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PubMed1995

Combination antiviral therapy with ribavirin and interferon alfa in interferon alfa relapsers and non-responders: Italian experience.

BACKGROUND/AIMS: A sustained biochemical and virologic response to standard interferon therapy for chronic hepatitis C is seen in no more than 25% of patients, and the efficacy of re-treatment or of higher doses in non-responders and relapsers has not been established. A more effective therapy for interferon alfa-resistant hepatitis C is needed. METHODS: A study of ribavirin plus interferon alfa combination therapy was conducted in 30 patients with chronic hepatitis C resistant to a previous standard course of interferon alfa (14 interferon non-responders, 16 interferon relapsers). Patients were randomly assigned to receive either ribavirin, 800 mg daily, and interferon alfa, 3 MU thrice weekly (n = 15), or interferon alfa alone, 3 MU thrice weekly (n = 15), for 6 months. RESULTS: At the end of treatment, normal alanine aminotransferase levels were observed in eight patients in the combination therapy group: one (14%) interferon non-responder and seven (87%) interferon relapsers (p = 0.01). Six months post-therapy, sustained normalization of alanine aminotransferase was achieved in seven (87%) interferon alfa relapsers, but not in any of the interferon alfa non-responders (p = 0.001). In the group of patients treated with interferon alfa alone, sustained normalization of alanine aminotransferase was observed in one interferon relapser only. Serum HCV RNA became negative in eight patients receiving combination therapy--two (28%) interferon non-responders and six (75%) interferon relapsers. Six months later, circulating HCV RNA remained negative in seven patients: one (14%) interferon non-responder and six (75%) interferon relapsers (p = 0.04). Sustained clearance of HCV RNA was not observed in patients re-treated with interferon alone. The sustained response to combination therapy was accompanied by reduced hepatic necroinflammatory activity on liver biopsy. Hepatitis C virus genotype was not significantly associated with response to combination therapy. Side effects were mild and well tolerated. CONCLUSIONS: Our experience indicates that combination therapy of ribavirin plus interferon alfa induces sustained biochemical, virologic, and histologic responses in most patients who are interferon relapsers.

Antiviral Agents↗
PubMed1994

Immunolocalisation of interferon-alpha in hepatitis C patients and its correlation with response to interferon-alpha therapy.

Localised interferon-alpha production was investigated in hepatitis C patients entered into a trial of interferon-alpha-2a therapy. Antibodies capable of reacting specifically with interferon-alpha-2, interferon-alpha-4 or with all interferon-alpha subtypes were used as immunohistochemical and immunofluorescence probes to study interferon-alpha production in liver biopsy tissue, and peripheral blood mononuclear cells prior to and after stimulation with Sendai virus. Measurement of cytoplasmic interferon-alpha, specifically interferon-alpha-2 and interferon-alpha-4, in peripheral blood mononuclear cells isolated from the hepatitis C patients and of total interferon-alpha secreted into culture supernatants by these cells showed interferon-alpha production similar to that of peripheral blood mononuclear cells isolated from normal individuals. Interferon-alpha-positive cells were observed in the infiltrating mononuclear cells of the liver biopsy tissue obtained from 8 of the 14 patients. Lymphocytes, fibroblasts, Kupffer cells, polymorphonuclear cells and monocytes stained positive for interferon-alpha, and specifically interferon-alpha-4, in all of the eight patients. The cytoplasm of hepatocytes also stained weakly positive in three of these patients. Interferon-alpha positive cells showed a good correlation with the degree of histological damage observed in the liver biopsies but not with presence of antibodies towards hepatitis C virus or levels of serum alanine aminotransferase measured prior to interferon-alpha-2a therapy. Interestingly, response to therapy seemed linked to local interferon-alpha production status. Those patients who responded best to therapy displayed no or only low levels of interferon-alpha positive cells in liver biopsy tissue. Thus patients with a lower activation of their endogenous interferon-alpha system may benefit from administration of exogenous interferon-alpha.

Adolescent↗
PubMed2001

Interferon-kappa, a novel type I interferon expressed in human keratinocytes.

