Potential of Interferon-α in Solid Tumours

Interferon-alpha (IFNalpha) is a pleiotropic cytokine with direct and indirect antitumour effects. These include prolongation of the cell cycle time of malignant cells, inhibition of biosynthetic enzymes and apoptosis, interaction with other cytokines, and immunomodulatory and antiangiogenic effects. The first clinical trials in solid tumours used crude preparations of natural IFNalpha and demonstrated that tumour regressions in solid tumours and haematological malignancies were possible. Since the advent of genetic engineering technology, recombinant (r) IFNalpha has been widely evaluated in solid tumours. This review discusses the use and potential of rIFNalpha in solid tumours; the first part focuses on malignant melanoma and metastatic renal cell carcinoma (RCC). In the adjuvant treatment of malignant melanoma, rIFNalpha has been tested in randomised trials in more than 6000 patients. High-dosage IFNalpha (> or =10MU) prolongs disease-free survival (DFS) but not overall survival (OS). Low-dosage IFNalpha (< or =3MU) has not been shown to prolong DFS or OS, and current data do not support its use outside clinical trials. The latest United Kingdom Co-ordinating Committee on Cancer Research meta-analysis of ten randomised trials that used adjuvant rIFNalpha has shown that there is a benefit in DFS but not OS. No conclusions can be reached for intermediate-dosage IFNalpha (5 to 10MU) until the mature results of the European Organization for Research and Treatment of Cancer (EORTC) study 18952 are available. In RCC, current evidence does not support the use of adjuvant IFNalpha. In metastatic malignant melanoma and RCC, reported response rates to rIFNalpha are approximately 15%. In a minority of responding patients, however, these responses can be long-standing. In metastatic malignant melanoma, IFNalpha combined with other cytotoxic agents with or without interleukin-2 has achieved high response rates but has not improved survival. In metastatic RCC, intermediate dosages of rIFNalpha should be used and therapy should probably be prolonged (>12 months); response depends on prognostic factors such as good performance status, whereas survival is affected by factors such as low tumour burden. Nephrectomy should therefore be considered in patients with good performance status prior to IFNalpha immunotherapy in advanced RCC, even in patients with metastatic disease. The toxicity of high-dosage IFNalpha and the lack of definite benefit on OS with high- or low-dosage IFNalpha do not support its use outside clinical trials. Data from the ongoing US Intergroup studies, the ongoing EORTC 18991 study (long-term therapy with pegylated IFNalpha) and mature data from EORTC 18952 (intermediate-dosage IFNalpha) will help establish the role of IFNalpha as adjuvant therapy in malignant melanoma.     

Role of Natural Interferon-α Producing Cells (Plasmacytoid Dendritic Cells) in Autoimmunity

The type I interferons (IFNs) have antiviral, cytostatic and prominent immunomodulatory effects, which all are of great importance during viral infections. However, prolonged exposure of the immune system to type I IFN can break tolerance and initiate an autoimmune reaction, eventually leading to autoimmune disease. Recent observations in patients with systemic lupus erythematosus (SLE) have revealed that such individuals have endogenous IFN-α inducers, causing an ongoing IFN-α production and consequently a continuous stimulation of the immune system. These IFN-α inducers consist of small immune complexes (IC) containing DNA or RNA and act on the principal IFN-α producing cell, the natural IFN-α producing cell (NIPC), also termed the plasmacytoid dendritic cell (PDC). The NIPC/PDC is a key cell in both the innate and adaptive immune response but can also, either directly or via produced IFN-α, have a pivotal role in autoimmunity. In this review we summarize recent data concerning NIPC/PDC, including their activation, regulation, function and possible role in autoimmune diseases, especially SLE.     

Could Autoimmunity Be Induced by Vaccination?

Autoimmune reactions to vaccinations may rarely be induced in predisposed individuals by molecular mimicry or bystander activation mechanisms. Autoimmune reactions reliably considered vaccine-associated, include Guillain-Barré syndrome after 1976 swine influenza vaccine, immune thrombocytopenic purpura after measles/mumps/rubella vaccine, and myopericarditis after smallpox vaccination, whereas the suspected association between hepatitis B vaccine and multiple sclerosis has not been further confirmed, even though it has been recently reconsidered, and the one between childhood immunization and type 1 diabetes seems by now to be definitively gone down. Larger epidemiological studies are needed to obtain more reliable data in most suggested associations.     

