Role Of Interferon Alpha Research Articles

Association study of promoter polymorphisms of interferon alpha and beta receptor subunit 1 (IFNAR1) gene and therapeutic response to interferon-beta in patients with multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease described by inflammatory neuronal losses and resultant failures. The disease could abate by interferon-beta (IFN-β) therapy in MS patients. However, the drug response productivity is changeable between patients, and the accurate mechanism of action of the IFN-β is not obvious. The present study aims to investigate the role of interferon alpha and beta receptor subunit 1 (IFNAR1) promoter polymorphisms towards IFN-β treatment response in MS patients. The subjects herein were separated into either responder (n = 57) or non-responder (n = 43) groups according to IFN-β treatment and Expanded Disability Status Scale score. The Sanger sequencing method was used for genotyping. Among nearly 64 Single Nucleotide Polymorphisms (SNPs), we found a significant association between the rs2850015 polymorphism and the responders and non-responders to IFN-β treatment in the recessive model of inheritance (P = 0.02). The results also revealed a significant change in the two groups of responders and non-responders to the treatment for rs36158718 as an Insertion/Deletion (INDEL) (P = 0.02). Moreover, bioinformatic analyses predicted a remarkable role for both rs2850015 and rs36158718 related to the changes of binding affinity of transcription factors and alterations in their alleles. The present study results suggest that the genetic heterogeneity in the promoter region of IFNAR1 could affect the response to IFN-β. However, further studies with a larger sample size are needed to further demonstrate this relationship.

Effectiveness of electrochemotherapy after IFN-α adjuvant therapy of melanoma patients.

BackgroundThe combination of electrochemotherapy with immuno-modulatory treatments has already been explored and proven effective. However, the role of interferon alpha (IFN-α) adjuvant therapy of melanoma patients and implication on electrochemotherapy effectiveness has not been explored yet. Therefore, the aim of the study was to retrospectively evaluate the effectiveness and safety of electrochemotherapy after the previous adjuvant treatment with IFN-α in melanoma patients.Patients and methodsThe study was a retrospective single-center observational analysis of the patients with advanced melanoma, treated with electrochemotherapy after previous IFN-α adjuvant therapy. Five patients, treated between January 2008 and December 2014, were included into the study, regardless of the time point of IFN-α adjuvant therapy.ResultsElectrochemotherapy of recurrent melanoma after the IFN-α adjuvant therapy proved to be a safe and effective treatment. Patients with one or two metastases responded completely. Among patients with multiple metastases, there was a variable response rate. In one patient all 23 metastases responded completely, in second patient more than 85% of all together 80 metastases responded completely and in third patient all 5 metastases had partial response. Taking into account all metastases from all patients together there was an 85% complete response rate.ConclusionsThe study showed that electrochemotherapy of recurrent melanoma after the IFN-α adjuvant therapy is a safe and effective treatment modality, which results in a high complete response rate, not only in single metastasis, but also in multiple metastases. The high complete response rate might be due to an IFN-α immune-editing effect, however, further studies with a larger number of patients are needed to support this presumption.

Factors Affecting Response to Bacillus Calmette-Guérin Plus Interferon for Urothelial Carcinoma in Situ

The unpredictable behavior of carcinoma in situ and its high potential for recurrence and progression make identifying patient characteristics predicting a poor prognosis a priority. We assessed which factors affect the response to bacillus Calmette-Guérin plus interferon-α therapy in patients with urothelial carcinoma in situ. We analyzed data on a subset of 231 patients with carcinoma in situ enrolled in a multicenter, phase II trial of bacillus Calmette-Guérin plus interferon-α therapy for nonmuscle invasive bladder cancer. Analysis included patients who were bacillus Calmette-Guérin naïve and those with previous exposure to failed bacillus Calmette-Guérin therapy. We evaluated factors potentially affecting the bacillus Calmette-Guérin plus interferon-α response, including patient age, gender, tumor stage, multifocality, prior tumor stage, the previous bacillus Calmette-Guérin failure pattern, courses and maintenance, and prior chemotherapy. The complete response rate at 3 and 6 months in naïve vs previously failed bacillus Calmette-Guérin cases was 76% and 70% vs 76% and 66%, respectively. The 24-month disease-free rate was decreased in the 53 patients with a history of 2 or more failed bacillus Calmette-Guérin courses vs that in the 71 with a history of 1 failed course and bacillus Calmette-Guérin naïve patients (23% vs 57% and 60%, respectively). The 22 patients with refractory carcinoma in situ had the worst outcome of a 23% disease-free rate at 24 months while the 59 with relapse within 1 year had an intermediate outcome of 42% vs 59% in the 33 with relapse after 1 year. Patients with a history of papillary disease did better than those without such a history (p=0.019). Factors associated with a poor response to bacillus Calmette-Guérin plus interferon-α therapy in patients with carcinoma in situ are prior tumor stage, 2 or more prior bacillus Calmette-Guérin failures and a bacillus Calmette-Guérin failure pattern.

