Interferons action mechanisms

The ability of interferons (especially type I interferons) to induce an antiviral state is unlikely to be solely dependent upon the enzymatic mechanisms discussed above. Furthermore the 2 -5 A synthetase and eIF-2a kinase systems may play important roles in mediating additional interferon actions. The ability of such systems to stall protein synthesis in cells may play a role in interferon-induced alterations of cellular differentiation or cell cycle progression. They may also be involved in mediating interferon-induced anti-proliferative effects on various transformed cells. 

Teaman, D.W, Mechanisms of interferon action. Prog Mol SnbceU Biol, 1998. 20 101-42. 

Tomkins WA (1999) Immunomodulation and therapeutic effects of the oral use of interferon-alpha mechanism of action. J Interferon Cytokine Res 19 817-828. 

Billiau, A. and Dijkmans, R. (1990). Interferon-gamma mechanism of action and therapeutic potential. Biochem. Pharmacol. 40, 1433-1439. 

Experiments using TSH or cholera toxin as probes of the mechanism of interferon action also indicate the following (i) The initial binding of... 

Guilhot E, Lacotte-Thierry L. Interferon-alpha Mechanisms of action in chronic myelogenous leukemia in chronic phase. Hematol Cell Ther 1998 40 237-239. 

Other routes of administration have been evaluated, such as inhalation, intrale-sional, intranasal, intraperitoneal, intraventricular, and intraocular rates, in clinical studies. For the most part, these alternative routes were attempts to improve the delivery of interferon to sites not easily accessible via the systemic circulation. These dosing strategies have provided adequate concentrations of interferon in cerebrospinal fluid, lymph, nasal mucosa, and peritoneal fluid, but have not led to clinical success, undoubtedly reflecting the lack of understanding of the inherent mechanism of interferon action [164]. 

Arnaud P (2002). The interferons Pharmacology, mechanism of action, tolerance and side effects. Rev. Med. Inter. 23 (suppl 4) 449s-458s. 

Rhizopus oryzae lactate dehydrogenase 24 rhizosecretion 48 ribosome 13 rice 27 rifamycin 14 rituxan 213 rituximab 213 application 226 approval 225 B-cell recovery 222 clinical development 215 combination 223 development 221 EMEA 225 first phase I study 219 future applications 226, 228 IDEC 219 indications 226 interferon 224 mechanism of action 215 optimizing the dose and schedule 222 pharmacokinetic 222 phase I and I/II clinical trials 219 phase I/II 216... 

Bischoff JR, Samuel CE (1985) Mechanism of interferon action. The interferon-induced phosphoprotein PI possesses a double-stranded RNA-dependent ATP-binding site. J Biol Chem 260 8237-8239 Bolovan CA, Sawtell NM, Thompson RL (1994) ICP34.5 mutants of herpes simplex virus type 1 strain 17syn+ are attenuated for neurovirulence in mice and for replication in confluent primary mouse embryo cell cultures. J Virol 68 48-55... 

THE INTERFERON SYSTEM STUDIES ON THE MOLECULAR MECHANISM OF INTERFERON ACTION... 

Samuel, C. E., 1979, Mechanism of interferon action Phosphorylation of protein synthesis initiation factor eIF-2 in interferon treated human cells by a ribosome associated kinase processing site specificity similar to hemin-regulated rabbit reticulocyte kinase, Proc. Natl Acad. Sci. USA 76 600. 

Sen, G. C., 1982, Mechanisms of interferon action Progress toward its understanding, Prog. Nucl. Acid. Res. Mol. Biol. 17 106. 

Taylor, J., 1965, Studies on the mechanism of action of interferon, 1. Interferon action and RNA synthesis in chick embryo fibroblasts infected with Semliki Forest virus. Virology 25 340. 

Pharmacology and Mechanism of Action The mechanism of action of beta interferons is complex and not completely understood. The following properties are thought to be important to the mechanism of action ... 

Prior to the introduction of imatinib, the combination of interferon-alfa and low dose cytarabine was the nontransplant treatment of choice for patients in chronic phase CML. The precise mechanism of action of interferon-alfa remains unknown. The addition of cytarabine to interferon-alfa improves the response compared with interferon alone. This combination produces cytogenetic response rates of 30%, much lower than imatinib.13 One of the major drawbacks, in addition to the low response rates, is interferon s toxicity,... 

Interferon-a2b has diverse mechanisms of action, including antiviral activity, impact on cellular metabolism and differentiation, and antitumor activity.42 The antitumor activity is due to a combination of direct antiproliferative effect on tumor cells and indirect immune-mediated effects.42 Interferon-a2b is currently approved by the Food and Drug Administration (FDA) as adjuvant therapy for patients who are free of disease after curative surgical resection but are at high risk of MM recurrence. This includes patients with bulky disease or regional lymph node involvement such as stage IIB, IIC, or III disease.43 It is controversial if interferon-a2b (IFN) should be offered as adjuvant therapy for every high-risk MM patient. The reason is because clinical trials with different doses of IFN have not proved definitively that IFN improves overall patient survival. 

Pharmacology Interferon beta-1 a and beta-lb have antiviral, antiproliferative, and immunoregulatory activities. The mechanisms by which they exert their actions in MS are not clearly understood. 

Cytokines, including tumour necrosis factor (TNF) and interferon-y, favour the secretion of numerous chemokines and the expression of adhesion molecules by endothelial cells. The mechanisms of action of the principle drugs used in MS, and in priority beta interferons, are the following (1) inhibition of the expression of major histocompatibility complex class II molecules, (2) inhibition of metal-loproteases, (3) induction of immunosuppressor cytokines. 

A. Oseltamivir inhibits neuraminidase, an enzyme that cleaves neuraminic acid from oligosaccharides. Neuraminidase activity aids the movement of viral particles through neuraminic acid-rich respiratory secretions and is required for the release of progeny virions. Inhibition of viral DNA polymerase is the mechanism of action of nucleoside analogue antiviral drugs. Interferons do stimulate the JAK-STAT signaling pathway but do not stimulate proliferation of immune cells. Ribavirin inhibits GTP synthesis, and the antiretroviral protease inhibitors (e.g., ritonavir) inhibit HIV protease. 

Interferon alfa-2b (Intron A) is a recombinant DNA product derived from the interferon alfa-2b gene of human white blood cells. Its mechanism of antitumor action involves binding to a plasma membrane receptor but is otherwise poorly understood. Its serum half-life is 2 to 3 hours after parenteral administration. 

While the specific mechanisms of action of interferon-pia and interferon-pib in MS are not fully understood, each interferon has a number of immune-mediating activities (see Section 7.1). A recent review article on multiple sclerosis observed The interferons reduce the proliferation of T cells and the production of tumor necrosis factor a, decrease antigen presentation, alter cytokine production to favor ones governed by type 2 helper T (Th2) cells, increase the secretion of interleukin-10, and reduce the passage of immune cells across the blood-brain barrier by means of their effects on adhesion molecules, chemokines, and proteases [2]. 

Disis ML, Feld JJ Mechanism of action of interferon and ribavirin in treatment of hepatitis C. Nature 2005 436 967. 

Imiquimod (Aldara) is an immunomodulator approved for the treatment of external genital and perianal warts in adults, actinic keratoses on the face and scalp, and biopsy-proven primary basal cell carcinomas on the trunk, neck, and extremities. The mechanism of its action is thought to be related to imiquimod s ability to stimulate peripheral mononuclear cells to release interferon- and to stimulate macrophages to produce interleukins-1, -6, and -8, and tumor necrosis factor- (TNF-k). 

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