The Potential Mechanisms Underlying Aspirin-induced Inhibition of Ovarian Tumor Cell Growth

1 IntroductionOvarian cancer remains the most lethal disease of the gynecological cancers. Owing to the lack of an effective screening approach combined with inadequate therapeutic approach for advanced disease, fewer than 25% of ovarian cancers are identified at an early curable stage. Thus these make ovarian cancer a strong candidate for chemoprevention. In 2001, Akhmedkhanov et al. demonstrated a 2-3 folds decrease in epithelial ovarian cancer associated with Aspirin use. These epidemiolo…     

Interfreron-α Alone versus Interferon-α plus Ribavirin in Patients with Chronic Hepatitis C Not Responding to Previous Interferon-α Treatment

OBJECTIVE: To study the effects of monotherapy with leucocyte interferon-alpha (IFNalpha) versus IFNalpha + ribavirin in patients with chronic hepatitis C who were nonresponders to previous courses of recombinant or lymphoblastoid IFNalpha. DESIGN AND SETTING: This was a nonblind randomised study of outpatients at 3 centres in Palermo, Sicily, Italy. PATIENTS AND PARTICIPANTS: We recruited 72 patients (48 males, 24 females), mean age 48.8 +/- 6.6 years (range 31 to 63 years), with biopsy-proven chronic hepatitis C, predominantly genotype 1b. INTERVENTIONS: 24 patients (group A) received IFNalpha 6MU 3 times weekly for 6 months, and 48 patients (group B) received IFNalpha 6MU 3 times weekly + ribavirin 1200 mg/day for 6 months. ALT levels and adverse effects were monitored monthly, and hepatitis C virus (HCV) RNA levels were measured at study entry, at the end of treatment and after a 6-month follow-up. RESULTS: At baseline all patients were HCV-RNA positive and had ALT levels greater than twice normal. Mean post-treatment serum HCV-RNA levels were below baseline in group A, but the virus was eradicated in only 1 patient; 6 patients had normalised serum ALT levels. In group B at end of treatment, 12 patients were negative for HCV-RNA and serum ALT levels were normal in 18. At follow-up, all group A patients had elevated ALT levels and positive HCV-RNA. In group B, 3 patients were still negative for HCV-RNA and 4 had normal ALT. In 4 patients in group B, therapy was suspended because of anaemia, depression and decrease in neutrophil count; a flu-like syndrome was recorded with no frequency difference between groups. CONCLUSIONS: These results suggest that patients with chronic hepatitis C unresponsive to IFNalpha monotherapy could benefit from combination therapy with IFNalpha + ribavirin.     

Clinical Significance of Pharmacokinetic Drug Interactions between Interferon-α and Antineoplastic Drugs

The major problems in chemotherapy are occasional low response rates in patients despite favourable in vitro action, the development of drug resistance and long or short term adverse effects. Therefore, in the past decade efforts have been made to circumvent these problems by combining antineoplastic drugs with biomodulating or cytoprotective agents. Most of the clinically useful drug regimens consist of a cocktail of drugs with different mechanisms of action, and hence different toxicity profiles. Dose-limiting factors in regard to toxicity and therapeutic efficacy predominate, and it is therefore clinically essential to know whether or not a pharmacokinetic drug interaction occurs. The introduction of interferon-alpha (IFNalpha) in chemotherapy is an alternative investigational approach to amplify the cytotoxicity of an antineoplastic drug in order to increase tumour response. Most of the clinical studies reported with IFNalpha provide useful information and identify major pharmacodynamic interactions, but only a few focus on and report potential pharmacokinetic interactions between antineoplastic drugs and IFNalpha in patients. The broad spectrum of antineoplastic drugs whose activity can be enhanced by IFNalpha argues for multiple levels of drug-drug interactions: protein binding (cisplatin), alteration in cellular uptake, modulation of drug target enzymes (dihydropyrimidine hydrogenase) and changes in biotransformation (tretinoin) or excretion. Pharmacokinetic and/or pharmacodynamic interactions may be beneficial (fluorouracil) or sometimes detrimental and coincidental (doxorubicin). This article focuses on observed pharmacokinetic drug interactions between IFNalpha and antineoplastic drugs and discusses possible mechanisms of action.     

