Asparaginase

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Asparaginase
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Clinical data
Trade names Elspar, Spectrila, Rylaze, others
Other namescrisantaspase, colaspase, asparaginase erwinia chrysanthemi (recombinant)-rywn
AHFS/Drugs.com Monograph
MedlinePlus a682046
License data
Pregnancy
category
Routes of
administration 		Intramuscular, intravenous
Drug class Antineoplastic
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 39-49 hours (IM), 8-30 hours (IV)
Identifiers
  • E. coli L-asparagine amidohydrolase
CAS Number
IUPHAR/BPS
DrugBank
ChemSpider
  • none
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard 100.029.774 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C1377H2208N382O442S17
Molar mass 31732.06 g·mol−1
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Asparaginase is an enzyme that is used as a medication and in food manufacturing. [6] [7] As a medication, L-asparaginase is used to treat acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). [6] It is given by injection into a vein, or muscle. [6] A pegylated version is also available. [8] In food manufacturing it is used to decrease acrylamide. [7]

Contents

Common side effects when used by injection include allergic reactions, pancreatitis, blood clotting problems, high blood sugar, kidney problems, and liver dysfunction. [6] Use in pregnancy may harm the baby. [9] As a food it is generally recognized as safe. [7] Asparaginase works by breaking down the amino acid known as asparagine without which the cancer cells cannot make protein. [6]

Asparaginase was approved for medical use in the United States in 1978. [8] It is on the World Health Organization's List of Essential Medicines. [10] It is often made from Escherichia coli (E. coli) or Erwinia chrysanthemi . [8] [11]

Development of the drug

In 1963, asparaginase (ASNase) was identified as an effective antileukemic agent, and subsequent efforts were made to isolate it from bacterial sources and scale up production for clinical trials. [12] Clinical testing with bacterial-derived ASNase commenced in 1966, and in 1978, E. coli–derived ASNase received approval from the United States for the treatment of acute lymphoblastic leukemia. [13] Subsequently, pegylated E. coli ASNase was approved in 1994 as a second-line treatment and later in 2006 as a first-line treatment for acute lymphoblastic leukemia. [13] Another ASNase variant, ASNase Erwinia chrysantemi, obtained authorization for use in the United Kingdom in 1985, and gained approval from the US Food and Drug Administration in 2011. [12]

Uses

Asparaginases are primarily used as pharmaceuticals and as industrial food processing agents.

Medical

E. coli strains are the main source of medical asparaginase. [14] Branded formulations (with different chemical and pharmacological properties) available in 1998 include Asparaginase Medac, Ciderolase, and Oncaspar. [14] : 5  (Crasnitin has been discontinued.) Spectrila is a recombinant E. coli asparaginase. [2]

Asparaginase produced by Dickeya dadantii (formerly called Erwinia chrysanthemi) instead is known as crisantaspase (BAN), and is available in the United Kingdom under the brand name Erwinase. [15]

One of the E. coli asparaginases marketed under the brand name Elspar for the treatment of acute lymphoblastic leukemia [15] is also used in some mast cell tumor protocols. [16]

In July 2006, the US Food and Drug Administration (FDA) granted approval to pegaspargase for the first-line treatment of people with acute lymphoblastic leukemia as a component of a multiagent chemotherapy regimen. Pegaspargase was previously approved in February 1994 for the treatment of patients with acute lymphoblastic leukemia who were hypersensitive to native forms of L-asparaginase. [17] [18] [19] Similar designations were later applied to calaspargase (December 2018) and asparaginase erwinia chrysanthemi (June 2021), both identified as orphan drugs. [20] [21]

Food manufacturing

Asparaginases are used as a food processing aid to reduce the formation of acrylamide, a suspected carcinogen, in starchy food products such as snacks, biscuits and fried potato. [22]

