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Identification
Name Aldesleukin
Accession Number DB00041 (BIOD00082, BTD00082)
Type biotech
Groups approved
Description

Aldesleukin, a lymphokine, is produced by recombinant DNA technology using a genetically engineered E. coli strain containing an analog of the human interleukin-2 gene. Genetic engineering techniques were used to modify the human IL-2 gene, and the resulting expression clone encodes a modified human interleukin-2. This recombinant form differs from native interleukin-2 in the following ways: a) Aldesleukin is not glycosylated because it is derived from E. coli; b) the molecule has no N-terminal alanine; the codon for this amino acid was deleted during the genetic engineering procedure; c) the molecule has serine substituted for cysteine at amino acid position 125.
Protein structure Db00041
Display: 3D Structure
Protein chemical formula C690H1115N177O202S6
Protein average weight 15314.8000
Sequences 
>DB00041 sequence
PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE
ELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRW
ITFAQSIISTLT

FASTA
Synonyms
IL-2
Interleukin-2 precursor
T-cell growth factor
TCGF
Salts Not Available
Brand names
Name Company
Proleukin
Proleukin (Chiron Corp)
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
CAS number 85898-30-2
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication For treatment of adults with metastatic renal cell carcinoma.
Pharmacodynamics Used to treat renal cell carcinoma, Aldesleukin induces the enhancement of lymphocyte mitogenesis and stimulation of long-term growth of human interleukin-2 dependent cell lines, the enhancement of lymphocyte cytotoxicity, the induction of killer cell (lymphokine-activated (LAK) and natural (NK)) activity; and the induction of interferon-gamma production. IL-2 is normally produced by the body, secreted by T cells, and stimulates growth and differentiation of T cell response. It can be used in immunotherapy to treat cancer. It enhances the ability of the immune system to kill tumor cells and may interfere with blood flow to the tumor.
Mechanism of action Aldesleukin binds to the IL-2 receptor which leads to heterodimerization of the cytoplasmic domains of the IL-2R beta and gamma(c) chains, activation of the tyrosine kinase Jak3, and phosphorylation of tyrosine residues on the IL-2R beta chain. These events led to the creation of an activated receptor complex, to which various cytoplasmic signaling molecules are recruited and become substrates for regulatory enzymes (especially tyrosine kinases) that are associated with the receptor. These events stimulate growth and differentiation of T cells.
Absorption Not Available
Volume of distribution

0.18 l/kg
Protein binding Not Available
Metabolism Not Available
Route of elimination The pharmacokinetic profile of Proleukin is characterized by high plasma concentrations following a short IV infusion, rapid distribution into the extravascular space and elimination from the body by metabolism in the kidneys with little or no bioactive protein excreted in the urine. Following the initial rapid organ distribution, the primary route of clearance of circulating proleukin is the kidney. Greater than 80% of the amount of Proleukin distributed to plasma, cleared from the circulation and presented to the kidney is metabolized to amino acids in the cells lining the proximal convoluted tubules.
Half life 13 min-85 min
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers
Dosage forms
Form Route Strength
Powder, for solution Intravenous
Prices
Unit description Cost Unit
Proleukin 22 million unit vial 1092.34 USD each
Proleukin 22000000 unit Solution Vial 976.66 USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State liquid
Experimental Properties
Property Value Source
hydrophobicity -0.192 Not Available
isoelectric point 7.31 Not Available
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
UniProt P60569 Link_out
Genbank M11144 Link_out
PharmGKB PA448081 Link_out
Drug Product Database 2130181 Link_out
RxList http://www.rxlist.com/cgi/generic2/aldesleukin.htm Link_out
Drugs.com http://www.drugs.com/cdi/aldesleukin.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Aldesleukin Link_out
ATC Codes
  • L03AC01
AHFS Codes
  • 10:00.00
PDB Entries
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Clobetasol Corticosteroids such as clobetasol may diminish the antineoplastic effect of aldesleukin. Avoid conccurent use of corticosteroids with aldesleukin.
Clocortolone Corticosteroids such as clocortolone may diminish the antineoplastic effect of aldesleukin. Avoid conccurent use of corticosteroids with aldesleukin.
Corticotropin Corticosteroids may diminish the antineoplastic effect of Aldesleukin. Avoid conccurent use of corticosteroids with aldesleukin.
Food Interactions Not Available
Targets