High throughput cDNA sequencing has led to the identification of interferon-kappa, a novel subclass of type I interferon that displays approximately 30% homology to other family members. Interferon-kappa consists of 207 amino acids, including a 27-amino acid signal peptide and a series of cysteines conserved in type I interferons. The gene encoding interferon-kappa is located on the short arm of chromosome 9 adjacent to the type I interferon gene cluster and is selectively expressed in epidermal keratinocytes. Expression of interferon-kappa is significantly enhanced in keratinocytes upon viral infection, upon exposure to double-stranded RNA, or upon treatment with either interferon-gamma or interferon-beta. Administration of interferon-kappa recombinant protein imparts cellular protection against viral infection in a species-specific manner. Interferon-kappa activates the interferon-stimulated response element signaling pathway and a panel of genes similar to those regulated by other type I interferons including anti-viral mediators and transcriptional regulators. An antibody that neutralizes the type I interferon receptor completely blocks interferon-kappa signaling, demonstrating that interferon-kappa utilizes the same receptor as other type I interferons. Interferon-kappa therefore defines a novel subclass of type I interferon that is expressed in keratinocytes and expands the repertoire of known proteins mediating host defense.

Amino Acid Sequence↗
PubMed2001

Efficacy of high-dose interferon in combination with ribavirin in patients with chronic hepatitis C resistant to interferon alone.

OBJECTIVE: Interferon combined with ribavirin has efficacy in the treatment of patients with chronic hepatitis C virus (HCV) infection. However, its utility in patients who have not responded to prior interferon therapy is not clear. Furthermore, the effect of using an increased dose of interferon in combination with ribavirin in patients with chronic hepatitis C resistant to conventional doses of interferon is not known. The aim of our study was to evaluate the effect of high-dose interferon in combination with ribavirin on the efficacy of treating patients with chronic hepatitis C resistant to interferon monotherapy in a large multicenter trial. METHODS: We randomized 154 patients with chronic hepatitis C who failed to achieve a sustained response with prior interferon therapy to receive either 3 or 5 MU of interferon alpha-2b and ribavirin (1000-1200 mg/day) for 12 months. There were 119 patients who had not responded and 35 who initially responded but relapsed after prior interferon monotherapy. Serum HCV RNA levels were measured at entry, 6, and 12 months of treatment and at the end of a 6-month follow-up period. RESULTS: The mean age of the subjects was 47 yr (range 28-68 yr), and 110 (71.4%) were men. One hundred thirty-two patients (86%) had HCV genotype 1, whereas 21 (14%) had cirrhosis. Eighty-one subjects (53%) were randomized to receive 3 MU of interferon alpha-2b. Fifteen of 35 relapse subjects (43%) and 12 of 119 prior nonresponder entrants (10%) achieved a sustained virological response to the 12-month course of treatment. Overall, 11 of 81 patients (14%) receiving 3 MU, and 16 of 73 patients (22%) receiving 5 MU of interferon maintained an undetectable HCV RNA level after cessation of therapy. The difference in sustained response rates between the two interferon dosage groups did not reach statistical significance (p = 0.09). However, among the nonresponder patients alone, there was an increased sustained response in the high-dose interferon group compared with the standard interferon dose group (15.5% vs 4.9%, p = 0.055). Twenty-six patients discontinued therapy before 6 months, including 10 patients (12.3%) in the 3-MU and 16 patients (21.9%) in the 5-MU groups (p = 0.17). CONCLUSIONS: Sustained virological response to combined interferon alpha-2b and ribavirin was significantly higher in relapse patients than those who did not respond to prior interferon monotherapy. Although, when all treated patients were analyzed, there was no significant difference in sustained response between subjects receiving 3 and 5 MU of interferon, among the prior nonresponder patients, treatment with 5 MU of interferon with ribavirin resulted in a slightly increased response compared with treatment with the standard interferon dosage. The tolerability of the treatment regimens was comparable.

Adult↗
PubMed1989

Beta and gamma interferons act synergistically to produce an antiviral state in cells resistant to both interferons individually.

