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Toxicology and Applied Pharmacology Apr 2024Asparaginase-associated pancreatitis (AAP) is a severe and potentially life-threatening drug-induced pancreas targeted toxicity in the combined chemotherapy of acute...
Asparaginase-associated pancreatitis (AAP) is a severe and potentially life-threatening drug-induced pancreas targeted toxicity in the combined chemotherapy of acute lymphoblastic leukemia among children and adolescents. The toxicological mechanism of AAP is not yet clear, and there are no effective preventive and treatment measures available clinically. Fibroblast growth factor 21 (FGF21) is a secretory hormone that regulates lipid, glucose, and energy metabolism balance. Acinar tissue is the main source of pancreatic FGF21 protein and plays an important role in maintaining pancreatic metabolic balance. In this study, we found that the decrease of FGF21 in pancreas is closely related to AAP. Pegaspargase (1 IU/g) induces widespread edema and inflammatory infiltration in the pancreas of rats/mice. The specific expression of FGF21 in the acinar tissue of AAP rats was significantly downregulated. Asparaginase caused dysregulation of the ATF4/ATF3/FGF21 axis in acinar tissue or cells, and thus mediated the decrease of FGF21. It greatly activated ATF3 in the acinar, which competed with ATF4 for the Fgf21 promoter, thereby inhibiting the expression of FGF21. Pharmacological replacement of FGF21 (1 mg/kg) or PERK inhibitors (GSK2656157, 25 mg/kg) can significantly mitigate the pancreatic tissue damage and reduce markers of inflammation associated with AAP, representing potential strategies for the prevention and treatment of AAP.
Topics: Animals; Fibroblast Growth Factors; Asparaginase; Pancreatitis; Male; Rats; Pancreas; Mice; Rats, Sprague-Dawley; Polyethylene Glycols; Antineoplastic Agents; Activating Transcription Factor 4; Mice, Inbred C57BL; eIF-2 Kinase
PubMed: 38582373
DOI: 10.1016/j.taap.2024.116920 -
Folia Microbiologica Apr 2024L-asparaginase is an essential enzyme used in cancer treatment, but its production faces challenges like low yield, high cost, and immunogenicity. Recombinant production...
L-asparaginase is an essential enzyme used in cancer treatment, but its production faces challenges like low yield, high cost, and immunogenicity. Recombinant production is a promising method to overcome these limitations. In this study, response surface methodology (RSM) was used to optimize the production of L-asparaginase 1 from Saccharomyces cerevisiae in Escherichia coli K-12 BW25113. The Box-Behnken design (BBD) was utilized for the RSM modeling, and a total of 29 experiments were conducted. These experiments aimed to examine the impact of different factors, including the concentration of isopropyl-b-LD-thiogalactopyranoside (IPTG), the cell density prior to induction, the duration of induction, and the temperature, on the expression level of L-asparaginase 1. The results revealed that while the post-induction temperature, cell density at induction time, and post-induction time all had a significant influence on the response, the post-induction time exhibited the greatest effect. The optimized conditions (induction at cell density 0.8 with 0.7 mM IPTG for 4 h at 30 °C) resulted in a significant amount of L-asparaginase with a titer of 93.52 μg/mL, which was consistent with the model-based prediction. The study concluded that RSM optimization effectively increased the production of L-asparaginase 1 in E. coli, which could have the potential for large-scale fermentation. Further research can explore using other host cells, optimizing the fermentation process, and examining the effect of other variables to increase production.
PubMed: 38581537
DOI: 10.1007/s12223-024-01163-2 -
Indian Journal of Otolaryngology and... Apr 2024Extranodal natural killer T-cell lymphoma, nasal type (ENKTCL), is a rare form of non-Hodgkin lymphoma that is strongly related to Epstein-Barr Virus (EBV) infection and...
Extranodal natural killer T-cell lymphoma, nasal type (ENKTCL), is a rare form of non-Hodgkin lymphoma that is strongly related to Epstein-Barr Virus (EBV) infection and commonly presents as "midline lethal granuloma." Herein, we report a middle-aged lady who presented with a two-week history of fever, sore throat and constitutional symptoms. Intraoral examination revealed a lacerated soft palate with an ulcerated uvula. A diagnosis of ENKTCL was confirmed through deep biopsies under general anaesthesia supplemented with a positive serum EBV genome. Unfortunately, she succumbed due to disease progression with left frontal brain metastasis with concurrent pulmonary tuberculosis before treatment was completed. The recommended treatment is multimodality with L-asparaginase-containing regimes chemotherapy in an advanced stage, relapsed, or refractory ENKTCL for better outcomes. The quantification of circulating plasma EBV deoxyribonucleic acid (DNA) is helpful as the baseline of tumour load and a biomarker for monitoring treatment response and prognostication. We advocate repeated and deeper core tissue biopsies.
