Asparaginase Escherichia coli

Identification

Summary

Asparaginase Escherichia coli is an asparaginase enzyme from E. coli used as part of treatment regimens for acute lymphoblastic leukemias.

Brand Names
Rylaze, Spectrila
Generic Name
Asparaginase Escherichia coli
DrugBank Accession Number
DB00023
Background

Asparaginase derived from Escherichia coli (L-asparagine amidohydrolase, EC 3.5.1.1) is an enzyme responsible for the metabolism of L-asparagine, by catalyzing L-asparagine into L-aspartic acid and ammonia. It also facilitates the production of oxaloacetate which is needed for general cellular metabolism. Asparaginase from E. coli has clinically shown to exhibit antitumor actions in models of leukaemias 1,2. L-asparaginase of E. coli is marketed under several different trade names, including Elspar, for the treatment of acute lymphoblastic leukemia (ALL) as part of a multi-agent chemotherapeutic regimen. It is available as intramuscular or intravenous injections. Therapeutic L-asparaginase from E. coli works by depleting the levels of non-essential amino acid, asparagine, in lymphoblastic leukemic cells thus promoting apoptotic cell death 3. For patients who develop hypersensitivity to E. coli-derived formulations of L-asparaginase, the use of PEGylated or non-PEGylated Asparaginase Erwinia chrysanthemi is recommended 3.

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
Protein Structure
Protein Chemical Formula
C1377H2208N382O442S17
Protein Average Weight
Not Available
Sequences
>sp|P00805|ASPG2_ECOLI L-asparaginase 2 OS=Escherichia coli (strain K12) GN=ansB PE=1 SV=2
MEFFKKTALAALVMGFSGAALALPNITILATGGTIAGGGDSATKSNYTVGKVGVENLVNA
VPQLKDIANVKGEQVVNIGSQDMNDNVWLTLAKKINTDCDKTDGFVITHGTDTMEETAYF
LDLTVKCDKPVVMVGAMRPSTSMSADGPFNLYNAVVTAADKASANRGVLVVMNDTVLDGR
DVTKTNTTDVATFKSVNYGPLGYIHNGKIDYQRTPARKHTSDTPFDVSKLNELPKVGIVY
NYANASDLPAKALVDAGYDGIVSAGVGNGNLYKSVFDTLATAAKTGTAVVRSSRVPTGAT
TQDAEVDDAKYGFVASGTLNPQKARVLLQLALTQTKDPQQIQQIFNQY
Download FASTA Format
Synonyms
  • Asparaginase
  • Asparaginase (E. coli)
  • Colaspase
  • Escherichia coli L-asparaginase
  • L-asparaginase
  • L-asparagine amidohydrolase

Pharmacology

Indication

Indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL).5

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Adjunct therapy in treatment ofAcute lymphoblastic leukemia•••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

In clinical trials of patients with previously untreated, standard-risk ALL, administration of asparaginase resulted in a decrease of plasma asparagine levels from average of 41 μM to less than 3 μM Label. The native asparaginase in whom plasma enzyme activity before treatment was greater than 0.1 International Units/mL Label. In this study, cerebrospinal fluid asparagine levels in patients treated with asparaginase decreased from 2.8 μM (pretreatment) to 1.0 μM and 0.3 μM at day 7 and day 28 of induction, respectively Label. Native E. coli asparaginase results in asparagine depletion in 14 to 23 days following administration 3.

Mechanism of action

Asparagine is a non-essential amino acid that maintains DNA, RNA and protein synthesis and promotes cell growth. While healthy and normal cells are capable of obtaining asparagine via dietary intake or synthesizing the asparagine from aspartate via asparagine synthetase activity, lymphoblastic leukemic cells lack the asparagine synthetase enzyme and cannot produce asparagine de novo 3. Thus, leukemic cells rely on exogenous source of asparagine for protein synthesis and cell survival 3. L-asparagine from E. coli serves to deplete plasma levels of asparagine in leukemic cells by converting L-asparagine to L-aspartic acid and ammonia 3, leading to reduced reduced DNA, RNA and protein synthesis; inhibition of cell growth; and ultimately the activation of apoptotic cell-death mechanisms 3. Normal cells, however, are able to synthesize asparagine and thus are affected less by the rapid depletion produced by treatment with the enzyme asparaginase Label.

