{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T08:18:26Z","timestamp":1794039506925,"version":"4.8.0"},"reference-count":189,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T00:00:00Z","timestamp":1644537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>L-Asparaginase (L-ASNase) is an enzyme that hydrolyses the amino acid asparagine into aspartic acid and ammonia. Systemic administration of bacterial L-ASNase is successfully used to lower the bioavailability of this non-essential amino acid and to eradicate rapidly proliferating cancer cells with a high demand for exogenous asparagine. Currently, it is a cornerstone drug in the treatment of the most common pediatric cancer, acute lymphoblastic leukemia (ALL). Since these lymphoblasts lack the expression of asparagine synthetase (ASNS), these cells depend on the uptake of extracellular asparagine for survival. Interestingly, recent reports have illustrated that L-ASNase may also have clinical potential for the treatment of other aggressive subtypes of hematological or solid cancers. However, immunogenic and other severe adverse side effects limit optimal clinical use and often lead to treatment discontinuation. The design of optimized and novel L-ASNase formulations provides opportunities to overcome these limitations. In addition, identification of multiple L-ASNase resistance mechanisms, including ASNS promoter reactivation and desensitization, has fueled research into promising novel drug combinations to overcome chemoresistance. In this review, we discuss recent insights into L-ASNase adverse effects, resistance both in hematological and solid tumors, and how novel L-ASNase variants and drug combinations can expand its clinical applicability.<\/jats:p>","DOI":"10.3390\/cancers14040902","type":"journal-article","created":{"date-parts":[[2022,2,13]],"date-time":"2022-02-13T20:32:30Z","timestamp":1644784350000},"page":"902","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":132,"title":["Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7033-9569","authenticated-orcid":false,"given":"Maaike","family":"Van Trimpont","sequence":"first","affiliation":[{"name":"Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium"},{"name":"Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium"},{"name":"Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9438-1876","authenticated-orcid":false,"given":"Evelien","family":"Peeters","sequence":"additional","affiliation":[{"name":"Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium"},{"name":"Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium"},{"name":"Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanti","family":"De Visser","sequence":"additional","affiliation":[{"name":"Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium"},{"name":"Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium"},{"name":"Department of Imaging and Pathology, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda M.","family":"Schalk","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, IL 60607, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veerle","family":"Mondelaers","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hemato-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2449-539X","authenticated-orcid":false,"given":"Barbara","family":"De Moerloose","sequence":"additional","affiliation":[{"name":"Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium"},{"name":"Department of Pediatric Hemato-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium"},{"name":"Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnon","family":"Lavie","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, IL 60607, USA"},{"name":"The Jesse Brown VA Medical Center, Chicago, IL 60607, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8733-4027","authenticated-orcid":false,"given":"Tim","family":"Lammens","sequence":"additional","affiliation":[{"name":"Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium"},{"name":"Department of Pediatric Hemato-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium"},{"name":"Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5693-8570","authenticated-orcid":false,"given":"Steven","family":"Goossens","sequence":"additional","affiliation":[{"name":"Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium"},{"name":"Department of Diagnostic Sciences, Ghent University, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9063-7205","authenticated-orcid":false,"given":"Pieter","family":"Van Vlierberghe","sequence":"additional","affiliation":[{"name":"Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium"},{"name":"Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Choi, B.H., and Coloff, J.L. (2019). The Diverse Functions of Non-Essential Amino Acids in Cancer. Cancers, 11.","DOI":"10.3390\/cancers11050675"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1007\/s00726-021-03052-1","article-title":"Amino acid metabolism as a therapeutic target in cancer: A review","volume":"53","author":"Endicott","year":"2021","journal-title":"Amino Acids"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Jiang, J., Batra, S., and Zhang, J. (2021). Asparagine: A Metabolite to Be Targeted in Cancers. Metabolites, 11.","DOI":"10.3390\/metabo11060402"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"19952","DOI":"10.1074\/jbc.R117.819060","article-title":"Asparagine synthetase: Function, structure, and role in disease","volume":"292","author":"Lomelino","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_5","first-page":"321","article-title":"Uber desamidierung im Tierkorper","volume":"5","author":"Lang","year":"1904","journal-title":"Beitr. Chem. Physiol. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1084\/jem.118.1.99","article-title":"Evidence that the L-asparaginase of guinea pig serum is responsible for its antilymphoma effects. I. Properties of the L-asparaginase of guinea pig serum in relation to those of the antilymphoma substance","volume":"118","author":"Broome","year":"1963","journal-title":"J. Exp. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1084\/jem.98.6.565","article-title":"Regression of transplanted lymphomas induced in vivo by means of normal guinea pig serum. I. Course of transplanted cancers of various kinds in mice and rats given guinea pig serum, horse serum, or rabbit serum","volume":"98","author":"Kidd","year":"1953","journal-title":"J. Exp. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1002\/1097-0142(196612)19:12<1813::AID-CNCR2820191208>3.0.CO;2-E","article-title":"Toxic and antineoplastic effects of L-asparaginase. Study of mice with lymphoma and normal monkeys and report on a child with leukemia","volume":"19","author":"Dolowy","year":"1966","journal-title":"Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1007\/s12010-015-1917-3","article-title":"A Comprehensive Review on L-Asparaginase and Its Applications","volume":"178","author":"Batool","year":"2016","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.bjm.2016.10.004","article-title":"Current applications and different approaches for microbial l-asparaginase production","volume":"47","author":"Cachumba","year":"2016","journal-title":"Braz. J. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"256","DOI":"10.3109\/10428194.2013.803224","article-title":"L-asparaginase: An effective agent in the treatment of acute lymphoblastic leukemia","volume":"55","author":"Kumar","year":"2014","journal-title":"Leuk. Lymphoma"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1146\/annurev.biochem.75.103004.142520","article-title":"Asparagine synthetase chemotherapy","volume":"75","author":"Richards","year":"2006","journal-title":"Annu. Rev. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/0003-9861(68)90273-7","article-title":"Asparagine synthetase in normal and malignant tissues: Correlation with tumor sensitivity to asparaginase","volume":"127","author":"Prager","year":"1968","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2578","DOI":"10.1016\/0006-2952(69)90375-X","article-title":"l-asparaginase resistance in human leukemia--asparagine synthetase","volume":"18","author":"Haskell","year":"1969","journal-title":"Biochem. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.3389\/fonc.2019.01480","article-title":"Asparagine Synthetase in Cancer: Beyond Acute Lymphoblastic Leukemia","volume":"9","author":"Chiu","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1007\/s00280-014-2402-3","article-title":"Asparaginase in the treatment of non-ALL hematologic malignancies","volume":"73","author":"Emadi","year":"2014","journal-title":"Cancer Chemother. Pharm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1097\/MPA.0b013e318247d903","article-title":"Pancreatic tumor sensitivity to plasma L-asparagine starvation","volume":"41","author":"Dufour","year":"2012","journal-title":"Pancreas"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2613","DOI":"10.1158\/1535-7163.MCT-06-0447","article-title":"Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells","volume":"5","author":"Lorenzi","year":"2006","journal-title":"Mol. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1111\/j.1582-4934.2012.01547.x","article-title":"L-asparaginase inhibits invasive and angiogenic activity and induces autophagy in ovarian cancer","volume":"16","author":"Yu","year":"2012","journal-title":"J. Cell Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/nature25465","article-title":"Asparagine bioavailability governs metastasis in a model of breast cancer","volume":"554","author":"Knott","year":"2018","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"748","DOI":"10.3109\/10428194.2015.1101098","article-title":"Asparaginase-associated toxicity in children with acute lymphoblastic leukemia","volume":"57","author":"Hijiya","year":"2016","journal-title":"Leuk. Lymphoma"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E248","DOI":"10.1188\/17.CJON.E248-E259","article-title":"Asparaginase Toxicities: Identification and Management in Patients with Acute Lymphoblastic Leukemia","volume":"21","author":"Bergeron","year":"2017","journal-title":"Clin. J. Oncol. Nurs."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1002\/cncr.25489","article-title":"L-asparaginase treatment in acute lymphoblastic leukemia: A focus on Erwinia asparaginase","volume":"117","author":"Pieters","year":"2011","journal-title":"Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e29169","DOI":"10.1002\/pbc.29169","article-title":"Can recombinant technology address asparaginase Erwinia chrysanthemi shortages?","volume":"68","author":"Maese","year":"2021","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"S14","DOI":"10.1016\/j.clml.2014.06.017","article-title":"Asparaginase in acute lymphoblastic leukemia","volume":"14","author":"Kawedia","year":"2014","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1007\/s40265-019-01120-1","article-title":"Pegaspargase: A Review in Acute Lymphoblastic Leukaemia","volume":"79","author":"Heo","year":"2019","journal-title":"Drugs"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1158\/1078-0432.CCR-19-2975","article-title":"Space for Calaspargase? A New Asparaginase for Acute Lymphoblastic Leukemia","volume":"26","author":"Lew","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3874","DOI":"10.1200\/JCO.2014.55.5763","article-title":"Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: Results from Children\u2019s Oncology Group Study AALL07P4","volume":"32","author":"Angiolillo","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0378-5173(02)00046-7","article-title":"Effects of polyethylene glycol attachment on physicochemical and biological stability of E. coli L-asparaginase","volume":"237","author":"Soares","year":"2002","journal-title":"Int. J. Pharm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.htct.2019.07.010","article-title":"Asparaginase: An old drug with new questions","volume":"42","author":"Cecconello","year":"2020","journal-title":"Hematol. Transfus. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"212","DOI":"10.3389\/fbioe.2018.00212","article-title":"Development of L-Asparaginase Biobetters: Current Research Status and Review of the Desirable Quality Profiles","volume":"6","author":"Brumano","year":"2019","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"25","DOI":"10.2147\/BLCTT.S245210","article-title":"Clinical Utility of Pegaspargase in Children, Adolescents and Young Adult Patients with Acute Lymphoblastic Leukemia: A Review","volume":"11","author":"Bender","year":"2021","journal-title":"Blood Lymphat. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S1040-8428(98)00015-8","article-title":"Use of l-asparaginase in childhood ALL","volume":"28","author":"Boos","year":"1998","journal-title":"Crit. Rev. Oncol.