The role of interferon alpha in initiation of type I diabetes in the NOD mouse

Type 1 diabetes (T1D) is an autoimmune disease in both humans and the nonobese diabetic (NOD) mouse, in which the insulin-producing-cells of the pancreatic islets are destroyed by a beta islet cell-specific T cell immune response. We recently reported that interferon (IFN)-α is an early trigger of the T1D process in NOD mice. Here, we show that extensive blockade of IFN-α action by a monoclonal antibody specific to IFN-α receptor 1 results in nearly complete prevention of T1D in NOD mice. Whether professional IFN-α producing cells, plasmacytoid dendritic cells (pDCs), are responsible for the initiation of T1D has been unclear. Here we demonstrate that depletion of pDCs in NOD mice by a specific mAb given at 15-25 days of age significantly delays the onset and decreases the incidence of T1D. These findings indicate that pDC and pDC-derived IFN-α are the prime initiators of the pathogenesis of T1D in NOD mice.

Challenges in understanding Sjögren's syndrome - improved insights into the pathogenesis generate hope for innovative therapies?

The reviews in this series on Sjögren syndrome provide an up-to-date summary and perspectives on the pathogenesis of this interesting entity with glandular and frequently systemic manifestations, the value of preclinical models, and our current understanding of therapeutic approaches. The last of these includes what has been learned from trials blocking tumor necrosis factor and, more recently, anti-CD20 therapy. Potential therapeutic targets, such as blockade of the B cell-activating factor, the role of interferon-alpha, and targeting CD22, are discussed.

Safety and Efficacy of Intravesical Bacillus Calmette-Guérin Plus Interferon α-2b Therapy for Nonmuscle Invasive Bladder Cancer in Patients With Prosthetic Devices

Patients with bladder cancer who have prosthetic devices, such as a cardiac pacemaker, artificial heart valve or orthopedic hardware, and who undergo intravesical bacillus Calmette-Guérin therapy are theoretically at higher risk for complications, including bacterial seeding of pacemaker wires or orthopedic hardware, and at further risk for infective endocarditis. We assessed the safety and efficacy of bacillus Calmette-Guérin plus interferon α-2b therapy in patients with nonmuscle invasive bladder cancer and a pacemaker, artificial heart valve or orthopedic hardware. We evaluated 1,045 patients with nonmuscle invasive bladder cancer enrolled in a multicenter American phase II trial of bacillus Calmette-Guérin plus interferon α-2b therapy, including 143 with a prosthetic device (pacemaker in 87, artificial heart valve in 13 and orthopedic hardware in 43). Weekly physician toxicity assessments and standard adverse effect reporting were done. No patient had infective endocarditis or hardware infection. One patient with a pacemaker, 2 with orthopedic hardware and none with an artificial heart valve required treatment cessation for fever greater than 102.5F. All defervesced within 24 hours and had no long-term sequelae. Due to intolerable, nonlife threatening side effects 12 patients with a pacemaker, 2 with orthopedic hardware and 1 with an artificial heart valve stopped treatment. Of the remaining patients with a prosthesis 99 and 24 stopped treatment due to intolerable, nonlife threatening and serious side effects, respectively. Patients with a pacemaker, artificial heart valve or orthopedic hardware were no more likely than the general population to have infection or fever, or discontinue treatment due to side effects. These patients should not be excluded from intravesical bacillus Calmette-Guérin plus interferon α-2b therapy for nonmuscle invasive bladder cancer.

Moyamoya in a Child Treated With Interferon for Recurrent Osteosarcoma

Moyamoya is a cerebral vasculopathy of unknown etiology rarely described as a late effect after the treatment of childhood cancer. We describe a 12-year-old female who developed moyamoya after the completion of systemic chemotherapy, surgery, and adjuvant interferon alpha for osteosarcoma with pulmonary metastases. Given the importance of characterizing late effects after the treatment of childhood cancer, the potential role of interferon alpha in the development of moyamoya is discussed.