We showed previously that the mouse fibroblastoid cell line Ltk-aprt- is resistant to the antiviral effects of beta interferon. This lack of response reflects a partial sensitivity to the interferon that is accompanied by a failure to activate expression of several interferon-regulated genes, although certain other genes respond in a normal manner. We show here that Ltk-aprt- cells were also unable to establish an antiviral state and to activate expression of 2,5-oligo(A) synthetase when treated with gamma interferon. Strikingly, however, treatment with a combination of beta interferon and gamma interferon provided complete protection against viral replication. Although the cells were completely insensitive to up to 250 U of the interferons per ml added singly, essentially complete protection from viral cytopathic effects was achieved when as little as 10 U of each of the interferons per ml were combined. Expression of 2,5-oligo(A) synthetase was also sensitive to this synergistic effect. Activation of an antiviral state could also be achieved by sequential treatment, first with gamma interferon and then with beta interferon. Partial protection against viral replication could be achieved by pretreatment with gamma interferon for as little as 1 h before incubation with beta interferon and could be blocked by the addition of specific antibodies or by cycloheximide, indicating that gamma interferon induces the synthesis of a protein which can act synergistically with a signal produced by the beta-interferon receptor. We suggest that Ltk-aprt- cells suffer from defects in one or more components of the gene activation pathways for both type I and type II interferons. Nonetheless, gamma interferon is able to activate the expression of a gene encoding a protein required for signal transduction. This protein acts synergistically with a transient signal produced in response to beta interferon, thereby activating the expression of a further group of genes.

2',5'-Oligoadenylate Synthetase↗
PubMed1988

Agonist and antagonist effects of interferon alpha and beta on activation of human macrophages. Two classes of interferon gamma receptors and blockade of the high-affinity sites by interferon alpha or beta.

H2O2-releasing capacity and limited antitoxoplasma activity could be induced in human macrophages (derived from monocytes cultured greater than or equal to 5 d) but not in monocytes themselves (cells cultured less than or equal to 4 d) by a further 3-d incubation with pure natural or rIFN-alpha or -beta. More than 3 pM (10 U/ml) of these IFNs was required, with greatest effects at approximately 300 pM (10(3) U/ml). At 300 pM, H2O2-releasing capacity was enhanced 4.4 +/- 1.6-fold over medium control (mean +/- SD for natural INF-alpha, rIFN-alpha A, rIFN-alpha D, and rIFN-beta) compared to an 8.4 +/- 4.8-fold increase with rIFN-gamma (100 pM, 100 U/ml) in the same experiments. Unexpectedly, low concentrations of IFN-alpha or -beta (3 fM-300 pM) blocked induction of H2O2-releasing capacity by rIFN-gamma (10 pM), with a 50% inhibitory dose of approximately 80 fM. However, IFN-alpha or -beta (3 fM-300 pM) could not inhibit the effect of higher concentrations of rIFN-gamma (1 nM). In contrast to results with monocytes or young macrophages, Scatchard plots of binding of 125I-rIFN-gamma to mature macrophages (day 8 of culture) indicated two classes of binding sites: approximately 2,000 high-affinity sites (Kd approximately 0.43 nM) and approximately 23,000 low-affinity sites (Kd approximately 6.4 nM) per cell. Binding of 125I-rIFN-gamma to the high- but not the low-affinity sites was blocked by simultaneously added IFN-alpha or -beta, with a 50% inhibitory dose of approximately 2 U/0.25 ml (approximately 2 pM), or reversed by subsequently added IFN-alpha or -beta. Thus, differentiation of human mononuclear phagocytes in vitro is accompanied by the emergence of (a) an agonist response to submicromolar concentrations of IFN-alpha or -beta, (b) antagonism of the effect of picomolar IFN-gamma by femtomolar IFN-alpha or -beta, (c) two classes of IFN-gamma-Rs, and (d) nonstimulatory binding of IFN-alpha or -beta to the high- but not the low-affinity IFN-gamma-Rs, with higher affinity than rIFN-gamma itself. We speculate that traces of IFN-alpha or -beta derived from stromal cells, parenchymal cells, or resident macrophages may dampen the activation of mature tissue macrophages by the small amounts of IFN-gamma that diffuse from inflammatory sites into normal tissues. Such a mechanism could constrain the potentially destructive phenomenon of macrophage activation to areas where monocytes have recently immigrated and/or the concentration of IFNs is high.

