Interferon alfa mechanisms

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 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. 

Clinical pharmacology The mechanism by which interferon alfa-2a recombinant, or any other interferon, exerts antitumor or antiviral activity is not clearly... 

Hypothyroidism occurs more often than hyperthyroidism, and spontaneous resolution is expected in almost 60% of patients with or without interferon alfa withdrawal. Finally, female sex and the presence of baseline thyroid autoimmunity were confirmed to be the most significant risk factors. The mechanisms of interferon alfa-induced thyroid dysfunction are not yet fully clarified. Although an autoimmune reaction or immune dys-regulation are the most likely mechanisms, a direct inhibitory effect of interferon alfa on thyrocytes should be considered in patients without thyroid antibodies. 

More direct interference with glucose metabolism cannot be excluded. Interferon alfa can reduce the sensitivity of peripheral tissues or liver to insulin and accelerate the destruction of stimulated pancreatic beta-cells (540,541) this could be a possible mechanism in patients not exhibiting islet cell antibodies. This is also in keeping with rare instances of induction or exacerbation of type II noninsulin dependent diabetes mellitus (SEDA-19, 335). 

Several mechanisms involved in the pathogenesis of interferon alfa-induced psychiatric adverse effects have been hypothesized (Loftis 175), but the mechanisms by which interferon alfa enters the brain to produce neurotransmitter changes are unclear. In a prospective study in 48 patients who received adjuvant interferon alfa for malignant melanoma there was a positive correlation between the increase in serum concentration of soluble ICAM-1 and depression scores the authors suggested that induction of soluble ICAM-1 by interferon alfa increased the permeability of the blood-brain barrier, allowing the drug to enter the brain more readily (358). 

The mechanism by which the systemic administration of interferon alfa produces neurotoxicity is unclear, and might result from a complex of direct and indirect effects involving the brain vasculature, neuroendocrine system, neurotransmitters and the secondary cytokine cascade with cytokines which exert effects on the nervous system, for example interleukin-1, interleukin-2, or tumor necrosis factor alfa (363). Whether a clinical effect is directly mediated through the action of a given cytokine or results from a secondary pathway through the induction of other cytokines or second messengers is difficult to determine. 

Mild liver dysfunction, hypophosphatemia, and hypomag-nesmia are the most common laboratory abnormahties caused by aldesleukin (76,77). About 20% of patients develop mild to severe intrahepatic cholestasis with reversible and dose-dependent rises in bilirubin and alkahne phosphatase while serum transaminases were only shghtly increased (4,78). Recurrence of cholestasis after aldesleukin rechallenge was not always observed (79). The mechanism of aldesleukin-induced intrahepatic cholestasis is unknown, but it might be mediated by activation of Kupfer cells and the subsequent release of cytokines (SEDA-20, 335). Focal fatty infiltrates of the liver mimicking metastases were also reported in a patient receiving both aldesleukin and a short course of interferon alfa (80). 

During the first days of treatment, virtually all patients have a flu-hke sjmdrome with fever, chills, tachycardia, malaise, headache, arthralgias and myalgias, but tachyphylaxis usually develops after 1-2 weeks of treatment (20). Late febrile reactions are rarely noted (21). Although the severity increases with the dose, the flu-hke syndrome is rarely treatment-limiting and it can be partly prevented by the prophylactic administration of paracetamol (acetaminophen). The acute release of fever-promoting factors, for example the eicosanoids, IL-1, and TNF alfa, secondary to interferon alfa is the suggested mechanism. 

Interferon alfa was also suspected to be involved in one case of biopsy-proven bronchiolitis obliterans-organizing pneumonia (41). Clinical symptoms of pneumonitis appeared 3-12 weeks after the onset of interferon alfa therapy, and after withdrawal of treatment they usually completely resolved, either spontaneously or after a short course of glucocorticoid treatment. Immune-mediated pulmonary toxicity involving the activation of T cells was considered as a likely mechanism. The uncommon features of bronchiolitis obliterans-organizing pneumonia have been reported in three other patients who received interferon alfa together with ribavirin or cytosine arabino-side (42,43). 

Although the mechanism of this adverse effect was purely speculative, it was suggested that interferon alfa might have induced a reaction similar to the immunopathologi-cal mechanism involved in serositis associated with systemic lupus erythematosus. 

Possible mechanisms need to be clarified. Since thyroid autoantibodies are detected in most patients who develop thyroid disorders, the induction or exacerbation of preexisting latent thyroid autoimmunity is the most attractive hypothesis. This is in accordance with the relatively frequent occurrence of other autoantibodies or clinical autoimmune disorders in patients who develop thyroid disorders (168). However, 20-30% of patients who develop thyroid diseases have no thyroid antibodies, and it is thus not yet proven that autoimmunity is the universal or primary mechanism. In fact, there were subtle and reversible defects in the intrathjroidal organification of iodine in 22% of antithyroid antibody-negative patients treated with interferon alfa (169). In addition, the acute systemic administration of interferon alfa in volunteers or chronic hepatitis patients reduces TSH concentrations (SED-13,1093) (170), and in vitro studies have suggested that interferon alfa directly inhibits thyrocyte function (SED-13, 1093) (171). Finally, the thyroid autoantibody... 

Autoimmunity was suggested as a likely mechanism, with HLA-DR4 haplotype and/or islet cell antibody (ICA) positivity at the time of diagnosis in several patients. Because the induction of ICA antibodies in patients treated with interferon alfa has never been otherwise demonstrated (21), the triggering, rather than the induction, of a latent autoimmune phenomenon in patients with a genetic susceptibility is probable (192). 

