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At least 271 records · Page 15Linked to original sources
PubMed2004

Racial differences in responses to interferon-beta-1a in chronic hepatitis C unresponsive to interferon-alpha: a better response in Chinese patients.

Re-treatment with interferon-alpha alone for chronic hepatitis C nonresponders to interferon-alpha monotherapy is almost ineffective. This multicentre, randomized, parallel-group, dose-finding study evaluated the efficacy of interferon-beta-1a in the treatment of chronic hepatitis C patients unresponsive to interferon-alpha. A total of 267 patients were randomized to one of four groups: subcutaneous interferon-beta-1a 12 MIU (44 microg) or 24 MIU (88 microg) administered three times weekly or daily. Patients were treated for 48 weeks and then followed up for an additional 24 weeks. There was a trend towards a dose-response relationship regarding virological [loss of detectable serum hepatitis C virus (HCV) RNA] and biochemical response (normalization of serum alanine aminotransferase). Overall, 22 patients (8.3%) had a virological response at the end of treatment; nine patients (3.4%) had a sustained virological response (SVR). Strikingly, 21.7% (5/23) of Chinese patients achieved SVR. Univariate analysis revealed that race was the only variable related to SVR [odds ratio (OR) 16.6; 95% CI 4.1-67.3; P < 0.0001]. Multiple logistic regression analysis also confirmed that more Chinese patients achieved SVR than non-Chinese patients (OR 12.3; 95% CI 2.6-59.3; P = 0.0017). In addition, complete clearance of HCV-RNA occurred earlier in Chinese than in non-Chinese responders (median 2 vs 30 weeks; P = 0.020). Thirty-six patients were withdrawn from treatment because of adverse events. Most adverse events were mild or moderate in severity. In conclusion, interferon-beta-1a provided considerable clinical benefit in Chinese patients with chronic hepatitis C unresponsive to interferon-alpha. The evaluation of interferon-beta-1a in this setting is progressing.

Adolescent↗
PubMed2003

Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group.

PURPOSE: Somatostatin analogs and interferon alfa control hormone-active/functional neuroendocrine gastroenteropancreatic tumors. In addition to hormonal control, variable degrees of antiproliferative effects for both agents have been reported. Until now, however, no prospective, randomized studies in therapy-naive patients have compared somatostatin analogs or interferon alfa alone with a combination of the two. METHODS: Eighty therapy-naive patients with histologically verified neuroendocrine tumor disease (primary localization: foregut, n = 36; midgut, n = 30; hindgut, n = 3; unknown, n = 11; functional, n = 29; nonfunctional, n = 51) were randomly treated either with lanreotide (1 mg three times a day administered subcutaneously [SC]) or interferon alfa (5 x 106 U three times a week SC) or both. All patients had disease progression in the 3 months before study entry, verified with imaging procedures. RESULTS: Twenty-five patients were treated with lanreotide, 27 patients were treated with interferon alfa, and 28 patients were treated with the combination. Partial tumor remission was seen in four patients (one patient who received lanreotide, one patient who received interferon alfa, and two patients who received the combination). During the 12 months of therapy, stable disease was observed in 19 patients (seven patients who received lanreotide, seven patients who received interferon alfa, and five patients who received the combination), whereas tumor progression occurred in 14 of 25 patients (lanreotide), 15 of 27 patients (interferon alfa), and 14 of 28 patients (combination). Side effects leading to an interruption of therapy were more frequent in the combination group than in the monotherapy arms. CONCLUSION: This prospective, randomized, multicenter study shows for the first time that somatostatin analogs, interferon alfa, or the combination of the two had comparable antiproliferative effects in the treatment of metastatic neuroendocrine gastroenteropancreatic tumors. Response rates were lower compared with those published in previous, nonrandomized studies. The antiproliferative effect of the tested substances was similar for functional and nonfunctional neuroendocrine tumors.

Adult↗
PubMed1998

Kaposi's sarcoma-associated herpesvirus viral interferon regulatory factor confers resistance to the antiproliferative effect of interferon-alpha.