Side effects

The main side effect is an allergic or hypersensitivity reaction; anaphylaxis is a possibility. [15] Additionally, it can also be associated with a coagulopathy as it decreases protein synthesis, including synthesis of coagulation factors (e.g. progressive isolated decrease of fibrinogen) and anticoagulant factor (generally antithrombin III; sometimes protein C and S as well), leading to bleeding or thrombotic events such as stroke. [14] Bone marrow suppression is common but only mild to moderate, rarely reaches clinical significance and therapeutic consequences are rarely required. [23]

The most common nonhematological adverse reactions of asparaginase erwinia chrysanthemi (recombinant) include abnormal liver test, nausea, musculoskeletal pain, infection, fatigue, headache, febrile neutropenia, pyrexia, hemorrhage (bleeding), stomatitis, abdominal pain, decreased appetite, drug hypersensitivity, hyperglycemia, diarrhea, pancreatitis, and hypokalemia. [24] [25] The most common side effects of asparaginase erwinia chrysanthemi (recombinant) when given in combination with chemotherapy for the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma are abnormal liver tests, nausea, muscle and bone pain, and fatigue. [26]

Mechanism of action

As a food processing aid

Acrylamide is often formed in the cooking of starchy foods. During heating the amino acid asparagine, naturally present in starchy foods, undergoes a process called the Maillard reaction, which is responsible for giving baked or fried foods their brown color, crust, and toasted flavor. Suspected carcinogens such as acrylamide and some heterocyclic amines are also generated in the Maillard reaction. By adding asparaginase before baking or frying the food, asparagine is converted into another common amino acid, aspartic acid, and ammonium. As a result, asparagine cannot take part in the Maillard reaction, and therefore the formation of acrylamide is significantly reduced. Complete acrylamide removal is probably not possible due to other, minor asparagine-independent formation pathways. [22]

As a drug

Applications of asparaginase in cancer therapy take advantage of the fact that acute lymphoblastic leukemia cells and some other suspected tumor cells are unable to synthesize the non-essential amino acid asparagine, whereas normal cells are able to make their own asparagine; thus leukemic cells require a high amount of asparagine. [27] These leukemic cells depend on circulating asparagine. Asparaginase, however, catalyzes the conversion of L-asparagine to aspartic acid and ammonia. This deprives the leukemic cell of circulating asparagine, which leads to cell death. [28]

Enzyme regulation

Type I L-asparaginase protein may use the morpheein model of allosteric regulation. [29]

History

The discovery and development of asparaginase as an anti-cancer drug began in 1953, when scientists first observed that lymphomas in rat and mice regressed after treatment with guinea pig serum. [30] Later it was found out that it is not the serum itself which provoke the tumour regression, but rather the enzyme asparaginase. [31]

After researchers comparing different kinds of asparaginases, the one derived from Escherichia coli and Erwinia chrysanthemi turned out to have the best anti-cancer ability. E. coli has thereby become the main source of asparaginase due to the factor that it is also easy to produce in large amounts. [14]

Names and synonyms

Crisantaspase is the British Approved Name (BAN) for asparaginase obtained from Erwinia chrysanthemi . Colaspase is the BAN of asparaginase obtained from Escherichia coli . [32] [14] [15] The United States Adopted Name of crisantaspase is asparaginase Erwinia chrysanthemi. [32] Elspar, Kidrolase, Leunase and Spectrila are brand names for colaspase, while Erwinase and Erwinaze are brand names for crisantaspase. [32] Oncaspar is the brand name of pegaspargase. [32]

Synonyms: (1) crisantaspase biobetter JZP-458, (2) RC-P JZP-458, (3) recombinant Asparaginase erwinia chrysanthemi JZP-458, (4) recombinant asparaginase Erwinia chrysanthemi-rywn, and (5) recombinant crisantaspase JZP-458. US brand name: Rylaze and Code name: (1) JZP 458, (2) JZP-458, (3) JZP458, and (4) PF743. [33]

