods Dec 2021L-asparaginase from endophytic Fusarium proliferatum (isolate CCH, GenBank accession no. MK685139) isolated from the medicinal plant Cymbopogon citratus (Lemon grass),...
L-asparaginase from endophytic Fusarium proliferatum (isolate CCH, GenBank accession no. MK685139) isolated from the medicinal plant Cymbopogon citratus (Lemon grass), was optimized for its L-asparaginase production and its subsequent cytotoxicity towards Jurkat E6 cell line. The following factors were optimized; carbon source and concentration, nitrogen source and concentration, incubation period, temperature, pH and agitation rate. Optimization of L-asparaginase production was performed using One-Factor-At-A-Time (OFAT) and Response surface methodology (RSM) model. The cytotoxicity of the crude enzyme from isolate CCH was tested on leukemic Jurkat E6 cell line. The optimization exercise revealed that glucose concentration, nitrogen source, L-asparagine concentration and temperature influenced the L-asparaginase production of CCH. The optimum condition suggested using OFAT and RSM results were consistent. As such, the recommended conditions were 0.20% of glucose, 0.99% of L-asparagine and 5.34 days incubation at 30.50 °C. The L-asparaginase production of CCH increased from 16.75 ± 0.76 IU/mL to 22.42 ± 0.20 IU/mL after optimization. The cytotoxicity of the crude enzyme on leukemic Jurkat cell line recorded IC value at 33.89 ± 2.63% v/v. To conclude, the enzyme extract produced from Fusarium proliferatum under optimized conditions is a potential alternative resource for L-asparaginase.
Topics: Antineoplastic Agents; Asparaginase; Carbon; Culture Media; Cytotoxins; Databases, Nucleic Acid; Endophytes; Fusarium; Hydrogen-Ion Concentration; Microbiological Techniques; Nitrogen; Plants, Medicinal; Temperature
PubMed: 34743930
DOI: 10.1016/j.mimet.2021.106358