BACKGROUND: Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a 442 amino acid polypeptide-designated viral interferon regulatory factor (vIRF) that displays homology to members of the interferon regulatory factor (IRF) family that bind to consensus interferon sequences and transactivate cellular genes that can modulate growth inhibition. Studies were conducted to determine whether vIRF affects the growth suppression mediated by interferon-alpha (IFN-alpha) in a human B lymphocyte cell line. MATERIALS AND METHODS: The human B lymphocyte cell line Daudi, which is sensitive to the antiproliferative effects of IFN-alpha, was stably transfected to express vIRF, and the proliferative response of vIRF expressing cells to IFN-alpha was compared with controls. The effect of vIRF on IRF- 1 transactivation was analyzed by co-transfection of an IFN-alpha-responsive chloramphenicol acetyltransferase reporter and expression plasmids encoding IRF-1 and vIRF. Electrophoretic mobility shift assays were conducted to determine whether vIRF interferes with the DNA binding activity of IRF-1. RESULTS: Daudi human B lymphocyte cells expressing vIRF were resistant to the antiproliferative effects of IFN-alpha, whereas wild-type Daudi or Daudi cells transformed with vector DNA were growth inhibited by IFN-alpha. The activation of an interferon-responsive reporter by IFN-alpha or IRF-1 was repressed by expression of vIRF. IRF-1 DNA binding activity was unaffected by vIRF, and vIRF alone did not bind to the interferon consensus sequence. CONCLUSIONS: These studies revealed that vIRF functions to inhibit interferon-mediated growth control of a human B lymphocyte cell line by targeting IRF-1 transactivation of interferon-inducible genes. Since KSHV is a B lymphotropic herpesvirus associated with two forms of B lymphocyte neoplasms, these effects of vIRF likely contribute to B cell oncogenesis associated with KSHV infection.

3T3 Cells↗
PubMedDate not supplied

Regulation of class II MHC gene expression by interferons: insights into the mechanism of action of interferon (review).

Modulation of class I and II MHC antigen expression by interferons has been the focus of considerable attention because the regulation of these molecules serves as a useful model system to study factors exerting transcriptional control of gene expression and because of the relevance of these molecules to expression of the neoplastic phenotype. While our knowledge of the molecular mechanisms regulating the ability of interferon to mediate enhancement of MHC genes has increased, this information is primarily based on studies employing established cell lines, and it remains to be determined whether similar controls are also exerted in short term cultured cell lines. In this short review, we have discussed the structural organization of the 5' flanking regions of the MHC genes, with special emphasis on class II genes, and the implications of these data for the transcriptional regulation of these and of other interferon inducible genes. Present evidence indicates the existence of at least four conserved upstream sequences which are shared by interferon responsive genes and which appear to be involved in the transcriptional control of these genes. The pattern of metabolic requirements for IFN-alpha and IFN-beta versus IFN-gamma upregulation of the class I and II MHC genes suggests that the regulation of gene expression by IFN-gamma requires unique regulatory molecules, i.e. newly synthesized proteins, which are not required by IFN-alpha and IFN-beta treated cells. These putative mediators of gene expression are likely to be shared by many of the biochemical induction pathways involved in the regulation of genes which exhibit interferon responsive sequences. However, in addition to common regulatory signals, other specific pathways and possibly additional regulatory sequences, are also required to account for locus--or subunit-specific patterns of antigenic modulation. Future studies are required, including those employing short term tumor cell cultures, to precisely define the molecular details of gene regulation of class I and II MHC genes, as well as other interferon--responsive--genes, by interferons. These investigations will not only prove valuable on a fundamental scientific level, but they will also be crucial for the more effective application of interferons in clinical oncology.

Gene Expression Regulation↗
PubMed1990

Anti-tumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend erythroleukemia cells. VIII. Role of the immune system in the inhibition of visceral metastases.

DBA/2 mice were injected i.v. with IFN alpha/beta-resistant 3CI8 Friend erythroleukemia cells (FLC) which metastasize to the liver and spleen. IFN alpha/beta treatment of FLC-injected mice increased their survival time and these mice developed a resistance to a second challenge with FLC. The efficacy of IFN alpha/beta in increasing the survival time was compared between normal immunocompetent and immunodeficient mice. The anti-tumor action of IFN was markedly reduced or abolished in newborn DBA/2 mice, in adult athymic nu/nu and beige DBA/2 mice, and in BALB/c scid/scid mice. To determine the phenotype of the effector cells involved, FLC-injected DBA/2 mice were treated with antibodies to asialo-GMI, CD4, or CD8 antigens, or with cyclosporin A or silica. IFN alpha/beta treatment proved much less effective in these mice, indicating that a variety of effector cell types participated in the IFN-induced suppression of visceral metastases. Thus, an intact immune system appears to be essential to obtain optimal therapeutic effects of IFN alpha/beta in this experimental model.