Adult↗
PubMed1989

Interferon and interferon inhibitor levels in patients infected with varicella-zoster virus, acquired immunodeficiency syndrome, acquired immunodeficiency syndrome-related complex, or Kaposi's sarcoma, and in normal individuals.

PURPOSE: Previous studies had reported that normal individuals do not have measurable levels of interferons in their circulation, whereas high levels have been found in patients in the early stages of AIDS (acquired immunodeficiency syndrome) and in those with AIDS-related complex (ARC). This study was undertaken to compare levels of interferon and interferon inhibitors in plasma samples from patients with AIDS, ARC, Kaposi's sarcoma, or varicella-zoster virus infection, and from control subjects. PATIENTS AND METHODS: A total of 206 persons were tested for the presence of interferon and interferon inhibitors in their plasma: 76 with ARC or AIDS, with or without Kaposi's sarcoma or lymphoma; 32 with varicella-zoster infection; 12 with AIDS-unrelated Kaposi's sarcoma; and 86 normal control subjects at high or low risk of AIDS with or without positive antibody levels to human immunodeficiency virus-1. Total interferon activity was measured by bioassay and the subtypes were not separated. RESULTS: Of 86 normal control subjects, 85 had no significant levels of interferon or interferon inhibitor. One disease-free homosexual exhibited measurable interferon levels. Patients acutely infected with varicella-zoster virus showed no measurable interferon or inhibitor levels except if they were in a high-risk group for AIDS. Seventy-six patients with ARC or AIDS exhibited measurable circulating interferon levels. Only patients with AIDS had interferon inhibitors in their circulation. Of 12 patients with Kaposi's sarcoma unrelated to AIDS, none had measurable interferon inhibitor levels, but some exhibited measurable interferon levels. CONCLUSION: It is suggested that levels of interferon inhibitor should be considered when interferon is used therapeutically in viral or neoplastic diseases.

AIDS-Related Complex↗
PubMed1981

Analysis of interferon mRNA in human fibroblast cells induced to produce interferon.

The levels of interferon mRNA as a function of interferon induction by poly(rI) . poly(rC) in human fibroblast cells were determined by RNA hybridization using a cloned beta interferon cDNA and by translation in Xenopus oocytes. Whereas previous studies analyzed mixtures of interferons, the availability of the cloned beta interferon cDNA and the antiserum to purified beta interferon enabled us to focus on the expression of only one class (beta) of interferon genes. The induction of interferon synthesis depends primarily on the accumulation of interferon beta mRNA in the cells, and the interferon beta mRNA rapidly disappears several hours after its appearance in the cytoplasm. No detectable interferon beta mRNA sequences are present in uninduced cells. The degradation of interferon beta mRNA in the induced cells requires ongoing protein synthesis; accumulation of interferon beta mRNA was observed in the continuous presence of cycloheximide. The interferon beta mRNA detected at the early stages of induction is 1100 nucleotides long and its size progressively decreases with time. By both the hybridization and the translational assay in Xenopus oocytes, only one size of interferon beta mRNA and one species of beta interferon could be identified.

Cells, Cultured↗
PubMed1997

Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group.

BACKGROUND: Treatment with interferon prolongs survival in chronic myelogenous leukemia. We conducted a clinical trial to assess the efficacy of treatment with a combination of interferon and cytarabine. METHODS: Previously untreated patients with chronic myelogenous leukemia were randomly assigned to receive either hydroxyurea (50 mg per kilogram of body weight per day) and interferon alfa-2b (5 million units per square meter of body-surface area per day), or hydroxyurea and interferon in the same dosages plus monthly courses of cytarabine (20 mg per square meter per day, for 10 days). The end points were overall survival, complete hematologic remission at 6 months, and major cytogenetic response (less than 35 percent Philadelphia chromosome-positive cells in the bone marrow) at 12 months. RESULTS: The trial was stopped when a sequential analysis showed a benefit of interferon and cytarabine. A significant improvement in survival was observed in the interferon-cytarabine group (360 patients) as compared with the interferon group (361 patients) (P=0.02; relative risk of death, 0.64; 95 percent confidence interval, 0.44 to 0.93). After three years, the survival rate was 85.7 percent with interferon and cytarabine and 79.1 percent with interferon alone. The rate of hematologic response was higher in the interferon-cytarabine group than in the interferon group (P=0.003). Major cytogenetic responses were observed 12 months after randomization in 126 of 311 patients treated with interferon and cytarabine (41 percent) and in 75 of 314 patients treated with interferon only (24 percent, P<0.001). CONCLUSIONS: The combination of interferon and cytarabine, as compared with interferon alone, increases the rate of major cytogenetic response and prolongs survival in patients with the chronic phase of chronic myelogenous leukemia.