TargetActionsOrganism
AL-asparagine
other/unknown
Humans
Absorption

In a study in patients with metastatic cancer and leukemia, daily intravenous administration of L-asparaginase derived from E. coli resulted in a cumulative increase in plasma levels. Following intramuscular injection in patients with metastatic cancer and leukemia, peak plasma levels of asparaginase was achieved 14 to 24 hours post-dosing Label.

Peak asparaginase activity of native E. coli asparaginase can be observed in 24 to 48 hours following administration 3.

Volume of distribution

Apparent volume of distribution was slightly greater than the plasma volume. Asparaginase levels in cerebrospinal fluid were less than 1% of concurrent plasma levels 3.

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Plasma half life of L-asparagine derived from E. coli following intravenous injection was 8-30 hrs Label. Plasma half-life was 34 to 49 hours after intramuscular injection Label. Half-life (mean ± SD) of native E. coli asparaginase is approximately 1.28 ± 0.35 days 3.

Clearance

Not Available

Adverse Effects
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Toxicity

No studies assessing the mutagenic or carcinogenic potential of E. coli L-asparagine have been conducted. In the Ames assay, no mutagenic effect was demonstrated when tested against Salmonella typhimurium strains Label. No studies have been performed on impairment of fertility Label. Following a single, intravenous injection of 12,500 to 50,000 International Units L-asparagine/kg in rabbits, edema and necrosis of pancreatic islets were observed. The clinical relevance of this finding is unclear as it does not indicate pancreatitis Label.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AllantoinThe therapeutic efficacy of Allantoin can be increased when used in combination with Asparaginase Escherichia coli.
AmbroxolThe risk or severity of methemoglobinemia can be increased when Asparaginase Escherichia coli is combined with Ambroxol.
ArticaineThe risk or severity of methemoglobinemia can be increased when Asparaginase Escherichia coli is combined with Articaine.
BenzocaineThe risk or severity of methemoglobinemia can be increased when Asparaginase Escherichia coli is combined with Benzocaine.
Benzyl alcoholThe risk or severity of methemoglobinemia can be increased when Asparaginase Escherichia coli is combined with Benzyl alcohol.
Food Interactions
No interactions found.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ElsparInjection, powder, lyophilized, for solution10000 [iU]/1Intramuscular; IntravenousLundbeck Inc.1978-01-102013-07-18US flag
KidrolasePowder, for solution10000 unit / vialIntramuscular; IntravenousJazz Pharmaceuticals France Sas1974-12-312021-07-07Canada flag
RylazeInjection20 mg/1mLIntramuscularJazz Pharmaceuticals, Inc.2021-06-30Not applicableUS flag
SpectrilaInjection, powder, for solution10000 UIntravenousMedac Gesellschaft Fuer Klinische Spezialpraeparate Mb H2016-09-08Not applicableEU flag
SpectrilaInjection, powder, for solution10000 UIntravenousMedac Gesellschaft Fuer Klinische Spezialpraeparate Mb H2016-09-08Not applicableEU flag

Categories

ATC Codes
L01XX02 — Asparaginase
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
G4FQ3CKY5R
CAS number
9015-68-3

References

Synthesis Reference

Masao Nambu, "Process for producing immobilized L-asparaginase preparations for the therapy of leukemia." U.S. Patent US4617271, issued January, 1977.