1. Interleukin-2 receptor subunit beta

Pharmacological action: yes
Actions: agonist, modulator

Receptor for interleukin-2. This beta subunit is involved in receptor mediated endocytosis and transduces the mitogenic signals of IL2

Organism class: human
UniProt ID: P14784 Link_out
Gene: IL2RB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA: Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2788-93. Epub 2006 Feb 13. Pubmed
  2. Steppan S, Eckart MR, Bajsarowicz K, Sternberg LR, Greve JM, Cassell DJ: Reduced secondary cytokine induction by BAY 50-4798, a high-affinity receptor-specific interleukin-2 analog. J Interferon Cytokine Res. 2006 Mar;26(3):171-8. Pubmed
  3. Cornish GH, Sinclair LV, Cantrell DA: Differential regulation of T-cell growth by IL-2 and IL-15. Blood. 2006 Jul 15;108(2):600-8. Epub 2006 Mar 28. Pubmed
  4. Lee KD, Chen HW, Chen CC, Shih YC, Liu HK, Cheng ML: Construction and characterization of a novel fusion protein consisting of anti-CD3 antibody fused to recombinant interleukin-2. Oncol Rep. 2006 May;15(5):1211-6. Pubmed
  5. Maclennan C, Hutchinson P, Holdsworth S, Bardin PG, Freezer NJ: Airway inflammation in asymptomatic children with episodic wheeze. Pediatr Pulmonol. 2006 Jun;41(6):577-83. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Interleukin-2 receptor alpha chain

Pharmacological action: yes
Actions: agonist, modulator

Receptor for interleukin-2

Organism class: human
UniProt ID: P01589 Link_out
Gene: IL2RA Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Waldmann TA: Anti-Tac (daclizumab, Zenapax) in the treatment of leukemia, autoimmune diseases, and in the prevention of allograft rejection: a 25-year personal odyssey. J Clin Immunol. 2007 Jan;27(1):1-18. Epub 2007 Jan 11. Pubmed
  2. Recchia F, Cesta A, Rea S: Low dose interleukin-2 and 13-cis-retinoic acid as maintenance therapy in patients with solid tumors responsive to chemotherapy. J Exp Clin Cancer Res. 2003 Dec;22(4 Suppl):135-43. Pubmed
  3. Waldmann TA: Daclizumab (anti-Tac, Zenapax) in the treatment of leukemia/lymphoma. Oncogene. 2007 May 28;26(25):3699-703. Pubmed
  4. Vlad G, Ho EK, Vasilescu ER, Fan J, Liu Z, Cai JW, Jin Z, Burke E, Deng M, Cadeiras M, Cortesini R, Itescu S, Marboe C, Mancini D, Suciu-Foca N: Anti-CD25 treatment and FOXP3-positive regulatory T cells in heart transplantation. Transpl Immunol. 2007 Jul;18(1):13-21. Epub 2007 Apr 2. Pubmed
  5. Liu BY, Zhu P, Luo HB, Fu N: [Screening of short peptides binding to cell surface interleukin-2 receptor alpha chain] Nan Fang Yi Ke Da Xue Xue Bao. 2006 Jul;26(7):971-4. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  7. Ouyang Y, Kaminski NE: Phospholipase A2 inhibitors p-bromophenacyl bromide and arachidonyl trifluoromethyl ketone suppressed interleukin-2 (IL-2) expression in murine primary splenocytes. Arch Toxicol. 1999 Feb;73(1):1-6. Pubmed