PubMed: 38566723
DOI: 10.1007/s12070-023-04466-x -
The Lancet. Haematology May 2024Programmed cell death protein 1 (PD-1) inhibitor sintilimab is effective in relapsed and refractory extranodal natural killer/T cell lymphoma (ENKTL), nasal type. We...
First-line sintilimab with pegaspargase, gemcitabine, and oxaliplatin in advanced extranodal natural killer/T cell lymphoma (SPIRIT): a multicentre, single-arm, phase 2 trial.
BACKGROUND
Programmed cell death protein 1 (PD-1) inhibitor sintilimab is effective in relapsed and refractory extranodal natural killer/T cell lymphoma (ENKTL), nasal type. We aimed to assess the safety and activity of sintilimab plus P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) in the first-line setting for advanced ENKTL.
METHODS
The multicentre, single-arm, phase 2 trial was done at three medical centres in China. Patients aged 18-75 years with treatment-naive pathologically confirmed advanced ENKTL and an with Eastern Cooperative Oncology Group performance status score of 0-2 were eligible. Patients received intravenous sintilimab (200 mg on day 1), intramuscular pegaspargase (2000 U/m on day 1), intravenous gemcitabine (1 g/m on days 1 and 8), and intravenous oxaliplatin (130 mg/m on day 1) every 3 weeks for six cycles, followed by intravenous sintilimab (200 mg) every 3 weeks for up to 2 years or until disease progression or unacceptable toxicities. The primary endpoint was the complete response rate in the intention-to-treat population. The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), disease-free survival (DFS), and overall survival. This trial is registered with ClinicalTrials.gov, NCT04127227. Enrolment has been completed, and follow-up is ongoing.
FINDINGS
Between Nov 29, 2019, and Sept 7, 2022, 34 eligible patients were enrolled (median age 39 years [IQR 32-55]; 25 [74%] of 34 patients were male; nine [26%] were female; and all were of Asian ethnicity). At the data cutoff (July 20, 2023), the median follow-up was 21 months (IQR 13-32). The complete response rate was 85% (29 of 34 patients, 95% CI 70-94). Five patients (15%; 95% CI 7-30) attained partial response and the ORR was 100% (34 of 34 patients). 24-month PFS was 64% (95% CI 48-86), 24-month DFS was 72% (54-95), and 36-month overall survival was 76% (52-100). The most common grade 3 or 4 treatment-related adverse events were neutropenia (17 [50%] of 34 patients), anaemia (10 [29%] patients), and hypertriglyceridemia (10 [29%] patients). Hypothyroidism was the most frequent immune-related adverse event (18 [53%]), including grade 3 hypothyroidism in one (3%) patient that caused treatment termination. No severe adverse events occurred. There were three deaths: one due to haemophagocytic syndrome, one due to disease progression, and one due to unknown cause, which were not considered to be treatment related.
INTERPRETATION
Combination of sintilimab with P-GEMOX seems to be an active and safe first-line regimen for patients with advanced ENKTL.
FUNDING
National Key Research and Development Program and National Natural Science Foundation of China, Guangzhou Science and Technology Program and the Clinical Oncology Foundation of Chinese Society of Clinical Oncology.
Topics: Humans; Middle Aged; Asparaginase; Male; Lymphoma, Extranodal NK-T-Cell; Female; Deoxycytidine; Gemcitabine; Polyethylene Glycols; Adult; Antineoplastic Combined Chemotherapy Protocols; Oxaliplatin; Aged; Antibodies, Monoclonal, Humanized; Young Adult; Adolescent
PubMed: 38554717
DOI: 10.1016/S2352-3026(24)00066-8 -
Thrombosis Journal Mar 2024Thromboembolic complications are well known in the treatment of childhood acute lymphoblastic leukemia. Over the years it has not been possible to reach a consensus on a...