US4617271
General References
  1. Roberts J, Prager MD, Bachynsky N: The antitumor activity of Escherichia coli L-asparaginase. Cancer Res. 1966 Oct;26(10):2213-7. [Article]
  2. Boyse EA, Old LJ, Campbell HA, Mashburn LT: Suppression of murine leukemias by L-asparaginase. Incidence of sensitivity among leukemias of various types: comparative inhibitory activities of guinea pig serum L-asparaginase and Escherichia coli L-asparaginase. J Exp Med. 1967 Jan 1;125(1):17-31. [Article]
  3. Asselin B, Rizzari C: Asparaginase pharmacokinetics and implications of therapeutic drug monitoring. Leuk Lymphoma. 2015;56(8):2273-80. doi: 10.3109/10428194.2014.1003056. Epub 2015 Mar 11. [Article]
  4. UniProtKB - V6FYV8 (V6FYV8_ECOLX): E. coli L-asparaginase, type II FASTA sequence [Link]
  5. FDA Approved Drug Products: Elspar (asparaginase) for intravenous or intramuscular injection [Link]
UniProt
P37595
Genbank
U00096
PubChem Substance
46507633
RxNav
1156
ChEMBL
CHEMBL2108989
PharmGKB
PA448492
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Asparaginase
FDA label
Download (176 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAcute Lymphobkastic Leukemia1
4CompletedTreatmentAcute Lymphoblastic Leukemia (ALL)5
4CompletedTreatmentLeukemia, Lymphocytic, Acute, Adult5
4CompletedTreatmentLymphoblastic Lymphoma1
4Unknown StatusTreatmentAcute Lymphoblastic Leukemia (ALL)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Lundbeck Inc.
  • Merck & Co.
  • Prescript Pharmaceuticals
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntramuscular; Intravenous10000 [iU]/1
Injection, powder, for solution10000 U
Injection, powder, for solutionParenteral
Powder, for solutionIntramuscular; Intravenous10000 unit / vial
Injection, powder, lyophilized, for solutionIntramuscular; Intrathecal; Intravenous10000 IU
Injection, powder, for solution
Injection, powder, lyophilized, for solutionIntravenous10000 iu
Injection, powder, for solutionIntravenous10000 iu
Powder10000 iu/1vial
InjectionIntramuscular20 mg/1mL
Injection, powder, for solutionIntravenous10000 U
Prices
Unit descriptionCostUnit
Elspar 10000 unit vial74.6USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
hydrophobicity0.059Not Available
isoelectric point4.67Not Available

Targets

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Kind
Small molecule
Organism
Humans
Pharmacological action
Yes
Actions
Other/unknown
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
  3. Wetzler M, Sanford BL, Kurtzberg J, DeOliveira D, Frankel SR, Powell BL, Kolitz JE, Bloomfield CD, Larson RA: Effective asparagine depletion with pegylated asparaginase results in improved outcomes in adult acute lymphoblastic leukemia: Cancer and Leukemia Group B Study 9511. Blood. 2007 May 15;109(10):4164-7. Epub 2007 Jan 30. [Article]
  4. Wenner KA, Vieira Pinheiro JP, Escherich G, Wessalowski R, Jorch N, Wolff J, Stehn M, Kohlschutter A, Boos J, Janka-Schaub GE: Asparagine concentration in plasma after 2,500 IU/m(2) PEG-asparaginase i.v. in children with acute lymphoblastic leukemia. Klin Padiatr. 2005 Nov-Dec;217(6):321-6. [Article]
  5. Appel IM, Pinheiro JP, den Boer ML, Lanvers C, Reniers NC, Boos J, Pieters R: Lack of asparagine depletion in the cerebrospinal fluid after one intravenous dose of PEG-asparaginase: a window study at initial diagnosis of childhood ALL. Leukemia. 2003 Nov;17(11):2254-6. [Article]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
Major thyroid hormone transport protein in serum.
Gene Name
SERPINA7
Uniprot ID
P05543
Uniprot Name
Thyroxine-binding globulin
Molecular Weight
46324.12 Da

Drug created at June 13, 2005 13:24 / Updated at March 18, 2024 16:48