\/Hematol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/bjh.16495","article-title":"Prospective, real-time monitoring of pegylated Escherichia coli and Erwinia asparaginase therapy in childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma in Belgium","volume":"190","author":"Mondelaers","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1007\/s00280-014-2464-2","article-title":"Successful challenges using native E. coli asparaginase after hypersensitivity reactions to PEGylated E. coli asparaginase","volume":"73","author":"Fernandez","year":"2014","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2144","DOI":"10.1007\/s12010-012-9755-z","article-title":"L-Asparaginase as potent anti-leukemic agent and its significance of having reduced glutaminase side activity for better treatment of acute lymphoblastic leukaemia","volume":"167","author":"Ramya","year":"2012","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s00280-017-3492-5","article-title":"Pharmacokinetics of recombinant asparaginase in children with acute lymphoblastic leukemia","volume":"81","author":"Pichlmeier","year":"2018","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3596","DOI":"10.1182\/blood-2013-10-535112","article-title":"The glutaminase activity of L-asparaginase is not required for anticancer activity against ASNS-negative cells","volume":"123","author":"Chan","year":"2014","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.leukres.2015.04.008","article-title":"Glutaminase activity determines cytotoxicity of L-asparaginases on most leukemia cell lines","volume":"39","author":"Parmentier","year":"2015","journal-title":"Leuk. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1158\/0008-5472.CAN-17-2106","article-title":"A Novel l-Asparaginase with low l-Glutaminase Coactivity Is Highly Efficacious against Both T- and B-cell Acute Lymphoblastic Leukemias In Vivo","volume":"78","author":"Nguyen","year":"2018","journal-title":"Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1158\/1535-7163.MCT-18-1329","article-title":"Glutaminase Activity of L-Asparaginase Contributes to Durable Preclinical Activity against Acute Lymphoblastic Leukemia","volume":"18","author":"Chan","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"279","DOI":"10.3324\/haematol.2015.137380","article-title":"Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation","volume":"101","author":"Vrooman","year":"2016","journal-title":"Haematologica"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1177\/1043454212471728","article-title":"Managing hypersensitivity to asparaginase in pediatrics, adolescents, and young adults","volume":"30","author":"Shinnick","year":"2013","journal-title":"J. Pediatr. Oncol. Nurs."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Pui, C.H., Liu, Y., and Relling, M.V. (2018). How to solve the problem of hypersensitivity to asparaginase?. Pediatr. Blood Cancer, 65.","DOI":"10.1002\/pbc.26884"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/bjh.15660","article-title":"Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008","volume":"184","author":"Wolthers","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1002\/pbc.25319","article-title":"PEG-asparaginase allergy in children with acute lymphoblastic leukemia in the NOPHO ALL2008 protocol","volume":"62","author":"Henriksen","year":"2015","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1080\/10428194.2018.1542146","article-title":"Plasma asparaginase activity and asparagine depletion in acute lymphoblastic leukemia patients treated with pegaspargase on Children\u2019s Oncology Group AALL07P4","volume":"60","author":"Schore","year":"2019","journal-title":"Leuk. Lymphoma"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1080\/10428194.2017.1386305","article-title":"Asparaginase activity levels and monitoring in patients with acute lymphoblastic leukemia","volume":"59","author":"Salzer","year":"2018","journal-title":"Leuk. Lymphoma"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2026","DOI":"10.1182\/blood-2013-10-534347","article-title":"A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia","volume":"123","author":"Tong","year":"2014","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1002\/pbc.25869","article-title":"Outcomes Following Discontinuation of E. coli l-Asparaginase Upon Severe Allergic Reactions in Children With Acute Lymphoblastic Leukemia","volume":"63","author":"Yen","year":"2016","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"367","DOI":"10.2165\/00003088-200544040-00003","article-title":"Pharmacokinetic\/pharmacodynamic relationships of asparaginase formulations: The past, the present and recommendations for the future","volume":"44","author":"Avramis","year":"2005","journal-title":"Clin. Pharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/cncr.22739","article-title":"Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients","volume":"110","author":"Armstrong","year":"2007","journal-title":"Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1111\/bjh.16254","article-title":"Acute lymphoblastic leukaemia patients treated with PEGasparaginase develop antibodies to PEG and the succinate linker","volume":"189","author":"Kloos","year":"2020","journal-title":"Br. J. Haematol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1021\/bc500215m","article-title":"Multivalent antiviral XTEN-peptide conjugates with long in vivo half-life and enhanced solubility","volume":"25","author":"Ding","year":"2014","journal-title":"Bioconjug. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1093\/protein\/gzt023","article-title":"PASylation: A biological alternative to PEGylation for extending the plasma half-life of pharmaceutically active proteins","volume":"26","author":"Schlapschy","year":"2013","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2882","DOI":"10.1016\/j.bmc.2017.09.016","article-title":"Prospects of PASylation\u00ae for the design of protein and peptide therapeutics with extended half-life and enhanced action","volume":"26","author":"Gebauer","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2669","DOI":"10.1182\/blood.V122.21.2669.2669","article-title":"Nanoparticle Encapsulated L-Asparaginase","volume":"122","author":"Ortac","year":"2013","journal-title":"Blood"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1007\/s10856-008-3684-y","article-title":"Hydrogel-magnetic nanoparticles with immobilized l-asparaginase for biomedical applications","volume":"20","author":"Teodor","year":"2009","journal-title":"J. Mater. Sci. Mater. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1038\/sj.leu.2401162","article-title":"Anti-asparaginase antibodies following E. coli asparaginase therapy in pediatric acute lymphoblastic leukemia","volume":"12","author":"Woo","year":"1998","journal-title":"Leukemia"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1080\/10428190701292049","article-title":"The anti-asparagines antibodies correlate with L-asparagines activity and may affect clinical outcome of childhood acute lymphoblastic leukemia","volume":"48","author":"Andrzejewski","year":"2007","journal-title":"Leuk. Lymphoma"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/pbc.25757","article-title":"Activity and Toxicity of Intravenous Erwinia Asparaginase Following Allergy to E. coli-Derived Asparaginase in Children and Adolescents With Acute Lymphoblastic Leukemia","volume":"63","author":"Vrooman","year":"2016","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1182\/blood-2013-01-480822","article-title":"Erwinia asparaginase achieves therapeutic activity after