BACKGROUND
Thromboembolic complications are well known in the treatment of childhood acute lymphoblastic leukemia. Over the years it has not been possible to reach a consensus on a possible prophylaxis of thromboembolic events during intensive therapy. Only the administration of enoxaparin was able to achieve evidence in the literature to date.
METHODS
In this retrospective study, 173 childhood leukemia patients were treated over 20 years with a thromboembolic prophylaxis including enoxaparin and AT III during induction therapy with L-asparaginase and cortisone.
RESULTS
We here report the effectiveness of administration of enoxaparin and AT III in childhood leukemia, showing a strikingly low prevalence of deep vein thrombosis (2.9%). Especially in adolescent patients, a particularly great need for AT III was demonstrated.
CONCLUSIONS
We recommend thromboembolic prophylaxis with enoxaparin and AT III substitution during induction/reinduction therapy with L-asparaginase and glucocorticosteroids, especially from adolescence onwards.
PubMed: 38539225
DOI: 10.1186/s12959-024-00602-x -
Pharmaceutical Research Apr 2024PEGasparaginase is known to be a critical drug for treating pediatric acute lymphoblastic leukemia (ALL), however, there is insufficient evidence to determine the...
BACKGROUND
PEGasparaginase is known to be a critical drug for treating pediatric acute lymphoblastic leukemia (ALL), however, there is insufficient evidence to determine the optimal dose for infants who are less than one year of age at diagnosis. This international study was conducted to identify the pharmacokinetics of PEGasparaginase in infants with newly diagnosed ALL and gather insight into the clearance and dosing of this population.
METHODS
Infants with ALL who received treatment with PEGasparaginase were included in our population pharmacokinetic assessment employing non-linear mixed effects modelling (NONMEM).
RESULTS
68 infants with ALL, with a total of 388 asparaginase activity samples, were included. PEGasparaginase doses ranging from 400 to 3,663 IU/m were administered either intravenously or intramuscularly. A one-compartment model with time-dependent clearance, modeled using a transit model, provided the best fit to the data. Body weight was significantly correlated with clearance and volume of distribution. The final model estimated a half-life of 11.7 days just after administration, which decreased to 1.8 days 14 days after administration. Clearance was 19.5% lower during the post-induction treatment phase compared to induction.
CONCLUSION
The pharmacokinetics of PEGasparaginase in infants diagnosed under one year of age with ALL is comparable to that of older children (1-18 years). We recommend a PEGasparaginase dosing at 1,500 IU/m for infants without dose adaptations according to age, and implementing therapeutic drug monitoring as standard practice.
Topics: Child; Infant; Humans; Adolescent; Child, Preschool; Asparaginase; Antineoplastic Agents; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Drug Monitoring
PubMed: 38538970
DOI: 10.1007/s11095-024-03693-3 -
Diagnostics (Basel, Switzerland) Mar 2024Among malignant diseases which develop during childhood, hematological cancers, such as leukemias and lymphomas, are the most common. Outcomes have greatly improved due...
BACKGROUND
Among malignant diseases which develop during childhood, hematological cancers, such as leukemias and lymphomas, are the most common. Outcomes have greatly improved due to the refinement of multiagent chemotherapy regimens that include enhanced asparaginase therapy. In this study, we aimed to evaluate our experiences related to the analytical and clinical significance of determining l-Asparaginase activity.
METHODS
Since 2016, the Laboratory of the Children's Hospital Zagreb has routinely measured l-Asparaginase activity and to date, has measured more than 280 examples of activity in a total of 57 children with hematological malignancy treated at the Pediatric Oncology Department of the Children's Hospital Zagreb. Three asparaginase products were available: native l-Asparaginase; a pegylated form of this enzyme; and a native product from Erwinia chrysanthemi. A retrospective data analysis was performed.
RESULTS
Out of the fifty-seven children, seven had an allergic reaction (12.3%), five (8.8%) had silent inactivation, and seven (12.3%) developed acute pancreatitis. Allergic reactions and silent inactivation were more common in children treated with native l-Asparaginase, while pancreatitis was more common in children treated with the pegylated form.
CONCLUSIONS
The monitoring of l-Asparaginase activity may help to optimize therapy by identifying patients with 'silent inactivation', and/or by dose correction when l-Asparaginase activity is too high (slow elimination).