ChemInform Abstract: The Role of Interferon-Alpha in the Treatment of Myeloproliferative Disorders

The interferons are cytokines with a wide array of biological properties. In hematological malignancies the most used IFN class is -alpha; it has been used for thirty years but the mode of action is still not absolutely clear. Nevertheless, the benefits of IFN-alpha for the treatment of CMD have been described in particular for CML and less for PV, ET and MMM. IFN-alpha is presently considered the golden standard of therapy for CML patients not eligible for SCT; the antileukemic effect has been well documented by hematological and cytogenetic response. The survival advantage for IFN treated patients is remarkable in comparison with patients treated with conventional chemotherapy. Recently, the combination IFN-alpha plus Ara-C has demonstrated to increase the rate of major cytogenetic response and to prolong survival. To date, there is not a generally accepted treatment for ET, PV and MMM, which can reduce the risk of thromboembolism and/or hemorragic events. In several subsets of ET and PV patients, IFN-alpha can be considered as first line therapy. IFN-alpha is usually associated with the development of early and later side effects, that reduce the enthusiasm for its use. In the future PEG-IFN-alpha would improve the quality of life of IFN-treated CMD patients.

Pegylated human interferon alpha 2a does not induce depression-associated changes in mice

Interferon (IFN) alpha proteins are proinflammatory cytokines having immunomodulating and antiviral properties. States during which cytokine systems are activated (e.g., during viral infection or during treatment of chronic hepatitis C and various malignancies with IFN alpha, etc.) can be associated with depression-like syndromes or even full-blown depressive episodes. Therefore, the role of IFN alpha and other cytokines in the pathogenesis of depressive disorder (“cytokine hypothesis of depression”) has been assessed for many years with contradictory results. We have investigated whether intraperitoneal administration of high doses (up to 600 µg/kg body weight) of pegylated, recombinant human IFN alpha 2a in mice induces changes known to be associated with depression using three different readouts: behavior in a model of despair (Porsolt swim test), presence of anhedonia (sucrose preference test), and sensitivity of the hypothalamic–pituitary–adrenal system (dexamethasone suppression test). We also assessed potential IFN-induced changes in gene expression in the liver. In none of the performed experiments, depression-associated effects could be found despite very high serum levels of IFN-induced antiviral activity compared to levels measured in hepatitis C virus (HCV) patients treated routinely with pegylated recombinant human IFN alpha 2a. The lack of such expected effects is probably due to the fact that pegylated human recombinant IFN alpha 2a does not activate the murine class I IFN receptor. Our results do not support the hypothesis that administration of recombinant pegylated human IFN alpha to mice produces a robust model of depression.

Interferon-α and -β in kidney inflammation

Type I interferons, interferon-alpha and interferon-beta, are central regulators of antiviral immunity and autoimmunity, but little is known about their role in renal inflammation. Recent work documents that viral nucleic acids are potent inducers of interferon-alpha and interferon-beta in mesangial cells and glomerular endothelial cells. This review discusses the available evidence on the role of interferon-alpha and interferon-beta in viral nephropathies, in kidney diseases triggered by extrarenal infections, in lupus nephritis, and in other kidney disease entities. Finally, we propose areas of research that may help unravel the roles of type I interferons and interferon-related genes in the renal field.

Altered chemotactic response of myeloid and plasmacytoid dendritic cells from patients with chronic hepatitis C: role of alpha interferon

Dendritic cell (DC) frequencies in the blood of patients with chronic hepatitis C virus (HCV) infection have been shown to be reduced significantly compared with those in healthy individuals. There is a further reduction of circulating myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) in HCV patients receiving alpha interferon (IFN-alpha)-based antiviral therapy. Altered homing behaviour of DCs may be a possible mechanism for their 'loss' in peripheral blood in these clinical conditions. Systemic chemokine levels were measured by ELISA. Phenotypes and migratory properties of MDCs and PDCs from HCV patients were analysed by flow cytometry and chemotaxis assay. Compared with healthy controls, HCV patients had increased serum levels of inflammatory and constitutively expressed chemokines. Spontaneously generated MDCs from HCV patients were less mature, and both MDCs and PDCs showed intrinsic activation of receptors for inflammatory chemokines, thus suggesting an increased propensity to migrate towards inflammatory sites. IFN-alpha treatment in vitro induced MDC maturation and skewed the migratory response of both MDCs and PDCs towards chemokines expressed constitutively in secondary lymphoid organs. In conclusion, our results hint at altered homing behaviour of DCs during chronic HCV infection. IFN-alpha therapy may redirect DC migration from inflamed hepatic portal areas towards secondary lymphoid tissue.