Animals↗
PubMed1974

Interferon synthesis in x-irradiated animals v. Origin of mouse serum interferon induced by polyinosinic-polycytidylic Acid and encephalomyocarditis virus.

The radioresistant cell systems producing serum interferon after intravenous administration of polyinosinic-polycytidylic acid [poly(I.C)] or encephalomyocarditis virus in mice were studied in rat-to-mouse radiation chimeras. Interferon induced by poly(I.C) became of donor type within 3 months after grafting of irradiated C3H/He mice with Wistar rat bone marrow cells; this indicated that it was made in cells derived from the hemopoietic system. In contrast, encephalomyocarditis virus-induced interferon remained of recipient type in xenogeneic chimeras up to 3 months after grafting, which indicated that the bulk of this interferon originated from a cell population not derived from the hemopoietic system. To ascertain that the respective radiosensitivities of the systems producing rat interferon in chimeras corresponded to that of normal mice, some rat-to-mouse chimeras were subjected to a second X irradiation 1 month after the first irradiation and restoration. Circulating interferon production was studied 4 days later. As expected, the re-irradiation strongly depressed rat serum interferon production induced by Newcastle disease virus but had no effect on rat interferon synthesis induced by poly (I.C). These results point to a macrophage origin for the bulk of poly(I.C)-induced circulating interferon.

Journal Article↗
PubMed1990

Interferon alfa-2c in chronic myelogenous leukemia (CML): hematologic, cytogenetic and molecular-genetic response of patients with chronic phase CML previously resistant to therapy with interferon gamma.

Alpha- and gamma-interferons have been shown to actively suppress hematopoiesis in patients in the chronic phase of chronic myelogenous leukemia in vitro and in vivo. Since both interferons act through different receptors on their hematopoietic target cells, they are expected to be capable of independently inhibiting abnormal blood cell development in patients with chronic myelogenous leukemia. We have utilized recombinant human interferon alfa-2c to treat 11 patients with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase, who were resistant to previous interferon gamma therapy. Ten of the patients were evaluable for hematologic, cytogenetic and molecular-genetic response following interferon alfa-2c therapy for 6 to 30 months. In 5 patients, IFN alfa-2c treatment failed due to lack of hematologic response. A complete hematologic or partial hematologic response was achieved in the remaining 5 patients. Three of these experienced cytogenetic improvement with reappearence of 100% diploid hematopoietic cells and disappearence of c-abl/bcr rearrangement in one patient. In two patients interferon alfa-2c did not prevent transformation of the disease into an accelerated state or blast crisis, respectively. We conclude that recombinant human interferon alfa-2c may also control hematopoiesis in interferon-gamma resistant chronic myelogenous leukemia patients, although the long-term response will need to be elucidated in further studies.

Adult↗
PubMed1985

The direct effects of interleukin 1, interleukin 2, interferon-alpha, interferon-gamma, B-cell growth factor, and a B-cell differentiation factor on resting and activated human B cells.

A wide variety of cytokines have been demonstrated to affect B-cell function. However, it is unclear which of these mediators actually exert direct effects on the B cells themselves. In the present study, the direct role of interleukin (IL) 1, IL-2, Interferon-gamma, or Interferon-alpha in human B-cell activation, proliferation, or differentiation was examined and compared with the effects of a B-cell growth factor (BCGF) or a B-cell differentiation factor (BCDF). Highly purified human B lymphocytes were separated according to size into two nonoverlapping populations. The fraction of small B cells was incubated with IL-1, IL-2, Interferon-gamma, Interferon-alpha, BCGF, or BCDF, and cell size changes, RNA synthesis, DNA synthesis, or supernatant immunoglobulin (Ig) production were measured. Neither IL-1, IL-2, Interferon-alpha, Interferon-gamma, nor the BCGF induced substantial cell size changes, RNA synthesis, DNA synthesis, or Ig production by the small fraction of B lymphocytes; however, the BCDF could directly activate a proportion of resting B lymphocytes to secrete Ig. The fraction of large B cells was also incubated with these cytokines. While neither IL-1, Interferon-alpha, nor Interferon-gamma enhanced DNA synthesis or Ig production by the fraction of large B lymphocytes, DNA synthesis was augmented 23-fold by BCGF and IgG production was increased 7-fold by BCDF. Additionally, IL-2 slightly enhanced both proliferation and differentiation of large B cells but substantially less so than BCGF and BCDF; DNA synthesis was increased 4-fold, while Ig production in the presence of IL-2 was increased by approximately 50%. Thus, the most important lymphokines modulating the function of these two fractions of tonsillar lymphocytes were a BCGF and a BCDF.

