Asparaginase

Asparaginase
Names
Trade namesElspar, Spectrila, others
Other namesCrisantaspase, colaspase
IUPAC name
  • E. coli L-asparagine amidohydrolase
Clinical data
Drug classEnzyme
Main usesAcute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), non-Hodgkin's lymphoma[1]
Side effectsAllergic reactions, pancreatitis, blood clotting problems, high blood sugar, kidney problems, liver dysfunction[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: D
  • US: C (Risk not ruled out)
    Routes of
    use    		IM or IV
    Defined daily doseNot established[2]
    External links
    AHFS/Drugs.comMonograph/Monograph
    MedlinePlusa682046
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • CA: ℞-only
    • UK: POM (Prescription only)
    • US: ℞-only
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Elimination half-life39-49 hours (IM), 8-30 hours (IV)
    Chemical and physical data
    FormulaC1377H2208N382O442S17
    Molar mass31732.06 g·mol−1

    Asparaginase is an enzyme that is used as a medication and in food manufacturing.[1][3] As a medication, L-asparaginase is used to treat acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and non-Hodgkin's lymphoma.[1] It is given by injection into a vein, muscle, or under the skin.[1] A pegylated version is also available.[4] In food manufacturing it is used to decrease acrylamide.[3]

    Common side effects when used by injection include allergic reactions, pancreatitis, blood clotting problems, high blood sugar, kidney problems, and liver dysfunction.[1] Use in pregnancy may harm the baby.[5] As a food it is generally recognized as safe.[3] Asparaginase works by breaking down the amino acid known as asparagine without which the cancer cells cannot make protein.[1]

    Asparaginase was approved for medical use in the United States in 1978.[4] It is on the World Health Organization's List of Essential Medicines.[6] The wholesale cost in the developing world is about US$42 per 10,000 IU vial.[7] This amount in the United Kingdom costs the NHS 613 pounds.[8] It is often made from Escherichia coli or Erwinia chrysanthemi.[4][9] There is also a form made via recombinant DNA techniques, which may be used in those allergic to other formulations.[10]

    Medical uses

    E. coli strains are the main source of medical asparaginase.[11] Branded formulations (with different chemical and pharmacological properties) available in 1998 include Asparaginase Medac, Ciderolase, and Oncaspar.[11]: 5  (Crasnitin has been discontinued.) Spectrila is a new recombinant E. coli asparaginase.[12]

    Asparaginase produced by Dickeya dadantii (formerly called Erwinia chrysanthemi) instead is known as crisantaspase (BAN), and is available in the United Kingdom under the trade name Erwinase.[13]

    One of the E. coli asparaginases marketed under the brand name Elspar for the treatment of acute lymphoblastic leukemia (ALL)[13] is also used in some mast cell tumor protocols.[14]

    Unlike most of other chemotherapy agents, asparaginase can be given as an intramuscular, subcutaneous, or intravenous injection without fear of tissue irritation.

    Dosage

    The defined daily dose is not established.[2]

    Side effects

    The main side effect is an allergic or hypersensitivity reaction; anaphylaxis is a possibility.[13] 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 & S as well), leading to bleeding or thrombotic events such as stroke.[11] Bone marrow suppression is common but only mild to moderate, rarely reaches clinical significance and therapeutic consequences are rarely required.[15]

    Other common side effects include pancreatitis. These side effects mainly attributes to the dual activity of L.Asparaginase as it can also hydrolysis L.Glutamine to Glutamic acid and ammonia

    Mechanism of action

    Food processing

    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.[16]

    As a food processing aid, asparaginases can effectively reduce the level of acrylamide up to 90% in a range of starchy foods without changing the taste and appearance of the end product.[17]

    Medication

    The rationale behind asparaginase is that it takes 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 high amount of asparagine.[18] 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.[19]

    Enzyme regulation

    Type I L-asparaginase protein may use the morpheein model of allosteric regulation.[20]

    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.[21] Later it was found out that it is not the serum itself which provoke the tumour regression, but rather the enzyme asparaginase.[22]

    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 amount.[11]

    Society and culture

    Names

    Crisantaspase is British Approved Name (BAN) for asparaginase obtained from Erwinia chrysanthemi. Colaspase is the BAN of asparaginase obtained from Escherichia coli.[23][11][13] The United States Adopted Name of crisantaspase is asparaginase Erwinia chrysanthemi.[23] Elspar, Kidrolase, Leunase and Spectrila are brand names for colaspase, while Erwinase and Erwinaze are brand names for crisantaspase.[23] The pegylated version of colaspase is called pegaspargase. Oncaspar is the brand name of pegaspargase.[23]

    Cost

    Normal asparaginase costs less than its pegylated version, pegaspargase.[24] However, because it doesn't stay as long in the body, the injections need to be more frequent, with the result that total cost of treatment may be lower for the pegylated version.[24]

