NAV

Asparaginase Escherichia coli

Targets (1)Carriers (1)

Identification

Name
Asparaginase Escherichia coli
Accession Number
DB00023
Description

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
Db00023
Protein Chemical Formula
C1377H2208N382O442S17
Protein Average Weight
31731.9 Da
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) Label.

Associated Conditions
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.

Affected organisms
  • Humans and other mammals
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
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AllantoinThe therapeutic efficacy of Allantoin can be increased when used in combination with Asparaginase Escherichia coli.
CarbamazepineThe therapeutic efficacy of Carbamazepine can be increased when used in combination with Asparaginase Escherichia coli.
DantroleneThe therapeutic efficacy of Dantrolene can be increased when used in combination with Asparaginase Escherichia coli.
Darbepoetin alfaThe risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Asparaginase Escherichia coli.
DexamethasoneThe serum concentration of Dexamethasone can be increased when it is combined with Asparaginase Escherichia coli.
EnzalutamideThe therapeutic efficacy of Enzalutamide can be increased when used in combination with Asparaginase Escherichia coli.
ErythropoietinThe risk or severity of Thrombosis can be increased when Erythropoietin is combined with Asparaginase Escherichia coli.
EthotoinThe therapeutic efficacy of Ethotoin can be increased when used in combination with Asparaginase Escherichia coli.
FosphenytoinThe therapeutic efficacy of Fosphenytoin can be increased when used in combination with Asparaginase Escherichia coli.
FurosemideThe therapeutic efficacy of Furosemide can be increased when used in combination with Asparaginase Escherichia coli.
Additional Data Available
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  • Severity
    Severity
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  • Evidence Level
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  • Action
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Food Interactions
Not Available

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Unlock Additional Data
ElsparInjection, powder, lyophilized, for solution10000 [iU]/1Intramuscular; IntravenousLundbeck Inc.1978-01-102013-07-18US flag
KidrolasePowder, for solutionIntramuscular; IntravenousJazz Pharmaceuticals France Sas1974-12-31Not applicableCanada 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
Additional Data Available
  • Application Number
    Application Number
    Available for Purchase

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
    Available for Purchase

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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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

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. [PubMed:5331901]
  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. [PubMed:5334543]
  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. [PubMed:25586605]
  4. UniProtKB - V6FYV8 (V6FYV8_ECOLX): E. coli L-asparaginase, type II FASTA sequence [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
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
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Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAcute Lymphobkastic Leukemia1
4CompletedTreatmentAcute Lymphoblastic Leukaemias (ALL)5
4CompletedTreatmentAdult Acute Lymphocytic Leukemia3
4CompletedTreatmentLymphoma, Lymphoblastic1
4RecruitingTreatmentPeripheral T Cell Lymphoma (PTCL) / Peripheral T-Cell Lymphoma (PTCL)1
4Unknown StatusTreatmentAcute Lymphoblastic Leukaemias (ALL)1
4Unknown StatusTreatmentAdult Acute Lymphocytic Leukemia2
3Active Not RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Acute Undifferentiated Leukemia (AUL) / Childhood T Acute Lymphoblastic Leukemia / Untreated Childhood Acute Lymphoblastic Leukemia1
3Active Not RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Adult B Lymphoblastic Lymphoma / Ann Arbor Stage I B Lymphoblastic Lymphoma / Ann Arbor Stage II B Lymphoblastic Lymphoma / Childhood B Acute Lymphoblastic Leukemia / Childhood B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1 / Childhood B Lymphoblastic Lymphoma / Down Syndrome (DS) / Hypodiploid B Acute Lymphoblastic Leukemia / Philadelphia Chromosome Positive1
3Active Not RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / B Acute Lymphoblastic Leukemia, Philadelphia Chromosome Negative1

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 solutionParenteral10000 IU
Powder, for solutionIntramuscular; Intravenous
Injection, powder, lyophilized, for solutionIntramuscular; Intrathecal; Intravenous10000 IU
Injection, powder, for solution10000 KU
Injection, powder, for solutionIntravenous10000 iu
Injection, powder, lyophilized, for solutionIntravenous10000 iu
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

Details1. L-asparagine
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. [PubMed:17139284]
  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. [PubMed:17016423]
  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. [PubMed:17264295]
  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. [PubMed:16307417]
  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. [PubMed:14523472]

Carriers

Details1. Thyroxine-binding globulin
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 on June 13, 2005 07:24 / Updated on January 14, 2021 04:10

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