B-Lymphocytes↗
PubMed1988

Induction of indoleamine dioxygenase by interferon in mice: a study with different recombinant interferons and various cytokines.

Since it is important the availability of a specific marker for interferon induction in vivo, we investigated the effect of different recombinant interferons and various cytokines on indoleamine 2,3-dioxygenase activity. Although with different magnitude, recombinant interferon-alpha A/D (Bgl II) hybrid, interferon-gamma and tumor necrosis factor, all increase the activity of this enzyme, whereas interleukin-1, recombinant interferon-alpha A and interferon-alpha D do not induce this activity in mice lung tissue. Dexamethasone is able to inhibit indoleamine 2,3-dioxygenase induction by lipopolysaccharide or by interferon-alpha A/D but it fails to prevent the induction by interferon-gamma.

Animals↗
PubMed1998

Effects of interferon-alpha, interferon-gamma and cAMP on the transcriptional regulation of the serotonin transporter.

We examined the effects of interferon-alpha and -gamma, which are known to have psychiatric side effects including depression, on the transcriptional regulation of the serotonin transporter and the uptake activity of the serotonin transporter in order to clarify the involvement of the serotonin transporter in the pathogenesis of interferon-induced depression. In human placental choriocarcinoma cells (BeWo cells), both messenger RNA (mRNA) for the serotonin transporter and the imipramine-sensitive uptake of serotonin were detected. The levels of serotonin transporter mRNA were increased by treatment with interferon-alpha and -gamma for 3 h. The increase in serotonin transporter mRNA elicited by the interferons was inhibited by treatment with actinomycin D, an inhibitor of transcription. Treatment with interferon-alpha or -gamma for 3-6 h, but not for 30 min, increased the uptake activity of the serotonin transporter. Treatment with dibutyryl cAMP (Dib-cAMP) which was reported to up-regulate the transcription of the serotonin transporter, also increased the mRNA levels and the activity of serotonin transporter in BeWo cells. The levels of serotonin transporter mRNA gradually increased after treatment with Dib-cAMP over 24 h, while the maximal increase in serotonin transporter mRNA elicited by the interferons was detected 3 h after the treatment. The level of serotonin transporter mRNA was increased both in the midbrain and adrenal glands of mice which were treated with interferons for 3 h. These results suggest that the interferon-induced psychiatric side effects arise through regulation of serotonin transporter transcription and that the transcriptional regulation of the serotonin transporter is a possible neurochemical mechanism of affective disorders.

Animals↗
PubMed2002

A pilot study of beta-interferon for treatment of patients with chronic hepatitis B who failed to respond to alpha-interferon.

BACKGROUND/AIMS: Alpha-interferon achieves persistent loss of hepatitis B virus (HBV) in about 30-40% of patients with chronic hepatitis B. In non-responder patients, the disease may progress leading to complications such as cirrhosis and hepatocellular carcinoma. The aim of the current study was to evaluate the efficacy of beta-interferon in patients with chronic hepatitis B who did not respond to one course of alpha-interferon. METHODS: Twenty nine alpha-interferon-non-responder patients with chronic hepatitis B (11 hepatitis B e antigen, HBeAg-positive; 18 HBeAg-negative) were treated with 6 million units beta-interferon five times a week for 24 weeks. The post-treatment follow-up lasted for 48 weeks. RESULTS: At the end of treatment, 38% of patients (18% HBeAg-positive; 50% HBeAg-negative) had normal serum aminotransferase levels and negative serum HBV DNA. At the end of follow-up, HBV DNA was no longer detectable in serum in 21% of patients (18% HBeAg-positive; 22% HBeAg-negative). Beta-interferon was well tolerated and safe. CONCLUSIONS: This pilot study suggests that beta-interferon therapy is effective and safe in the retreatment of patients with chronic hepatitis B who had not responded to a previous alpha-interferon cycle.

Adult↗