3. Cytokine receptor common gamma chain

Pharmacological action: yes
Actions: agonist

Common subunit for the receptors for a variety of interleukins

Organism class: human
UniProt ID: P31785 Link_out
Gene: IL2RG Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA: Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2788-93. Epub 2006 Feb 13. Pubmed
  2. Shibata F, Toma T, Wada T, Inoue M, Tone Y, Ohta K, Kasahara Y, Sano F, Kimura M, Ikeno M, Koizumi S, Yachie A: Skin infiltration of CD56 CD16 natural killer cells in a case of X-SCID with Omenn syndrome-like manifestations. Eur J Haematol. 2007 Jul;79(1):81-5. Pubmed
  3. Fonseca SG, Reis MM, Coelho V, Nogueira LG, Monteiro SM, Mairena EC, Bacal F, Bocchi E, Guilherme L, Zheng XX, Liew FY, Higuchi ML, Kalil J, Cunha-Neto E: Locally produced survival cytokines IL-15 and IL-7 may be associated to the predominance of CD8+ T cells at heart lesions of human chronic Chagas disease cardiomyopathy. Scand J Immunol. 2007 Aug-Sep;66(2-3):362-71. Pubmed
  4. Blank RB, Lamb EW, Tocheva AS, Crow ET, Lim KC, McKerrow JH, Davies SJ: The common gamma chain cytokines interleukin (IL)-2 and IL-7 indirectly modulate blood fluke development via effects on CD4+ T cells. J Infect Dis. 2006 Dec 1;194(11):1609-16. Epub 2006 Oct 23. Pubmed
  5. Smyth CM, Ginn SL, Deakin CT, Logan GJ, Alexander IE: Limiting {gamma}c expression differentially affects signaling via the interleukin (IL)-7 and IL-15 receptors. Blood. 2007 Jul 1;110(1):91-8. Epub 2007 Mar 15. Pubmed
Enzymes

1. Prostaglandin G/H synthase 2

Actions: inducer

May have a role as a major mediator of inflammation and/or a role for prostanoid signaling in activity-dependent plasticity

UniProt ID: P35354 Link_out
Gene: PTGS2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Pyeon D, Diaz FJ, Splitter GA: Prostaglandin E(2) increases bovine leukemia virus tax and pol mRNA levels via cyclooxygenase 2: regulation by interleukin-2, interleukin-10, and bovine leukemia virus. J Virol. 2000 Jun;74(12):5740-5. Pubmed
  2. Hamada T, Tsuchihashi S, Avanesyan A, Duarte S, Moore C, Busuttil RW, Coito AJ: Cyclooxygenase-2 deficiency enhances Th2 immune responses and impairs neutrophil recruitment in hepatic ischemia/reperfusion injury. J Immunol. 2008 Feb 1;180(3):1843-53. Pubmed

2. Cytosolic phospholipase A2

Actions: inducer

Selectively hydrolyzes arachidonyl phospholipids in the sn-2 position releasing arachidonic acid. Together with its lysophospholipid activity, it is implicated in the initiation of the inflammatory response

UniProt ID: P47712 Link_out
Gene: PLA2G4A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wolbink GJ, Schalkwijk C, Baars JW, Wagstaff J, van den Bosch H, Hack CE: Therapy with interleukin-2 induces the systemic release of phospholipase-A2. Cancer Immunol Immunother. 1995 Nov;41(5):287-92. Pubmed

3. Cytochrome P450 3A4

Actions: inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Elkahwaji J, Robin MA, Berson A, Tinel M, Letteron P, Labbe G, Beaune P, Elias D, Rougier P, Escudier B, Duvillard P, Pessayre D: Decrease in hepatic cytochrome P450 after interleukin-2 immunotherapy. Biochem Pharmacol. 1999 Apr 15;57(8):951-4. Pubmed
  2. Sunman JA, Hawke RL, LeCluyse EL, Kashuba AD: Kupffer cell-mediated IL-2 suppression of CYP3A activity in human hepatocytes. Drug Metab Dispos. 2004 Mar;32(3):359-63. Pubmed

4. Xanthine dehydrogenase/oxidase

Actions: inducer

This enzyme can be converted from the dehydrogenase form (D) to the oxidase form (O) irreversibly by proteolysis or reversibly through the oxidation of sulfhydryl groups

UniProt ID: P47989 Link_out
Gene: XDH Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Faggioni R, Allavena P, Cantoni L, Carelli M, Demitri MT, Delgado R, Gatti S, Gnocchi P, Isetta AM, Paganin C, et al.: Mechanisms of interleukin-2-induced hydrothoraxy in mice: protective effect of endotoxin tolerance and dexamethasone and possible role of reactive oxygen intermediates. J Immunother Emphasis Tumor Immunol. 1994 Apr;15(3):194-201. Pubmed

5. Cytochrome P450 2E1

Actions: inhibitor

Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms

UniProt ID: P05181 Link_out
Gene: CYP2E1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Elkahwaji J, Robin MA, Berson A, Tinel M, Letteron P, Labbe G, Beaune P, Elias D, Rougier P, Escudier B, Duvillard P, Pessayre D: Decrease in hepatic cytochrome P450 after interleukin-2 immunotherapy. Biochem Pharmacol. 1999 Apr 15;57(8):951-4. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on December 18, 2012 17:43