Intravenous Immunoglobulin Plus Interferon-α in Autoimmune Hepatitis C

Background: Hepatitis C virus (HCV) may be associated with a variety of autoimmune phenomena causing a therapeutic dilemma for treatment with interferon-α (IFNα), which stimulates autoimmune symptoms, or with corticosteroids, which may lead to an increasing of viral load. To evaluate the possible role of intravenous immunoglobulins (IVIg) in the response of patients treated with IFNα, we administered IVIg plus IFNα and compared the results with a group of patients treated with IFNα alone. Methods: Forty-two patients affected by chronic hepatitis C with probable autoimmune disease were eligible for this open-label, randomised study. All patients tested positively for anti-nuclear antibodies, anti-smooth muscle antibodies, anti-liver/kidney microsomal antibodies and anti-mitochondrial antibodies. Patients were randomly assigned to one of two groups: group A received IVIg at a dosage of 400 mg/kg each day for 5 days, and then 3 MUI of leucocyte IFNα three times a week, while group B received physiological solution followed by the administration of leucocyte IFNα three times a week at the same dosage for 6 months. Complete biochemical response was defined as a sustained normalisation of alanine aminotransferase levels, and complete virological response was defined as complete clearance of virus throughout the entire 6-month follow-up period. Immunological response was measured in terms of Autoimmune Hepatitis (AIH) score, while histological response was based on a reduction in histological activity index (HAI) score. Results: Compared with patients receiving IFNα alone, a higher percentage of patients who received IFNα plus IVIg showed complete virological and histological responses (p = 0.04). More patients in the combination therapy group achieved biochemical and immunological responses, although the differences between the groups were not statistically significant at all time points. Conclusions: Exogenously added Ig might modulate the immune network at various points. We propose that the immunomodulating action of IVIg acts synergistically with IFNα, achieving a better response to IFN treatment in patients with chronic HCV associated with autoimmunity. Data obtained from this preliminary study indicate a positive prospective for the clinical use of gamma globulins in patients with a high probability of autoimmune disorders associated with HCV infection.     

Impact of Three Anti-TNFα Biologics on Existing and Emergent Autoimmunity in Rheumatoid Arthritis and Spondylarthropathy Patients

OBJECTIVE: The objective of this study was to analyze the effects of 3 anti-TNFalpha agents on markers of autoimmunity in rheumatoid arthritis (RA) and spondylarthropathy (SPA) patients. METHODS: First-time anti-TNFalpha biologics (infliximab, etanercept, or adalimumab) were prescribed to 156 RA and 95 SPA (58 ankylosing spondylarthritides, 37 psoriatic arthritides). During 1-2 years of follow-up, clinical, biological [antinuclear (ANA) and anti-double-stranded (dsDNA) antibodies, rheumatoid factors (RF), and anti-cyclic citrullinated peptide (CCP) for RA], and therapeutic data were collected biannually. RESULTS: ANA appeared or ANA and anti-dsDNA titers increased significantly (P < 0.001) more under infliximab than etanercept in both rheumatisms and than adalimumab in RA patients. During the 2-year follow-up, ANA appeared more in RA patients taking adalimumab than etanercept (P = 0.003), but independently of the anti-TNFalpha used; anti-dsDNA titers rarely became positive. Under etanercept or infliximab, ANA and anti-dsDNA were not influenced by the underlying pathology nor were they affected by infliximab intensification over 18 months. Only one case of cutaneous lupus was observed in a patient having IgG anti-dsDNA. The therapeutic responses were independent of ANA and anti-dsDNA titers for all rheumatisms and biologics. In RA patients, RF titers, but not anti-CCP levels, declined with the therapeutic response for all biologics. CONCLUSION: This is the first study that has evaluated the impact of three TNFalpha blockers on ANA and anti-dsDNA antibodies in RA and SPA patients. Autoimmunity was more induced with infliximab than etanercept and to a lesser degree to adalimumab but, more importantly, this emergent autoimmunity was exceptionally associated to clinical manifestations of lupus.     