pegaspargase allergy: A report from the Children\u2019s Oncology Group","volume":"122","author":"Salzer","year":"2013","journal-title":"Blood"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1200\/JCO.19.03024","article-title":"Impact of Asparaginase Discontinuation on Outcome in Childhood Acute Lymphoblastic Leukemia: A Report From the Children\u2019s Oncology Group","volume":"38","author":"Gupta","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1097\/00043426-200404000-00002","article-title":"Asparaginase antibody and asparaginase activity in children with higher-risk acute lymphoblastic leukemia: Children\u2019s Cancer Group Study CCG-1961","volume":"26","author":"Panosyan","year":"2004","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1182\/blood.V97.5.1211","article-title":"Improved outcome for children with acute lymphoblastic leukemia: Results of Dana-Farber Consortium Protocol 91-01","volume":"97","author":"Silverman","year":"2001","journal-title":"Blood"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1038\/leu.2012.102","article-title":"Clinical utility and implications of asparaginase antibodies in acute lymphoblastic leukemia","volume":"26","author":"Liu","year":"2012","journal-title":"Leukemia"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2373","DOI":"10.1182\/blood.2020006583","article-title":"Relapse risk following truncation of pegylated asparaginase in childhood acute lymphoblastic leukemia","volume":"137","author":"Grell","year":"2021","journal-title":"Blood"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1111\/cts.12947","article-title":"A Randomized Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Recombinant Erwinia Asparaginase (JZP-458) in Healthy Adult Volunteers","volume":"14","author":"Lin","year":"2021","journal-title":"Clin. Transl. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1002\/cpdd.1002","article-title":"Population Pharmacokinetic Model Development and Simulation for Recombinant Erwinia Asparaginase Produced in Pseudomonas fluorescens (JZP-458)","volume":"10","author":"Lin","year":"2021","journal-title":"Clin. Pharm. Drug Dev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1111\/ejh.12600","article-title":"Toxicity profile of repeated doses of PEG-asparaginase incorporated into a pediatric-type regimen for adult acute lymphoblastic leukemia","volume":"96","author":"Aldoss","year":"2016","journal-title":"Eur. J. Haematol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.3324\/haematol.2014.109413","article-title":"The toxicity of very prolonged courses of PEGasparaginase or Erwinia asparaginase in relation to asparaginase activity, with a special focus on dyslipidemia","volume":"99","author":"Tong","year":"2014","journal-title":"Haematologica"},{"key":"ref_72","first-page":"107","article-title":"Changes of amino acid serum levels in pediatric patients with higher-risk acute lymphoblastic leukemia (CCG-1961)","volume":"18","author":"Grigoryan","year":"2004","journal-title":"In Vivo"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1182\/blood.V99.6.1986","article-title":"A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: A Children\u2019s Cancer Group study","volume":"99","author":"Avramis","year":"2002","journal-title":"Blood"},{"key":"ref_74","first-page":"103","article-title":"High incidence of symptomatic hyperammonemia in children with acute lymphoblastic leukemia receiving pegylated asparaginase","volume":"7","author":"Prinsen","year":"2013","journal-title":"JIMD Rep."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1111\/j.1365-2362.1988.tb01049.x","article-title":"Asparaginase-induced derangements of glutamine metabolism: The pathogenetic basis for some drug-related side-effects","volume":"18","author":"Roth","year":"1988","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/0378-4274(86)90113-X","article-title":"L-asparaginase effects on inhibition of protein synthesis and lowering of the glutamine content in cultured rat hepatocytes","volume":"32","author":"Villa","year":"1986","journal-title":"Toxicol. Lett."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1373\/49.10.1710","article-title":"Measurement of plasma ammonia is affected in patients receiving asparaginase therapy","volume":"49","author":"Laterza","year":"2003","journal-title":"Clin. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3","DOI":"10.3109\/08880018.2010.484852","article-title":"Transient hyperammonemia due to L-asparaginase therapy in children with acute lymphoblastic leukemia or non-Hodgkin lymphoma","volume":"28","author":"Kiess","year":"2011","journal-title":"Pediatr. Hematol. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1177\/1078155214551590","article-title":"Hyperammonemia secondary to asparaginase: A case series","volume":"22","author":"Nussbaum","year":"2016","journal-title":"J. Oncol. Pharm. Pract."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/0005-2787(71)90712-X","article-title":"Asparaginyl-transfer RNA: A substrate for L-asparaginase","volume":"240","author":"Kessel","year":"1971","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Nucleic Acids Protein Synth."},{"key":"ref_81","first-page":"2400","article-title":"Effects of L-asparaginase on lymphocyte surface and blastogenesis","volume":"32","author":"Fidler","year":"1972","journal-title":"Cancer Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1007\/BF02619582","article-title":"Effect of asparaginase on cell membranes of sensitive and resistants mouse lymphoma cells","volume":"20","author":"Ankel","year":"1984","journal-title":"In Vitro"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.bbrc.2017.08.078","article-title":"Rhodospirillum rubrum L-asparaginase targets tumor growth by a dual mechanism involving telomerase inhibition","volume":"492","author":"Zhdanov","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Plyasova, A.A., Pokrovskaya, M.V., Lisitsyna, O.M., Pokrovsky, V.S., Alexandrova, S.S., Hilal, A., Sokolov, N.N., and Zhdanov, D.D. (2020). Penetration into cancer cells via clathrin-dependent mechanism allows l-asparaginase from rhodospirillum rubrum to inhibit telomerase. Pharmaceuticals, 13.","DOI":"10.3390\/ph13100286"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"E789","DOI":"10.1152\/ajpendo.00015.2013","article-title":"Asparagine synthetase: Regulation by cell stress and involvement in tumor biology","volume":"304","author":"Balasubramanian","year":"2013","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"295","DOI":"10.3945\/an.112.001891","article-title":"The transcription factor network associated with the amino acid response in mammalian cells","volume":"3","author":"Kilberg","year":"2012","journal-title":"Adv. Nutr."