Peginterferon alfa-2b
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Peginterferon alfa-2b
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| Systematic (IUPAC) name | |
| PEGylated human interferon alpha 2b | |
| Identifiers | |
| CAS number | |
| ATC code | L03 |
| PubChem | ? |
| DrugBank | |
| Chemical data | |
| Formula | C860H1353N229O255S9 |
| Mol. mass | 19269.1 g/mol |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | ? |
| Half life | 22-60 hrs |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
? |
| Legal status | |
| Routes | ? |
Pegylated interferon alfa-2b is a treatment for hepatitis C developed by Schering-Plough, brand name is Peg Intron.
It was approved in January 2001.
PEG-interferon alpha is a pegylated interferon composed of 165 amino acids. The PEG (polyethylene glycol) protects the molecule from proteolytic breakdown and increasing the in vivo half-life of the interferon protein. While PEG-interferon alpha-2b is commonly used as a treatment for hepatitis C, it has also been shown to have optimistic effects in the treatment of malignant melanoma. [1], [2]
One of the major mechanisms of PEG-interferon alpha-2b utilizes the JAK-STAT signaling pathway. The basic mechanism works such that PEG-interferon alpha-2b will bind to its receptor, interferon-alpha receptor 1 and 2 (IFNAR1/2). Upon ligand binding the Tyk2 protein associated with IFNAR1 is phosphorylated which in turn phosphorylates Jak1 associated with IFNAR2. This kinase continues its signal transduction by phosphorylation of signal transducer and activator of transcription (STAT) 1 and 2 via Jak 1 and Tyk2 respectively. The phosphorylated STATs then dissociate from the receptor heterodimer and form an interferon transcription factor with p48 and IRF9 to form the interferon stimulate transcription factor-3 (ISGF3). This transcription factor then translocates to the nucleus where it will transcribe several genes involved in: cell cycle control, cell differentiation, apoptosis, and immune response. [3], [4]
PEG-interferon alpha-2b acts as a multifunctional immunoregulatory cytokine by transcribing several genes, including interleukin 4 (IL4). This cytokine is responsible for inducing T helper cells to become type 2 helper T cells. This ultimately results in the stimulation of B cells to proliferate and increase their antibody production. This ultimately allows for an immune response, as the B cells will help to signal the immune system that a foreign antigen is present. [5]
Another major mechanism of type I interferon alpha (IFNα) is to stimulate apoptosis in malignant cell lines. Previous studies have shown that IFNα can cause cell cycle arrest in U266, Daudi, and Rhek-1 cell lines. [6]
A follow-up study researched to determine if the caspases were involved in the apoptosis seen in the previous study as well as to determine the role of mitochondrial cytochrome c release. The study confirmed that there was cleavage of caspase-3, -8, and -9. All three of these cysteine proteases play an important role in the initiation and activation of the apoptotic cascade. Furthermore, it was shown that IFNα induced a loss in the mitochondrial membrane potential which resulted in the release of cytochrome c from the mitochondria. Follow-up research is currently being conducted to determine the upstream activators of the apoptotic pathway that are induced by IFNα. [7]
[edit] References
- ^ PEG-Interferon Alfa-2b in Treating Patients With Stage IV Melanoma - Full Text View - ClinicalTrials.gov
- ^ http://drugrxus.com/P/Peginterferon%20alfa-2b.htm
- ^ Ward A. et al. "The Jak-Stat pathway in normal and perturbed hematopoiesis". BLOOD. January 2000; VOL 95, Number 1, 19-26
- ^ PATHWAYS :: IFN alpha
- ^ Thomas H. et al. "Mechanisms of Action of Interferon and Nucleoside Analogues". Journal of hepatology.2004 Feb; 40(2):364.
- ^ Sangfel O, Erickson S, et al. (1997). Cell Growth Differ.,8;343-352
- ^ Thyrell et al. “Mechanisms of Interferon-alpha induced apoptosis in malignant cells”. Oncogene: Nature Publishing Group. 2002. 21; 1251-1262
[edit] External links
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