PubMed: 38535043
DOI: 10.3390/diagnostics14060623 -
Hematology (Amsterdam, Netherlands) Dec 2024This retrospective report presents the outcomes and adverse events (AEs) observed in 73 patients aged 60 years or older diagnosed with Philadelphia Chromosome-negative...
This retrospective report presents the outcomes and adverse events (AEs) observed in 73 patients aged 60 years or older diagnosed with Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia (Ph-negative ALL) treated with a pediatric-inspired protocol incorporating either Pegylated (PEG-ASP) or Native Asparaginase (EC-ASP). Notably, 61% of patients experienced AEs of Grade III-IV severity. The most prevalent AEs included thrombosis (35.6%), febrile neutropenia (38.4%), and transaminitis (34.2%). AEs did not translate into significant differences concerning overall survival, leukemia-free survival, or early mortality. Furthermore, we observed a reduction in early mortality rates (11% vs. 20%) and an increase in median overall survival (54 vs. 48 months) compared to our previous data. These findings suggest that the utilization of a pediatric-inspired chemotherapy protocol, with ASP, is an effective and well-tolerated therapeutic option for older patients with Ph-negative ALL. However, it emphasizes the importance of diligent monitoring and close follow-up throughout treatment.
Topics: Humans; Aged; Asparaginase; Retrospective Studies; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Combined Chemotherapy Protocols; Polyethylene Glycols
PubMed: 38526239
DOI: 10.1080/16078454.2024.2329027 -
Frontiers in Pharmacology 2024With the rapid advancement of genetic and protein engineering, proteins and peptides have emerged as promising drug molecules for therapeutic applications. Consequently,... (Review)
Review
With the rapid advancement of genetic and protein engineering, proteins and peptides have emerged as promising drug molecules for therapeutic applications. Consequently, there has been a growing interest in the field of chemical modification technology to address challenges associated with their clinical use, including rapid clearance from circulation, immunogenicity, physical and chemical instabilities (such as aggregation, adsorption, deamination, clipping, oxidation, etc.), and enzymatic degradation. Polyethylene glycol (PEG) modification offers an effective solution to these issues due to its favorable properties. This review presents recent progress in the development and application of PEGylated therapeutic proteins and peptides (TPPs). For this purpose, firstly, the physical and chemical properties as well as classification of PEG and its derivatives are described. Subsequently, a detailed summary is provided on the main sites of PEGylated TPPs and the factors that influence their PEGylation. Furthermore, notable instances of PEG-modified TPPs (including antimicrobial peptides (AMPs), interferon, asparaginase and antibodies) are highlighted. Finally, we propose the chemical modification of TPPs with PEG, followed by an analysis of the current development status and future prospects of PEGylated TPPs. This work provides a comprehensive literature review in this promising field while facilitating researchers in utilizing PEG polymers to modify TPPs for disease treatment.
PubMed: 38523641
DOI: 10.3389/fphar.2024.1353626 -
International Microbiology : the... Mar 2024The L-asparaginase (ASPN) enzyme has received recognition in various applications including acrylamide degradation in the food industry. The synthesis and application of...
The L-asparaginase (ASPN) enzyme has received recognition in various applications including acrylamide degradation in the food industry. The synthesis and application of thermostable ASPN enzymes is required for its use in the food sector, where thermostable enzymes can withstand high temperatures. To achieve this goal, the bacterium Bacillus subtilis was isolated from the hot springs of Tapovan for screening the production of thermostable ASPN enzyme. Thus, ASPN with a maximal specific enzymatic activity of 0.896 U/mg and a molecular weight of 66 kDa was produced from the isolated bacteria. The kinetic study of the enzyme yielded a Km value of 1.579 mM and a Vmax of 5.009 µM/min with thermostability up to 100 min at 75 °C. This may have had a positive indication for employing the enzyme to stop polyacrylamide from being produced. The current study has also been extended to investigate the interaction of native and mutated ASPN enzymes with acrylamide. This concluded that the M (with 10 mutations) has the highest protein and thermal stability compared to the wild-type ASPN protein sequence. Therefore, in comparison to a normal ASPN and all other mutant ASPNs, M is the most favorable mutation. This research has also demonstrated the usage of ASPN in food industrial applications.
PubMed: 38519776
DOI: 10.1007/s10123-024-00493-y