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s12276-020-0375-3","article-title":"Amino acids in cancer","volume":"52","author":"Lieu","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"603837","DOI":"10.3389\/fcell.2020.603837","article-title":"Metabolism of Amino Acids in Cancer","volume":"8","author":"Wei","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"4497","DOI":"10.1128\/MCB.15.8.4497","article-title":"The histidyl-tRNA synthetase-related sequence in the eIF-2 alpha protein kinase GCN2 interacts with tRNA and is required for activation in response to starvation for different amino acids","volume":"15","author":"Wek","year":"1995","journal-title":"Mol. Cell Biol."},{"key":"ref_90","first-page":"2820","article-title":"Identification of positive-acting domains in GCN2 protein kinase required for translational activation of GCN4 expression","volume":"10","author":"Wek","year":"1990","journal-title":"Mol. Cell Biol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"36393","DOI":"10.1074\/jbc.M112.399600","article-title":"ATF4-dependent regulation of the JMJD3 gene during amino acid deprivation can be rescued in Atf4-deficient cells by inhibition of deacetylation","volume":"287","author":"Shan","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"24120","DOI":"10.1074\/jbc.M201959200","article-title":"ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene","volume":"277","author":"Siu","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1002\/hep.22971","article-title":"Protein or amino acid deprivation differentially regulates the hepatic forkhead box protein A (FOXA) genes through an activating transcription factor-4-independent pathway","volume":"50","author":"Su","year":"2009","journal-title":"Hepatology"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.tem.2009.05.008","article-title":"ATF4-dependent transcription mediates signaling of amino acid limitation","volume":"20","author":"Kilberg","year":"2009","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"307","DOI":"10.3945\/an.112.002113","article-title":"Eukaryotic initiation factor 2 phosphorylation and translational control in metabolism","volume":"3","author":"Baird","year":"2012","journal-title":"Adv. Nutr."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/S1097-2765(00)00108-8","article-title":"Regulated translation initiation controls stress-induced gene expression in mammalian cells","volume":"6","author":"Harding","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"26976","DOI":"10.1016\/S0021-9258(19)61468-7","article-title":"Activation of the human asparagine synthetase gene by the amino acid response and the endoplasmic reticulum stress response pathways occurs by common genomic elements","volume":"275","author":"Chen","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3953","DOI":"10.1038\/sj.onc.1207498","article-title":"Methylation of the asparagine synthetase promoter in human leukemic cell lines is associated with a specific methyl binding protein","volume":"23","author":"Ren","year":"2004","journal-title":"Oncogene"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"18674","DOI":"10.1074\/jbc.RA119.010447","article-title":"Promoter demethylation of the asparagine synthetase gene is required for ATF4-dependent adaptation to asparagine depletion","volume":"294","author":"Jiang","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2483","DOI":"10.1158\/1078-0432.CCR-18-1844","article-title":"Epigenetic Silencing Affects l-Asparaginase Sensitivity and Predicts Outcome in T-ALL","volume":"25","author":"Touzart","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1126\/science.160.3827.533","article-title":"Asparagine synthetase activity of mouse leukemias","volume":"160","author":"Horowitz","year":"1968","journal-title":"Science"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1002\/pbc.21213","article-title":"Correlation between asparaginase sensitivity and asparagine synthetase protein content, but not mRNA, in acute lymphoblastic leukemia cell lines","volume":"50","author":"Su","year":"2008","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1038\/sj.leu.2404216","article-title":"Methylation analysis of asparagine synthetase gene in acute lymphoblastic leukemia cells","volume":"20","author":"Akagi","year":"2006","journal-title":"Leukemia"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1182\/blood.2019004090","article-title":"Association of aberrant ASNS imprinting with asparaginase sensitivity and chromosomal abnormality in childhood BCP-ALL","volume":"136","author":"Watanabe","year":"2020","journal-title":"Blood"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1054\/bjoc.2001.2000","article-title":"Hypermethylation of CpG islands in the mouse asparagine synthetase gene: Relationship to asparaginase sensitivity in lymphoma cells. Partial methylation in normal cells","volume":"85","author":"Peng","year":"2001","journal-title":"Br. J. Cancer"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"3521","DOI":"10.1182\/blood-2013-03-493163","article-title":"Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia","volume":"122","author":"Willems","year":"2013","journal-title":"Blood"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1002\/pbc.24470","article-title":"Sequential administration of methotrexate and asparaginase in relapsed or refractory pediatric acute myeloid leukemia","volume":"60","author":"Buaboonnam","year":"2013","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s00280-017-3459-6","article-title":"Asparaginase Erwinia chrysanthemi effectively depletes plasma glutamine in adult patients with relapsed\/refractory acute myeloid leukemia","volume":"81","author":"Emadi","year":"2018","journal-title":"Cancer Chemother. Pharm."},{"key":"ref_109","first-page":"2070","article-title":"Antiproliferative effects of L-asparaginase in acute myeloid leukemia","volume":"20","author":"Chen","year":"2020","journal-title":"Exp. Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1007\/s11306-014-0634-1","article-title":"Targeted metabolomic analysis of amino acid response to L-asparaginase in adherent cells","volume":"10","author":"Purwaha","year":"2014","journal-title":"Metabolomics"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"19","DOI":"10.4062\/biomolther.2017.178","article-title":"Targeting Glutamine Metabolism for Cancer Treatment","volume":"26","author":"Choi","year":"2018","journal-title":"Biomol. Ther."