Interferon-α as antiviral and antitumor vaccine adjuvants: mechanisms of action and response signature

Interferon-α (IFN-α) are cytokines endowed with multiple biologic effects, including activities on cells of the immune system, which are important for inducing protective antiviral and antitumor responses. Studies in mouse models have been instrumental for understanding the immune adjuvant activity of these cytokines and some of their mechanisms of action. In particular, recent studies conducted on both mouse and human models suggest that IFN-α act as effective immune adjuvants for inducing antiviral and antitumor immunity and that the effects of IFN on the differentiation and activation of dendritic cells (DC) play an important role in the induction of protective responses. In spite of the long record of IFN-α clinical use, a few clinical trials have attempted to evaluate the efficacy of these cytokines used as vaccine adjuvants. Recently, studies on the IFN-α signature in cells from patients treated with IFN-α under different modalities and various clinical settings have provided important insights for understanding the in vivo mechanisms of the IFN immune adjuvant activity in humans and may contribute to the identification of molecular markers with a clinical response. These studies further support the interest of evaluating the clinical efficacy of IFN-α when used as a vaccine adjuvant and also suggest that the DC generated in vitro from monocytes in the presence of this cytokine can exhibit a special advantage for the development of effective therapeutic vaccination strategies in cancer patients.     

Interferon-α as angiogenesis inhibitor: Learning from tumor models

Interferon-α (IFN-α), a cytokine with marked therapeutic activity in transplantable tumor models, has been identified as powerful angiogenesis inhibitor. The effects of IFN-α on the vasculature have been mainly attributed to inhibition of basic fibroblast growth factor production by tumor cells or downregulation of IL-8 and vascular endothelial growth factor gene expression. Moreover, IFN-α has direct effects on endothelial cells (EC), including impairment of their proliferation and migration. The gene expression profile induced by IFN-α in EC has recently been defined, and it was found that several genes encoding negative regulators of angiogenesis are upmodulated, thus providing a potential amplification mechanism for this biological activity. The anti-angiogenic effects of IFN-α appear to be associated with increased hypoxia and ischemic necrosis in subcutaneous xenograft models, whereas in transgenic mouse models, IFN-α may simultaneously interfere with both blood vessels and tumor cell proliferation, leading to regression of tumors without necrosis. The consequences of IFN-α therapy on the invasive and metastatic behavior of tumor cells are currently unknown. Finally, as effective anti-angiogenic therapy with IFN-α demands sustained localized production of this cytokine, innovative strategies of targeted delivery of the IFN-α gene into tumors are discussed.     

Combination Therapy with Interferon-α and Ribavirin for Hepatitis C

Combination therapy with ribavirin and interferon (IFN)-α for 6 to 12 months is currently the treatment of choice for chronic hepatitis C infection. The overall sustained response rate to treatment, defined as loss of hepatitis C virus (HCV) from serum 6 months after completion of treatment, is 40%. The indications for treatment are serum HCV RNA positivity, abnormal serum transaminases and the presence of portal fibrosis and/or moderate/severe inflammation. Response rates are lower in genotype 1 than in genotype 2 or 3 and in the presence of a high viral load. Anaemia is the most common adverse event and is due to ribavirin; neuropsychiatric adverse effects due to IFNα lead to premature cessation of therapy in 10 to 20% of patients. The current recommended dose of interferon is 3MU given subcutaneously 3 times a week. However, it is likely that longer-acting pegylated interferons, which may be more effective and can be administered once weekly, will in the future replace currently used IFNα.     

Kinetics of Receptor-Mediated Uptake and Processing of Interferon-α2a and Tumor Necrosis Factor-α by Human Tumor Cells

Abstract

The kinetics of uptake and processing of recombinant human interferon-a₂a (IFN) and recombinant human tumor necrosis factor-a (TNF) were studied in human epithelial rumor cell lines differing in sensitivity to growth inhibition by IFN and TNF. Concentrations of [¹²⁵I]IFN or [¹²⁵I]TNF at the cell surface and internalized by confluent cell monolayers incubated at 37°C were measured as a function of time. Cells incubated with [¹²⁵I]IFN exhibited transient maxima of surface-associated and internalized [^I25I]IFN after 1-2 hr of incubation followed by a steady-state attained after approximately 6 hr of exposure to [¹²⁵I]IFN. Concentration of [¹²⁵I]TNF associated with the plasma membrane displayed a maximum within 20 min of incubation. Internalized radioactivity increased with time and did not achieve a steady state. We analyzed the time-dependent concentrations of membrane-associated and internalized cytokines by use of a compartmental model. This model describes changes in concentrations of free surface receptors, of ligand-receptor complex at the membrane and of internalized ligand and contains a term for receptor recycling. The rate constants for concentration changes were evaluated by fitting model functions to data. The best fits for IFN were obtained without receptor recycling. The best-fit values for the endo-cytotic rate constant (k_tlFN) varied among cell lines from 2.4x10^?4 to 7.8 x10^?4 sec^?1. To obtain fits to time-dependent concentrations of surface-associated and internalized [¹²⁵I]TNF, introduction of a term for receptor recycling was required. Best-fit values for k, _TNF ranged among cell lines from 8.4x10^?4 to 2.5x10^?3 sec^?1. For every cell line, the value of k_lTNF was larger than the value of k_clFN. We tested the significance of these differences by substituting K.IFN ^tor K.TNT ^as fixed parameters in fits to data for TNF and v.v., respectively. Under these conditions, fits were significantly worse. Our data indicate that recycling is insignificant in kinetics of Type-I IFN receptor; recycling is necessary to explain the kinetics of TNF receptor. Upon binding, TNF is taken up by cells faster than IFN and is eliminated from cells more slowly than IFN.     