References

  1. 1 2 "Erwinase APMDS". Therapeutic Goods Administration (TGA). 27 February 2024. Archived from the original on 10 March 2024. Retrieved 7 March 2024.
  2. 1 2 "Spectrila 10,000 U powder for concentrate for solution for infusion - Summary of Product Characteristics (SmPC) - (eMC)". Archived from the original on 9 November 2016. Retrieved 8 November 2016.
  3. ↑ "Rylaze (asparaginase erwinia chrysanthemi- recombinant-rywn) injection". DailyMed. Archived from the original on 15 August 2021. Retrieved 20 August 2021.
  4. ↑ "List of nationally authorised medicinal products : Active substance: asparaginase, crisantaspase. Procedure no.: PSUSA/00003161/202108" (PDF). Ema.europa.eu. Archived (PDF) from the original on 10 March 2024. Retrieved 20 July 2022.
  5. ↑ "Enrylaze EPAR". European Medicines Agency. 5 October 2023. Archived from the original on 17 February 2024. Retrieved 5 October 2023.
  6. 1 2 3 4 5 "Asparaginase". The American Society of Health-System Pharmacists. Archived from the original on 27 March 2017. Retrieved 8 December 2016.
  7. 1 2 3 Gökmen V (2015). Acrylamide in Food: Analysis, Content and Potential Health Effects. Academic Press. p. 415. ISBN   978-0-12-802875-9. Archived from the original on 21 December 2016.
  8. 1 2 3 Kim KW, Roh JK, Wee HJ, Kim C (2016). Cancer Drug Discovery: Science and History. Springer. p. 147. ISBN   978-94-024-0844-7. Archived from the original on 21 December 2016.
  9. ↑ "Asparaginase escherichia coli (Elspar) Use During Pregnancy". www.drugs.com. Archived from the original on 27 March 2017. Retrieved 20 December 2016.
  10. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  11. ↑ Farmer PB, Walker JM (2012). The Molecular Basis of Cancer. Springer Science & Business Media. p. 279. ISBN   978-1-4684-7313-1. Archived from the original on 21 December 2016.
  12. 1 2 Salzer WL, Asselin BL, Plourde PV, Corn T, Hunger SP (November 2014). "Development of asparaginase Erwinia chrysanthemi for the treatment of acute lymphoblastic leukemia". Annals of the New York Academy of Sciences. 1329 (1): 81–92. Bibcode:2014NYASA1329...81S. doi: 10.1111/nyas.12496 . PMID   25098829. S2CID   25278669.
  13. 1 2 Asselin BL, Devidas M, Wang C, Pullen J, Borowitz MJ, Hutchison R, et al. (July 2011). "Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404)". Blood. 118 (4): 874–883. doi:10.1182/blood-2010-06-292615. PMC   3292437 . PMID   21474675.
  14. 1 2 3 4 5 Avramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ, et al. (March 2002). "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's Cancer Group study". Blood. 99 (6): 1986–1994. doi:10.1016/S1040-8428(98)00015-8. PMID   11877270.
  15. 1 2 3 4 "8.1.5: Other antineoplastic drugs". British National Formulary (BNF 57). United Kingdom: BMJ Group and RPS Publishing. March 2009. p. 476. ISBN   978-0-85369-845-6.
  16. ↑ Appel IM, van Kessel-Bakvis C, Stigter R, Pieters R (November 2007). "Influence of two different regimens of concomitant treatment with asparaginase and dexamethasone on hemostasis in childhood acute lymphoblastic leukemia". Leukemia. 21 (11): 2377–2380. doi: 10.1038/sj.leu.2404793 . PMID   17554375.
  17. ↑ Dinndorf PA, Gootenberg J, Cohen MH, Keegan P, Pazdur R (August 2007). "FDA drug approval summary: pegaspargase (oncaspar) for the first-line treatment of children with acute lymphoblastic leukemia (ALL)". The Oncologist. 12 (8): 991–998. doi:10.1634/theoncologist.12-8-991. PMID   17766659. S2CID   43076064.
  18. ↑ "FDA Approves Oncaspar for First-Line ALL". Oncology NEWS International Vol 15 No 8. 1 August 2006. Archived from the original on 21 November 2022. Retrieved 21 November 2022.