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.neo.2016.09.004","article-title":"Metabolic Alterations Caused by KRAS Mutations in Colorectal Cancer Contribute to Cell Adaptation to Glutamine Depletion by Upregulation of Asparagine Synthetase","volume":"18","author":"Toda","year":"2016","journal-title":"Neoplasia"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1158\/2159-8290.CD-19-1472","article-title":"Exploiting the Therapeutic Interaction of WNT Pathway Activation and Asparaginase for Colorectal Cancer Therapy","volume":"10","author":"Hinze","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/bjc.2013.293","article-title":"Asparagine synthetase is an independent predictor of surgical survival and a potential therapeutic target in hepatocellular carcinoma","volume":"109","author":"Zhang","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Li, W., and Dong, C. (2017). Polymorphism in asparagine synthetase is associated with overall survival of hepatocellular carcinoma patients. BMC Gastroenterol., 17.","DOI":"10.1186\/s12876-017-0635-4"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1158\/1541-7786.MCR-13-0576","article-title":"Asparagine depletion potentiates the cytotoxic effect of chemotherapy against brain tumors","volume":"12","author":"Panosyan","year":"2014","journal-title":"Mol. Cancer Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1007\/s11060-019-03351-4","article-title":"L-asparaginase and 6-diazo-5-oxo-L-norleucine synergistically inhibit the growth of glioblastoma cells","volume":"146","author":"Ohba","year":"2020","journal-title":"J. Neurooncol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1046\/j.1365-2141.2000.02015.x","article-title":"Asparagine synthetase activity in paediatric acute leukaemias: AML-M5 subtype shows lowest activity","volume":"109","author":"Winkelhorst","year":"2000","journal-title":"Br. J. Haematol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1046\/j.1365-2141.2003.04703.x","article-title":"In vitro efficacy of l-asparaginase in childhood acute myeloid leukaemia","volume":"123","author":"Okada","year":"2003","journal-title":"Br. J. Haematol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1111\/bjh.15920","article-title":"Acute myeloid leukaemia niche regulates response to L-asparaginase","volume":"186","author":"Michelozzi","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1111\/bjh.15924","article-title":"Acute myeloid leukaemia niche regulates response to L-asparaginase","volume":"186","author":"Kaspers","year":"2019","journal-title":"Br. J. Haematol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/73439","article-title":"A gene expression database for the molecular pharmacology of cancer","volume":"24","author":"Scherf","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"a031435","DOI":"10.1101\/cshperspect.a031435","article-title":"KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer","volume":"8","author":"Waters","year":"2018","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/msb.2011.56","article-title":"Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth","volume":"7","author":"Gaglio","year":"2011","journal-title":"Mol. Syst. Biol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nature12040","article-title":"Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway","volume":"496","author":"Son","year":"2013","journal-title":"Nature"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"31151","DOI":"10.18632\/oncotarget.5150","article-title":"Inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy","volume":"6","author":"Li","year":"2015","journal-title":"Oncotarget"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s13046-018-0719-1","article-title":"Targeting KRAS in metastatic colorectal cancer: Current strategies and emerging opportunities","volume":"37","author":"Porru","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/s41419-019-1481-9","article-title":"SOX12 promotes colorectal cancer cell proliferation and metastasis by regulating asparagine synthesis","volume":"10","author":"Du","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.7150\/thno.21477","article-title":"Twist promotes tumor metastasis in basal-like breast cancer by transcriptionally upregulating ROR1","volume":"8","author":"Cao","year":"2018","journal-title":"Theranostics"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.cmet.2018.06.006","article-title":"Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling","volume":"28","author":"Luo","year":"2018","journal-title":"Cell Metab."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s12943-020-01276-5","article-title":"Wnt signaling in breast cancer: Biological mechanisms, challenges and opportunities","volume":"19","author":"Xu","year":"2020","journal-title":"Mol. Cancer"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.cmet.2017.12.006","article-title":"As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid","volume":"27","author":"Pavlova","year":"2018","journal-title":"Cell Metab."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.tibs.2010.05.003","article-title":"Glutamine addiction: A new therapeutic target in cancer","volume":"35","author":"Wise","year":"2010","journal-title":"Trends Biochem. Sci."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1038\/bjc.2014.425","article-title":"Glutamine depletion by crisantaspase hinders the growth of human hepatocellular carcinoma xenografts","volume":"111","author":"Chiu","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1158\/1535-7163.MCT-13-0870","article-title":"Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer","volume":"13","author":"Gross","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/s13045-017-0509-9","article-title":"Drug-induced amino acid deprivation as strategy for cancer therapy","volume":"10","author":"Fung","year":"2017","journal-title":"J. Hematol. Oncol."},{"key":"ref_137","first-page":"157","article-title":"Chemoimmunotherapy for metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, methotrexate, L-asparaginase, Corynebacterium parvum, and Pseudomonas vaccine","volume":"64","author":"Hortobagyi","year":"1980","journal-title":"Cancer Treat. Rep."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"299","DOI":"10.3322\/caac.21613","article-title":"Management of glioblastoma: State of the art and future directions","volume":"70","author":"Tan","year":"2020","journal-title":"CA Cancer J. Clin."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"320941","DOI":"10.1155\/2015\/320941","article-title":"Blood brain barrier: A challenge for effectual therapy of brain tumors","volume":"2015","author":"Bhowmik","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"5335","DOI":"10.1158\/1078-0432.CCR-04-0222","article-title":"Asparaginase pharmacokinetics after intensive polyethylene glycol-conjugated L-asparaginase therapy for children with relapsed acute lymphoblastic leukemia","volume":"10","author":"Hawkins","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_141","first-page":"651","article-title":"Comparison of native E. coli and PEG asparaginase pharmacokinetics and pharmacodynamics in pediatric acute lymphoblastic leukemia","volume":"86","author":"Panetta","year":"2009","journal-title":"Clin. Pharm."