    Food manufacturing

    The most common use of asparaginases is as a processing aid in the manufacture of food. Marketed under the brand names Acrylaway and PreventASe, asparaginases are used as a food processing aid to reduce the formation of acrylamide, a suspected carcinogen, in starchy food products such as snacks and biscuits.[16]

    References

    1. 1 2 3 4 5 6 7 "Asparaginase". The American Society of Health-System Pharmacists. Archived from the original on 27 March 2017. Retrieved 8 December 2016.
    2. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 1 November 2020. Retrieved 17 September 2020.
    3. 1 2 3 Gökmen, Vural (2015). Acrylamide in Food: Analysis, Content and Potential Health Effects. Academic Press. p. 415. ISBN 9780128028759. Archived from the original on 2016-12-21.
    4. 1 2 3 Kim, Kyu-Won; Roh, Jae Kyung; Wee, Hee-Jun; Kim, Chan (2016). Cancer Drug Discovery: Science and History. Springer. p. 147. ISBN 9789402408447. Archived from the original on 2016-12-21.
    5. ↑ "Asparaginase escherichia coli (Elspar) Use During Pregnancy". www.drugs.com. Archived from the original on 27 March 2017. Retrieved 20 December 2016.
    6. ↑ 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.
    7. ↑ "Asparaginase". International Drug Price Indicator Guide. Archived from the original on 27 March 2017. Retrieved 8 December 2016.
    8. ↑ British National Formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 600. ISBN 9780857111562.
    9. ↑ Farmer, Peter B.; Walker, John M. (2012). The Molecular Basis of Cancer. Springer Science & Business Media. p. 279. ISBN 9781468473131. Archived from the original on 2016-12-21.
    10. ↑ "Asparaginase (Erwinia chrysanthemi) (recombinant)-rywn Monograph for Professionals". Drugs.com. Retrieved 29 October 2022.
    11. 1 2 3 4 5 Müller, H. (1998). "Use of L-asparaginase in childhood ALL". Critical Reviews in Oncology/Hematology. 28 (2): 97–113. doi:10.1016/S1040-8428(98)00015-8.
    12. ↑ "Spectrila 10,000 U powder for concentrate for solution for infusion - Summary of Product Characteristics (SmPC) - (eMC)". Archived from the original on 2016-11-09. Retrieved 2016-11-08.
    13. 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.
    14. ↑ Appel IM, van Kessel-Bakvis C, Stigter R, Pieters R (2007). "Influence of two different regimens of concomitant treatment with asparaginase and dexamethason] on hemostasis in childhood acute lymphoblastic leukemia". Leukemia. 21 (11): 2377–80. doi:10.1038/sj.leu.2404793. PMID 17554375.
    15. ↑ Johnston, P. G.; Hardisty, R. M.; Kay, H. E.; Smith, P. G. (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.
    16. 1 2 Kornbrust, B.A., Stringer, M.A., Lange, N.K. and Hendriksen, H.V. (2010) Asparaginase – an enzyme for acrylamide reduction in food products. In: Enzymes in Food Technology, 2nd Edition. (eds Robert J. Whitehurst and Maarten Van Oort). Wiley-Blackwell, UK, pp. 59-87.
    17. ↑ Hendriksen, H.V.; Kornbrust, B.A.; Oestergaard, P.R.; Stringer, M.A. (April 23, 2009). "Evaluating the Potential for Enzymatic Acrylamide Mitigation in a Range of Food Products Using an Asparaginase from Aspergillus oryzae". Journal of Agricultural and Food Chemistry. 57 (10): 4168–4176. doi:10.1021/jf900174q. PMID 19388639.
    18. ↑ Fernandes, H. S.; Teixeira, C. S. Silva; Fernandes, P. A.; Ramos, M. J.; Cerqueira, N. M. F. S. A. (4 November 2016). "Amino acid deprivation using enzymes as a targeted therapy for cancer and viral infections". Expert Opinion on Therapeutic Patents. 0 (ja): 283–297. doi:10.1080/13543776.2017.1254194. ISSN 1354-3776. PMID 27813440.
    19. ↑ Broome, J. D. (1981). "L-Asparaginase: Discovery and development as a tumor-inhibitory agent". Cancer Treatment Reports. 65 Suppl 4: 111–114. PMID 7049374.
    20. ↑ T. Selwood; E. K. Jaffe. (2011). "Dynamic dissociating homo-oligomers and the control of protein function". Arch. Biochem. Biophys. 519 (2): 131–43. doi:10.1016/j.abb.2011.11.020. PMC 3298769. PMID 22182754.
    21. ↑ Kidd, J. G. (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.
    22. ↑ Broome, J. D. (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.
    23. 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.
    24. 1 2 Gad, Shayne Cox (2007-05-25). Handbook of Pharmaceutical Biotechnology. John Wiley & Sons. p. 730. ISBN 978-0-470-11710-1. Archived from the original on 2021-08-27. Retrieved 2020-06-20.
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