  19. ↑ "FDA Approval for Pegaspargase". National Cancer Institute. 3 July 2013. Archived from the original on 9 June 2017. Retrieved 21 November 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  20. ↑ "FDA Approves New Enzyme Product for ALL". Medscape. Archived from the original on 21 November 2022. Retrieved 21 November 2022.
  21. ↑ "Jazz Pharmaceuticals Announces U.S. FDA Approval of Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn) for the Treatment of Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma" (Press release). Jazz Pharmaceuticals plc. 30 June 2021. Archived from the original on 1 July 2021. Retrieved 1 July 2021– via PR Newswire.
  22. 1 2 Kornbrust BA, Stringer MA, Lange NE, Hendriksen HV, Whitehurst R, Oort MV (2010). "Enzymes in food technology.". In Whitehurst RJ, Van Oort M (eds.). Asparaginase–an enzyme for acrylamide reduction in food products. Vol. 2. UK: Wiley-Blackwell. pp. 59–87.
  23. ↑ Johnston PG, Hardisty RM, Kay HE, Smith PG (July 1974). "Myelosuppressive effect of colaspase (L-asparaginase) in initial treatment of acute lymphoblastic leukaemia". British Medical Journal. 3 (5923): 81–83. doi:10.1136/bmj.3.5923.81. PMC   1611087 . PMID   4604804.
  24. ↑ "FDA approves asparaginase erwinia chrysanthemi (recombinant) for leukemia and lymphoma". U.S. Food and Drug Administration (FDA). 1 July 2021. Archived from the original on 1 July 2021. Retrieved 1 July 2021.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  25. ↑ "FDA approves a new dosing regimen for asparaginase erwinia chrysanthemi (recombinant)". U.S. Food and Drug Administration (FDA). 18 November 2022. Archived from the original on 22 November 2022. Retrieved 22 November 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  26. ↑ "Drug Trials Snapshots: Rylaze". U.S. Food and Drug Administration (FDA). 18 May 2023. Archived from the original on 10 March 2024. Retrieved 3 June 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  27. ↑ Fernandes HS, Silva Teixeira CS, Fernandes PA, Ramos MJ, Cerqueira NM (March 2017). "Amino acid deprivation using enzymes as a targeted therapy for cancer and viral infections". Expert Opinion on Therapeutic Patents. 27 (3): 283–297. doi:10.1080/13543776.2017.1254194. PMID   27813440. S2CID   7768944.
  28. ↑ Broome JD (1981). "L-Asparaginase: discovery and development as a tumor-inhibitory agent". Cancer Treatment Reports. 65 (Suppl 4): 111–114. PMID   7049374.
  29. ↑ Selwood T, Jaffe EK (March 2012). "Dynamic dissociating homo-oligomers and the control of protein function". Archives of Biochemistry and Biophysics. 519 (2): 131–143. doi:10.1016/j.abb.2011.11.020. PMC   3298769 . PMID   22182754.
  30. ↑ Kidd JG (December 1953). "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". The Journal of Experimental Medicine. 98 (6): 565–582. doi:10.1084/jem.98.6.565. PMC   2136344 . PMID   13109110.
  31. ↑ Broome JD (July 1963). "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". The Journal of Experimental Medicine. 118 (1): 99–120. doi:10.1084/jem.118.1.99. PMC   2137570 . PMID   14015821.
  32. 1 2 3 4 Brayfield A, ed. (June 2017). "Asparaginase: Martindale: The Complete Drug Reference". MedicinesComplete. London, UK: Pharmaceutical Press. Archived from the original on 27 August 2021. Retrieved 9 August 2017.
  33. ↑ "asparaginase erwinia chrysanthemi (recombinant)-rywn". National Cancer Institute . 2 February 2011. Archived from the original on 8 June 2023. Retrieved 8 June 2023.
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