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1002\/pbc.20406","article-title":"Serum asparaginase activities and asparagine concentrations in the cerebrospinal fluid after a single infusion of 2,500 IU\/m(2) PEG asparaginase in children with ALL treated according to protocol COALL-06-97","volume":"46","author":"Wenner","year":"2006","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s00280-016-3236-y","article-title":"Asparaginase pharmacology: Challenges still to be faced","volume":"79","year":"2017","journal-title":"Cancer Chemother. Pharm."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1023\/A:1008368916800","article-title":"L-asparagine depletion and L-asparaginase activity in children with acute lymphoblastic leukemia receiving i.m. or i.v. Erwinia C. or E. coli L-asparaginase as first exposure","volume":"11","author":"Rizzari","year":"2000","journal-title":"Ann. Oncol."},{"key":"ref_145","first-page":"24","article-title":"A pharmacological study on pegylated asparaginase used in front-line treatment of children with acute lymphoblastic leukemia","volume":"91","author":"Rizzari","year":"2006","journal-title":"Haematologica"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.3109\/10428194.2014.1003056","article-title":"Asparaginase pharmacokinetics and implications of therapeutic drug monitoring","volume":"56","author":"Asselin","year":"2015","journal-title":"Leuk. Lymphoma"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1111\/bjh.12865","article-title":"Cerebrospinal fluid asparagine depletion during pegylated asparaginase therapy in children with acute lymphoblastic leukaemia","volume":"166","author":"Henriksen","year":"2014","journal-title":"Br. J. Haematol."},{"key":"ref_148","first-page":"4554","article-title":"L-asparaginase pharmacokinetics and asparagine levels in cerebrospinal fluid of rhesus monkeys and humans","volume":"41","author":"Riccardi","year":"1981","journal-title":"Cancer Res."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1007\/s00280-017-3307-8","article-title":"Pharmacodynamic effects in the cerebrospinal fluid of rats after intravenous administration of different asparaginase formulations","volume":"79","author":"Ballerini","year":"2017","journal-title":"Cancer Chemother. Pharm."},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Koleva, L., Bovt, E., Ataullakhanov, F., and Sinauridze, E. (2020). Erythrocytes as Carriers: From Drug Delivery to Biosensors. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12030276"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1007\/s40259-020-00415-0","article-title":"Ongoing Developments and Clinical Progress in Drug-Loaded Red Blood Cell Technologies","volume":"34","author":"Rossi","year":"2020","journal-title":"BioDrugs"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1111\/j.1365-2141.2011.08588.x","article-title":"l-asparaginase loaded red blood cells in refractory or relapsing acute lymphoblastic leukaemia in children and adults: Results of the GRASPALL 2005-01 randomized trial","volume":"153","author":"Domenech","year":"2011","journal-title":"Br. J. Haematol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1002\/ajh.24093","article-title":"A Phase 2 study of L-asparaginase encapsulated in erythrocytes in elderly patients with Philadelphia chromosome negative acute lymphoblastic leukemia: The GRASPALL\/GRAALL-SA2-2008 study","volume":"90","author":"Leguay","year":"2015","journal-title":"Am. J. Hematol."},{"key":"ref_154","unstructured":"European Medicines Agency (2021, December 16). Graspa: Withdrawal of the Marketing Authorisation Application. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/withdrawn-applications\/graspa-0."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1097\/MPA.0000000000000394","article-title":"Asparagine Synthetase Expression and Phase I Study With L-Asparaginase Encapsulated in Red Blood Cells in Patients With Pancreatic Adenocarcinoma","volume":"44","author":"Bachet","year":"2015","journal-title":"Pancreas"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"v211","DOI":"10.1093\/annonc\/mdx369.005","article-title":"621PD\u2014A Phase 2b of eryaspase in combination with gemcitabine or FOLFOX as second-line therapy in patients with metastatic pancreatic adenocarcinoma (NCT02195180)","volume":"28","author":"Hammel","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ejca.2019.10.020","article-title":"Erythrocyte-encapsulated asparaginase (eryaspase) combined with chemotherapy in second-line treatment of advanced pancreatic cancer: An open-label, randomized Phase IIb trial","volume":"124","author":"Hammel","year":"2020","journal-title":"Eur. J. Cancer"},{"key":"ref_158","unstructured":"Erytech (2021, December 20). ERYTECH Granted, U.S. FDA Fast Track Designation for Eryaspase in Hypersensitive ALL. Available online: https:\/\/investors.erytech.com\/news-releases\/news-release-details\/erytech-granted-us-fda-fast-track-designation-eryaspase."},{"key":"ref_159","first-page":"252","article-title":"Alteration in spleen lymphoid populations associated with specific amino acid depletion during L-asparaginase treatment","volume":"42","author":"Distasio","year":"1982","journal-title":"Cancer Res."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"528","DOI":"10.3181\/00379727-155-39844","article-title":"Antilymphoma activity of a glutaminase-free L-asparaginase of microbial origin","volume":"155","author":"Distasio","year":"1977","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_161","first-page":"1125","article-title":"Comparison of the immunosuppressive effects of asparaginases from Escherichia coli and Vibrio succinogenes","volume":"40","author":"Durden","year":"1980","journal-title":"Cancer Res."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"6929","DOI":"10.1016\/S0021-9258(17)32924-1","article-title":"Purification and characterization of L-asparaginase with anti-lymphoma activity from Vibrio succinogenes","volume":"251","author":"Distasio","year":"1976","journal-title":"J. Biol. Chem."},{"key":"ref_163","first-page":"273","article-title":"Immunological effects of native and polyethylene glycol-modified asparaginases from Vibrio succinogenes and Escherichia coli in normal and tumour-bearing mice","volume":"48","author":"Bendich","year":"1982","journal-title":"Clin. Exp. Immunol."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"41643","DOI":"10.1038\/srep41643","article-title":"The differential ability of asparagine and glutamine in promoting the closed\/active enzyme conformation rationalizes the Wolinella succinogenes L-asparaginase substrate specificity","volume":"7","author":"Nguyen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"11690","DOI":"10.1073\/pnas.1932838100","article-title":"Complete genome sequence and analysis of Wolinella succinogenes","volume":"100","author":"Baar","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1111\/j.1432-1033.1996.0201t.x","article-title":"Crystal structure and amino acid sequence of Wolinella succinogenes L-asparaginase","volume":"241","author":"Lubkowski","year":"1996","journal-title":"Eur. J. Biochem."