Interferon-alpha (IFN-a) Given Alone to CML Patients with Undetectable Disease after Imatinib (IM) Is Able To Maintain Their Complete Molecular Remission after IM Discontinuation.

Cytotoxic lymphocytes (CTLs) which recognize distinct antigenic peptides on CML cells, contributed greatly to the cure after allografting. Previously, BCR-ABL specific peptides and the PR1 non-apeptide, were found to elicit a CML-specific CTL response (Molldrem, 1996/1997; Bocchia 1996, Clark 2001). PR1 is a peptide derived from myeloblastin (MBN), also known as proteinase 3. MBN is abundantly expressed in azurophil granules of normal myeloid cells and is substantially overexpressed in certain immature myeloid leukemia cells where it may be important for the maintenance of a leukemic phenotype. PR1-specific CTLs (PR1-CTLs) lyses and inhibits the proliferation of CML cells but not of normal myeloid precursors. The association between the emergence of PR1-CTLs and the response to IFN-a in vivo strongly implied that IFN-a can induce remissions via induction of a CML-specific PR1-CTLs response (Molldrem et al, 2000). Recent data demonstrating a failure of IM to kill cell cycle-arrested CML precursors advice us to be attentive to arising escape mechanisms of even chronic phase CML; therefore the sequential combination therapy of IFN-a given alone to CML patient with undetectable disease achieved with IM, might be more effective than any current monotherapy. We have treated until now 4 CML patients who had undetectable residual disease for at least one year after IM therapy. The patients discontinued IM and started IFN-a at the dose of 3 M/U/m2 weekly. The median duration of IM therapy was 58 (range, 31–68) months before IM interruption. At a median follow-up of 5 months (range, 3–12 months) after IFN-a, all patients still have an undetectable level of BCR-ABL transcript. The details of patients characteristics will be discussed during the presentation. These preliminary results demonstrate that treatment with low dose IFN-a in CML patients with undetectable disease is feasible and did not lead to a molecular relapse. We are starting a large prospective randomized study to evaluate the role of IFN-a employed alone after 1 year of complete molecular remission achieved with IM (Arm A) vs contination of IM alone (Arm B). The main objective of this study is to verify the real effect of the immune modulation following IFN-a in CML patients with undetectable disease.

The role of interferon-alpha in the treatment of chronic myeloid leukemia

Biological agents have long been used in the treatment of cancer, and interferon-alpha was the first human cytokine to be widely studied in this setting. Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder for which interferon-alpha has demonstrated substantial activity. In the 1980s interferon-alpha became first-line therapy for patients with chronic-phase CML, not eligible for allogeneic stem cell transplantation. Following the discovery of the leukemic oncogene BCR/ABL and its causal association with CML, the potent BCR/ABL tyrosine kinase inhibitor imatinib mesylate was developed. Imatinib proved to be superior to interferon-alpha in all outcome measures, making imatinib the new standard of care for patients with CML. There is both clinical and laboratory evidence suggesting imatinib therapy alone is not curative in CML, whereas IFN has induced a low but reproducible curative effect in some patients. This unique activity may be the basis for the reincorporation of IFN into the management of CML. These observations may be best explained by imatinib's negligible activity against the leukemic stem cell (LSC) population. This review discusses the history of interferon-alpha in the treatment of CML, the evolution of molecularly targeted therapies, and some of the lessons we have learned from years of informative research in CML. It also explores the new challenge of managing minimal residual disease in the imatinib era, and addresses the promising role for LSC-directed therapies in the future treatment of CML.

A large first-line, randomized, dose-finding, phase II study on thymosin-alpha 1 (T-alpha 1) plus dacarbazine (DTIC) with or without interferon-alpha (IFN-alpha) compared to DTIC plus IFN-alpha in stage IV melanoma. Tumor response and survival results