Adolescent↗
PubMed2003

Triple (interferon, ribavirin, amantadine) versus double (interferon, ribavirin) re-therapy for interferon relapser genotype 1b HCV chronic active hepatitis patients.

BACKGROUND: Retreatment for 6 months with the association ribavirin-interferon of HCV-related chronic active hepatitis relapser patients has high probability of failure, mostly in those with genotype 1b. We evaluated the efficacy of extending the therapy from 6 to 12 months without or with the addition of amantadine. METHODS: Forty-nine genotype 1b relapser patients were treated with 3 MU of IFN-alpha2b three times per week and ribavirin 1000-1200 mg daily (double therapy). Twenty-four patients, who did not respond after 6 months of treatment, were randomized to continue for further 6 months either with the same schedule or with also the addition of amantadine 200 mg daily (triple therapy). RESULTS: A sustained virological response was observed in 15/37 subjects (41%) treated for 12 months of double therapy. In the arm of the study evaluating amantadine, end of treatment virologic response was observed in 0/12 patients of double therapy group and in 4/12 of triple therapy (P=0.09). After 6 months of follow-up, a sustained virologic response (SVR) was observed in two patients treated with the triple therapy. CONCLUSIONS: This study confirms poor results of retreatment (even if 12 months double or triple therapy) in relapser patients with HCV hepatitis, genotype 1b. No gain was obtained in prolonging from 6 to 12 months the standard double therapy, while triple therapy with amantadine as an additional regimen for this difficult subgroup of patients showed some cases of SVRs: amantadine addition deserves to be evaluated in larger trials.

Journal Article↗
PubMed1997

Effectiveness of interferon-alpha therapy in chronic hepatitis C is associated with the amount of interferon-alpha receptor mRNA in the liver.

BACKGROUND/AIMS: This study aimed to investigate the relationship between interferon-alpha receptor mRNA in the liver and the response to interferon therapy in chronic hepatitis C. METHODS: Interferon-alpha receptor mRNA was quantified by reverse transcription polymerase chain reaction using liver biopsies from 40 patients, comprising 20 responders and 20 non-responders to subsequent interferon therapy. RESULTS: The amount of interferon-alpha receptor mRNA was significantly larger in interferon-responders (0.72+/-0.12) than non-responders (0.26+/-0.08) (p<0.01). Regardless of the response to interferon, histological activity index scores and the amount of HCV-RNA showed significant inverse correlation to the amount of interferon-alpha receptor mRNA, whereas the HCV-RNA genotype was not associated with the amount of interferon-alpha receptor mRNA. Logistic analysis and multiple regression analysis showed that the amount of interferon-alpha receptor mRNA was significantly associated with the efficacy of interferon (p=0.0275), but not with fibrosis of the liver (p= 0.2726). CONCLUSIONS: Our results suggest that the amount of interferon-alpha receptor mRNA is an important factor determining the response to interferon, and may be a new predictor of interferon response in chronic hepatitis C.

Actins↗
PubMed1996

The biologic activity and molecular characterization of a novel synthetic interferon-alpha species, consensus interferon.