Molecular Mechanisms of Changes in TNF-α Production by Blood Mononuclears in Chronic Viral Hepatitis C

Chronic viral hepatitis C is associated with decreased production of TNF- by the peripheral blood mononuclear leukocytes irrespective of virus genotype and degree of the morphological activity of the process in the liver. This process positively correlates with the increase in the content of TNF- soluble receptor (molecular weight 55 kDa), which can play a role in the mechanisms of immunopathogenesis of long persistence of hepatitis C virus in the body.__________Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 139, No. 2, pp. 191–195, February, 2005     

The Proinflammatory Cytokine TNF-α -308 AA Genotype is Associated with Polyglandular Autoimmunity

Data regarding polymorphisms of immunoregulatory genes in polyglandular autoimmunity (PGA) are lacking. We have analyzed whether the polymorphism of the proinflammatory cytokine gene TNF-α; -308 and mutations of the autoimmune regulator (AIRE) gene were associated with PGA in adults. Sixty-seven patients with PGA and 209 healthy controls were genotyped by multiplex minisequencing with capillary electrophoresis on an ABI PRISM-310 genetic analyzer. HLA DRB1 typing was performed using polymerase-chain-reaction-amplified DNA hybridized with sequence-specific-oligonucleotide probes (PCR-SSO). The TNF-α; -308*A allele occurred more frequently in patients (0.269) than in controls (0.163, P = 0.008, P_c = 0.016). Also, TNF-α; -308*A carriers were more frequent in patients than controls (47.8% vs. 31.1%, OR = 1.89, 95%CI = 1.19?3.00). The frequency of the AA genotype was increased in PGA (P = 0.014, P_c = 0.042). PGA patients with autoimmune thyroid disease and the TNF-α; -308 AA genotype showed the highest prevalence of thyroid autoantibodies (TPO, P = 0.04; Tg, P = 0.003). HLA-DRB1*03 and TNF-α; -308*A alleles were strongly associated in patients with PGA (87.5%, P_c < 0.00001). The AIRE R257X and 13bpdel mutations were not observed in patients with PGA. The association of TNF-α; -308*A with PGA might be directly or indirectly due to the association with HLA-DRB1*03.     

Production of Late IFN-α Induced by Plasma γ-Globulin Fraction Proteins and Their Metal Complexes

Plasma γ-globulin fraction proteins, copper and zinc cations, and metal complexes they form with human serum γ-globulin induce the production of IFN-α by human blood cells throughout the periods of up to 72 h. Zinc cation-modified protein by 1.6 times (p<0.05) more actively induces late IFN-α than the control γ-globulin; γ-globulin-copper metal complex is 2-fold (p<0.002) more effective than the control protein. The results indicate that functional relationships between the components inducing the production of late IFN-α differ from the effects realized during the early period of induction.     

Potential roles for tumour necrosis factorα during embryonic development

This paper reviews the evidence indicating possible roles for tumour necrosis factor-alpha (TNF) in development. It is proposed that TNF may have essentially three major roles during embryonic development, which may be analogous to its roles in the immune system and during inflammation: a role in programmed cell death; a role as a cellular growth and differentiation factor; and also a role in the remodelling of extracellular matrix, and the regulation of cell adhesion molecules and integrins. The concept of the existence of a cytokine array during embryogenesis, analogous to that occurring in inflammation, is discussed, as well as potential roles for TNF in the induction of ubiquitin; protective mechanisms embryonic cells may employ against TNF-mediated cytotoxicity; and a consideration of the role TNF may play in a free radical theory of development.