8535 Background: Thymosin alpha 1 is an immunomodulatory compound that promotes T cell maturation and upregulates T cell response. Ta1 showed clinical potential benefit in a previous pilot study in melanoma patients. Methods: Phase II, randomized, stratified, open-study testing different doses of Ta1 in association with DTIC and IFNa, as first-line therapy in stage IV melanoma patients (AJCC 2001) without brain metastases. The primary endpoint is tumor response and secondary overall survival. Four arms were initially planned: DTIC + IFNa + 1.6 or 3.2 mg Ta1, DTIC + 3.2 mg Ta1, and DTIC + IFNa (control group). A dose-response effect in a preliminary analysis on 142 patients led to the addition of a fifth arm with DTIC + IFNa + 6.4 mg Ta1. Ninety-five patients were allocated to each arm to test the hypothesis that P0 = 0.05 vs the alternative hypothesis that P1 = 0.15 (alpha = 5%, within-group statistical analysis, power = 95%). The five groups were analyzed independently one from the other, nine responses representing the minimal threshold for rejecting the null hypothesis Patients received DTIC (800 mg/m2) iv on day 1, Ta1 (1.6, 3.2 or 6.4 mg) sc on days 8–11 and 15–18, and IFNa (3 MIU) sc on days 11 and 18 during 28d cycles. Tumor response was evaluated every two cycles according to RECIST criteria, utilizing a central review. Results: Data of 483 pts (62% M1c; 25% M1b; 13% M1a) from 64 European sites are given in the table . Thirteen and 10 confirmed responses were observed for the DTIC+ 3.2 mg Ta1 and DTIC+ IFNa + 3.2 mg Ta1 arms (vs 5 in the control group) thus rejecting the null hypothesis that P0 = 0.05. No additional toxicity with the addition of Ta1 was observed. Conclusions: These results suggest a potential survival advantage with the addition of Ta1 to ‘standard‘ treatment of stage IV melanoma patients. The role of Interferon alpha in this therapeutic association is debatable. [Table: see text] [Table: see text]

Chemoimmunotherapy with 5-fluouracil, leucovorin and interferon alpha-2b as adjuvant therapy after surgery in Gastric Carcinoma patients

4581 Background: The main treatment of Gastric Carcinoma(GC) is Surgery, but 5 years recurrence risk is 70% and mortality 50%. So that, effective adyuvant therapy, like chemotherapy, is needed to impact on survival ; results, however have been inconsistent at best. Inmunotherapy with interferon alpha, in gastric carcinoma, has only been employed in metastatic disease. The objective of this study was evaluate chemoimmmunotherapy role of interferon alpha - 2b,5-FU and LCV as adjuvant therapy in GC Methods: This is a randomized prospective study. Beginning 2/Oct /97 and finalizing 31/march/2005. Patiens with gastric adenocarcinoma, clinical stages II, III and non metastatic IV, after gastrectomy, without cancer antecedent were included. Treatment groups were assigned at random: Group A: 5-FU: 400 mg/m2, days (1–3), leucovorin: 50 mg. days (1–3), interferon alpha - 2b: 5x10^6 units sq, every other day, days (1–15). Group B: 5-FU, LCV without interferon alpha, at the same doses. Nine (9) monthly cycles were aplied. Clinical and paraclinical follow up was made appropriately. Statistic analysis was performed by Kaplan Meier method. Results: 52 patients were studied, 25 in group A and 27 in group B. Both of them had similar characteristics in median age, sex, histology, differentiation grade, gastric location, clinical stage: A: II: 28%, III: 72% (IIIB: 56%). B: II: 29,6%, III: 70% (IIIB: 55%).General survival (SG) analysis: Mean SG (%): A: 64%. B: 18,5%. Mean SG (months): A: 68,5 m. (CI 95%: 59–78,15). B: 27,98 ( CI 95%: 18,92–37,04). Survival curves comparison, minimum until 5 years: Log Rank, Breslow, Tarone Ware: P<0,00001, all of them in favor to group A. Mortality: Total:31/52: 59,6%. A: 36%. B: 81,48% (P<0,05). Disease free survival (DFS) analysis: Mean DFS (%): A: 52%. B: 18, 52%. Mean DFS(months): A: 58,85m (CI 95%: 47,4–70.3). B: 24,98m (CI 95 %: 15,3–34.6). DFS curves comparison: Log Rank: 0,0008. Breslow: 0,0003. Tarone Ware: 0,0004. All of them in favor to group A. Recurrence (%): Total: 34/52:65%. A: 48%. B: 81,48% ( P <0,05). Conclusions: This is the first study of adjuvant chemoimmunotherapy (CI) that includes interferon alpha - 2b in GC. This study shows CI with 5-FU, LCV and interferon alpha -2b is effective as adjuvant treatment in GC. No significant financial relationships to disclose.