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"31222","DOI":"10.1074\/jbc.M604511200","article-title":"Role of glutamine depletion in directing tissue-specific nutrient stress responses to L-asparaginase","volume":"281","author":"Reinert","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1038\/s41375-020-01080-6","article-title":"Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia","volume":"35","author":"Emadi","year":"2021","journal-title":"Leukemia"},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"13864","DOI":"10.1074\/jbc.RA119.009864","article-title":"Age modulates liver responses to asparaginase-induced amino acid stress in mice","volume":"294","author":"Nikonorova","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"2318","DOI":"10.1021\/bi401692v","article-title":"Structural and kinetic characterization of guinea pig L-asparaginase type III","volume":"53","author":"Schalk","year":"2014","journal-title":"Biochemistry"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"33175","DOI":"10.1074\/jbc.M114.609552","article-title":"Identification and structural analysis of an L-asparaginase enzyme from guinea pig with putative tumor cell killing properties","volume":"289","author":"Schalk","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"10224","DOI":"10.1038\/s41598-017-10758-4","article-title":"Discovery of human-like L-asparaginases with potential clinical use by directed evolution","volume":"7","author":"Rigouin","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/S0021-9258(18)81247-9","article-title":"Guinea pig serum L-asparaginase. Properties, purification, and application to determination of asparagine in biological samples","volume":"238","author":"Tower","year":"1963","journal-title":"J. Biol. Chem."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"11026","DOI":"10.1021\/bi901397h","article-title":"The human asparaginase-like protein 1 hASRGL1 is an Ntn hydrolase with beta-aspartyl peptidase activity","volume":"48","author":"Cantor","year":"2009","journal-title":"Biochemistry"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"12962","DOI":"10.1074\/jbc.M113.545038","article-title":"Human 60-kDa lysophospholipase contains an N-terminal L-asparaginase domain that is allosterically regulated by L-asparagine","volume":"289","author":"Karamitros","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-15075-4","article-title":"A protease-resistant Escherichia coli asparaginase with outstanding stability and enhanced anti-leukaemic activity in vitro","volume":"7","author":"Maggi","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"17664","DOI":"10.1074\/jbc.M116.728485","article-title":"Design and characterization of erwinia chrysanthemi l-asparaginase variants with diminished l-glutaminase activity","volume":"291","author":"Nguyen","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_178","first-page":"1614","article-title":"Rational engineering of L-asparaginase reveals importance of dual activity for cancer cell toxicity","volume":"117","author":"Offman","year":"2011","journal-title":"Blood J. Am. Soc. Hematol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1385\/MB:33:1:57","article-title":"Probing the antigenicity of E. coli L-asparaginase by mutational analysis","volume":"33","author":"Jianhua","year":"2006","journal-title":"Mol. Biotechnol."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"7227","DOI":"10.1007\/s00253-017-8456-5","article-title":"Cloning and characterization of Halomonas elongata L-asparaginase, a promising chemotherapeutic agent","volume":"101","author":"Ghasemi","year":"2017","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1096\/fj.11-191254","article-title":"Hyperthermophilic asparaginase mutants with enhanced substrate affinity and antineoplastic activity: Structural insights on their mechanism of action","volume":"26","author":"Bansal","year":"2012","journal-title":"FASEB J."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1038\/emboj.2010.81","article-title":"The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation","volume":"29","author":"Ye","year":"2010","journal-title":"EMBO J."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"32742","DOI":"10.1074\/jbc.M109.047910","article-title":"GCN2 protein kinase is required to activate amino acid deprivation responses in mice treated with the anti-cancer agent L-asparaginase","volume":"284","author":"Bunpo","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"E7776","DOI":"10.1073\/pnas.1805523115","article-title":"Inhibition of GCN2 sensitizes ASNS-low cancer cells to asparaginase by disrupting the amino acid response","volume":"115","author":"Nakamura","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1021\/acsptsci.0c00196","article-title":"Therapeutic Assessment of Targeting ASNS Combined with l-Asparaginase Treatment in Solid Tumors and Investigation of Resistance Mechanisms","volume":"4","author":"Apfel","year":"2021","journal-title":"ACS Pharm. Transl. Sci."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1021\/acsmedchemlett.9b00400","article-title":"Identification of Novel, Potent, and Orally Available GCN2 Inhibitors with Type I Half Binding Mode","volume":"10","author":"Fujimoto","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1182\/blood.2021011787","article-title":"BTK inhibition sensitizes Acute Lymphoblastic Leukemia to asparaginase by suppressing the Amino Acid Response pathway","volume":"138","author":"Butler","year":"2021","journal-title":"Blood"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"e102147","DOI":"10.15252\/embj.2019102147","article-title":"SLC1A3 contributes to L-asparaginase resistance in solid tumors","volume":"38","author":"Sun","year":"2019","journal-title":"EMBO J."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.ccell.2019.03.004","article-title":"Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias","volume":"35","author":"Hinze","year":"2019","journal-title":"Cancer Cell"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/4\/902\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:17:50Z","timestamp":1760134670000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/4\/902"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,11]]},"references-count":189,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["cancers14040902"],"URL":"https:\/\/doi.org\/10.3390\/cancers14040902","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,11]]}}}