Rapid exacerbation (1-21 days) or delayed (3-38 months) de novo appearance of immune hemolytic anemia has been reported after initiation of interferon alfa treatment in nine patients with lymphoproliferative disorders (220). However, this rare event was identified in only 1% of 581 patients receiving interferon alfa alone or as part of a chemotherapeutic regimen for chronic myelogenous leukemia (221). A mechanism close to that observed with alpha-methyldopa has been thought to be involved (208). The direct antiglobulin test was positive in 32% of 28 chronic myeloid leukemia patients after a median of 1 year of treatment with interferon alfa (222). 

Although inhibition of stem-cell proliferation is the most likely mechanism of hematological toxicity, increased platelet hepatic uptake has been suggested to account for thrombocytopenia (227). Raised serum thrombopoietin concentrations were found in patients with interferon alfa-induced thrombocytopenia (228). However, there is evidence that serum thrombopoietin concentrations in patients who have had thrombocytopenia during interferon alfa treatment for chronic viral hepatitis C either do not increase (in patients with compensated cirrhosis) or increase only moderately and less than expected (in non-cirrhotic patients) (229). The authors proposed that interferon alfa impairs liver production of thrombopoietin, raising the possibility of testing thrombopoietin administration in patients with severe thrombocytopenia before or during treatment with interferon alfa (230). 

The mechanism of interferon alfa nephrotoxicity is probably multifactorial and may involve a direct... 

Sexual complaints attributed to interferon alfa, namely decreased hbido, impotence, or erectile failure, are usually concomitant to other neuropsychiatric symptoms, and cases of reversible impotence are anecdotal (315). The mechanisms accounting for these adverse effects are unclear, and changes in sex hormone concentrations have not been consistently reported. In one study in healthy women, interferon alfa produced falls in serum progesterone and estradiol concentrations (316), but neither impairment of libido nor impairment of fertility has apparently been reported in women. No evidence of gonadal toxicity or sexual dysfunction was found in 43 men with hairy cell leukemia who received interferon alfa for 2-12 months compared with 33 patients who... 

These cases do not formally show a causal relation with interferon alfa, and at best they suggest that an IgE-mediated reaction is probably not the cause of hypersensitivity reactions to interferon aha. In the first case, the mechanism may have been similar to that observed with angiotensin-converting enzjme inhibitors. 

Isolated reports of Candida esophagitis or Pneumocystis proved Pneumocystis carinii) infections in immunocompetent patients and the possible decrease in CD4-I- T cells with or without opportunistic infections in several HIV-infected patients (SED-13,1097) (379) suggest that unexpected immunosuppressive effects of interferon alfa can occur. An autoimmune destruction of CD4 cells in patients with a particular HLA haplotype has been proposed as a possible mechanism (380). One patient also had an acute and fatal acute precipitation of infection with Entamoeba histolytica (SEDA-22, 403). However, the available evidence is still very limited and no firm conclusion can be drawn on a possible association between interferon alfa treatment and a fall in CD4 cell count or an immunosuppressive effect. 

A 44-year-old woman received interferon alfa 6 MU/ day for relapse of chronic myeloid leukemia 7 years after successful bone marrow transplantation. About 2 years later, interferon alfa was withdrawn because of diffuse erythematous skin lesions with discoid lupus erythematosus on skin biopsy and severe dysphagia with esophagitis and pseudomembranes at endoscopy. Fever, bilateral pulmonary infiltrates, and respiratory distress syndrome subsequently developed, and she required mechanical ventilation. An open lung biopsy showed features of chronic pulmonary graft-versus-host disease. All her symptoms completely resolved with ciclosporin and corticosteroids. An infectious cause was ruled out. 

In contrast to previous claims, even low-dose interferon beta-lb can produce severe local reactions and cutaneous necrosis, with no recurrence after interferon alfa injection and expected better tolerance to interferon beta-la (52-55). The mechanisms of interferon beta-induced local skin reaction might involve a local vascular inflammatory process or platelet-dependent thrombosis, but positive intracutaneous tests to interferon beta have also been found (56). 

Ribavirin accnmnlates in erythrocytes, resnlting in hemolysis by an nnknown mechanism, perhaps related to oxidative damage to the erythrocyte membrane. Time-dependent and dose-dependent hemolytic anemia (eventnaUy associated with hyperbilirubinemia and a high reticnlocyte connt) is the only major toxic effect associated with oral or intravenons ribavirin and is reversible on withdrawal. There was a fall in hemoglobin concentrations below 10.0 g/dl in 9% of patients with hepatitis C treated with ribavirin and interferon alfa (6,7). 

Kirkwood JM, Bender C, Agarwala S, et al. Mechanisms and management of toxicities associated with high-dose interferon alfa-2b therapy. J Clin Oncol 2002 20 3703-3718. 

Interferon alfa-2b is an immnnomodnlator. Interferon alfa-2b inhibits virus replication in virns-infected cells and suppresses cell proliferation althongh the exact mechanism of action of ribavirin is not know, it has antiviral inhibitory activity against respiratory syncytial virns, influenza virus, and herpes simplex virus. It is indicated in the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with alpha interferon or who have relapsed after alpha interferon therapy. 

The mechanism of action of the interferon alfa-2a, recombinant is discussed as under ... 

Bajetta E, Di Leo A, Zampino MG, Sertoli MR, Cornelia G, Bardugni M et al (1994) Multicenter randomized trial of dacarbazine alone or in combination with two different doses and schedules of interferon alfa-2a in the treatment of advanced melanoma. J Clin Oncol 12 806-811 Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392 245-252 Baselga J, Albanell J, Molina MA, Arribas J (2001) Mechanism of action of trastuzumab and scientific update. Semin Oncol 28 4-11... 

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