P.322 The role of interferon alpha for limited growth of hepatitis A virus in cell culture

P.322 The role of interferon alpha for limited growth of hepatitis A virus in cell culture

Interferon Alpha 2b as Maintenance Therapy Improves Outcome In Follicular Lymphoma

The role of interferon alpha as maintenance therapy in follicular lymphoma (FL) remains unsolved. We started a controlled clinical trial to assess if interferon alpha 2b could improve outcome, measured with event free survival (EFS) and overall survival (OS) in patients with FL in complete remission after chemotherapy based anthracyclines and adjuvant radiotherapy to sites of initial bulky disease. Three hundred and eighty four patients in complete response after 6 cycles of CEOP-Bleo (cyclophosphamide, epirubicin, vincristine, prednisone and bleomycin, at standard doses), and adjuvant radiotherapy when necessary, were randomized to received Interferon alpha 2b, three times a week for 1 year or no treatment (control group). Median follow up was 9.8 years (range 7.0 - 15 years); actuarial curves showed that EFS was 64% (95% confidence interval (CI) 56 - 71%) in patients treated with interferon that was statistically significant to patients in the control group: 35% (95% CI: 28 - 43%) (p < .01). OS was also statistically significant: 81% in patients treated with interferon (95% CI: 74 - 93%) and 57% (95% CI: 50 - 63%) in the control group (p < .001). Toxicity was mild, all patients received the planned dose of interferon on time. The use of aggressive chemotherapy and maintenance therapy with interferon alpha 2b in follicular lymphoma improved outcome; more than 60% of patients remain alive free of disease at longer follow-up.

Tetrahydrobiopterin: Mediator of Endothelial Protection

During the past twenty years, the essential role of endothelial cells in preservation of vascular homeostasis has been well established.1,2⇓ Protection of the vascular endothelium against harmful influences of circulating substances including excessive levels of lipids has been a major therapeutic approach in prevention of atherosclerosis. While endothelial dysfunction, defined as a loss of biologically active nitric oxide (NO) produced in the endothelium, has been recognized as a prime target for prevention and reversal of atherosclerotic process, identification of exact molecular mechanisms responsible for the loss of endothelial NO have been more difficult to determine. In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Alp et al3 report a series of elegant studies on genetically modified mice supporting the concept that NO synthase cofactor, tetrahydrobiopterin (Figure 1), is an important vascular protective molecule. The beneficial effect of tetrahydrobiopterin in apolipoprotein E (ApoE)-deficient mice appears to be mediated by preservation of endothelial nitric oxide synthase (eNOS) activity and production of nitric oxide in endothelial cells. The major steps of tetrahydrobiopterin biosynthesis. GTP=guanosine 5′-triphosphate. See page 445 In the early 1990s it was recognized that in the presence of suboptimal concentrations of tetrahydrobiopterin, activation of purified neuronal nitric oxide synthase (nNOS) causes “uncoupling of NOS” with subsequent increase …

The role of alpha interferon

The absence of a basic understanding of the biology of giant cell lesions makes their management both challenging and controversial. There are no biologic markers of clinical activity. The natural history of giant cell lesions is unclear. We are not even confident of the tumor cell of origin. At our institution, treatment of giant cell lesions is dictated by their clinical behavior, that is, aggressive versus nonaggressive. The purpose of this presentation is to review the rationale for selecting alpha-interferon to manage aggressive giant cell lesions and to summarize our results to date.

Long-term high-dose interferon-alpha therapy delays Hepadnavirus-related hepatocarcinogenesis in X/myc transgenic mice.

The role of interferon-alpha (IFN-alpha) remains unclear in prevention of virus-induced hepatocellular carcinoma in humans. We have investigated it herewith in the X/myc transgenic mouse model of Hepadnavirus-related hepatocarcinogenesis because of upregulation of c-myc oncogene in the liver. We have demonstrated that IFN-alpha can downregulate dose-dependently hepatocyte proliferation and c-myc overexpression at early premalignant stages, while it does not affect either hepatocyte apoptosis or telomerase activity at these steps. However, continuous and long-term administration of IFN-alpha dose-dependently delays tumor onset in dysplastic livers and increases overall survival of animals, more efficiently whether started before the onset of dysplasia. The present study therefore highlights that early preventive administration of IFN-alpha can slow down evolution towards hepatocellular carcinoma via repression of c-myc and hepatocyte proliferation at premalignant steps in experimental c-myc-induced hepatocarcinogenesis. However, the transient effect observed in this study emphasizes a need to clarify the possible mechanisms of acquired resistance and subsequent therapeutic escape. Our experimental model may be a pertinent tool to explore antioncogenic properties of IFN-alpha in human cirrhotic livers showing c-myc upregulation.