Consensus interferon (Infergen) is a wholly synthetic type I interferon (IFN), developed by scanning several interferon-alpha nonallelic subtypes and assigning the most frequently observed amino acid in each position, resulting in a consensus sequence. The antiviral, antiproliferative, NK cell activation activity, cytokine induction, and interferon-stimulated gene-induction activity of consensus interferon has been compared with naturally occurring type I interferons. In all of these comparisons, consensus interferon had a higher activity when compared, on a mass basis, with IFN-alpha 2a and IFN-alpha 2b, although the activity was the same for all of these parameters on an antiviral unit basis. That a synthetic type I interferon could have higher activities than naturally occurring molecules is surprising and may be a result of the higher affinity for the array of type I interferon receptors demonstrated for consensus interferon when compared with IFN-alpha. In contrast, consensus interferon was shown to be an inferior inducer of IL-1 beta when compared with IFN-alpha. These results may reflect differential binding to multiple accessory proteins interacting with a type I interferon receptor. These unique biologic properties may lead to a favorable clinical benefit for consensus interferon when compared with the naturally occurring recombinant molecules. Ongoing clinical trials will ascertain whether consensus interferon can be used in a wide array of disease situations, such as chronic viral infections and certain malignancies.

Amino Acid Sequence↗
PubMed1990

Changes in interferon receptors on peripheral blood mononuclear cells from patients with chronic hepatitis B being treated with interferon.

We studied the binding of 125I-labeled human interferon-alpha to peripheral blood mononuclear cells and the activity of 2',5'-oligoadenylate synthetase in peripheral blood mononuclear cells obtained from 21 patients with chronic hepatitis B who were treated with human interferon-alpha or interferon-beta. Fourteen patients were given interferon daily for 4 wk. Interferon receptors per cell decreased to about 50% of baseline but increased to baseline by 2 wk after therapy ended. The activity of 2',5'-oligoadenylate synthetase rose about fivefold during therapy, decreasing to baseline by 1 wk after the end of therapy. The seven other patients were given interferon daily for 2 wk, no interferon for 2 wk and then interferon daily for 2 wk more. During both periods of therapy on this schedule, interferon receptors decreased to about 50% but returned to baseline 1 wk after the interferon was stopped. The activity of 2',5'-oligoadenylate synthetase increased about fivefold during both the first and second periods of therapy and decreased to baseline 1 wk after interferon was stopped. Close negative correlation existed between the number of interferon receptors and the 2',5'-oligoadenylate synthetase activity. The results of interferon therapy could not be predicted by either the numbers of interferon receptors before therapy or by the decrease in this number during therapy.

2',5'-Oligoadenylate Synthetase↗
PubMed2002

High-dose interferon alfa-2b and ribavirin in patients previously treated with interferon: results of a prospective, randomized, controlled trial.

BACKGROUND: Kinetic studies have demonstrated a more rapid reduction in hepatitis C virus (HCV) RNA levels among patients taking high daily doses of interferon compared with those taking standard-dose interferon. GOALS: To compare the efficacy and safety of high-dose interferon alfa-2b and ribavirin with standard-dose interferon alfa-2b and ribavirin in chronic hepatitis C patients previously treated with interferon. STUDY: One hundred seven patients (30 interferon relapsers and 77 interferon nonresponders) were randomized to take either high-dose interferon alfa-2b in combination with ribavirin (group A) (consisting of 5 MU/d for 4 weeks, 5 MU three times weekly for 8 weeks, and then 3 MU three times weekly for 36 weeks) or standard-dose interferon alfa-2b and ribavirin (group B) for 48 weeks. Serum alanine transaminase (ALT), HCV RNA levels, and safety data were prospectively collected and compared during treatment and at week 24 of follow-up. RESULTS: The mean serum ALT and HCV RNA levels, as well as the proportion of patients with genotype 1 and cirrhosis and who were African American, were similar in the two treatment groups at study entry. The rates of suppression of HCV RNA to undetectable levels at weeks 4, 12, and 48 were similar. In addition, the sustained virologic response rates at week 24 of follow-up were similar in groups A and B (29% vs. 39%, respectively, p = 0.277). Clinical variables that correlated with a sustained virologic response included a history of relapse to previous interferon therapy and non-1 HCV genotype ( p < 0.01). CONCLUSIONS: Short-term, high-dose interferon alfa-2b and ribavirin failed to demonstrate a tangible benefit compared with standard-dose interferon alfa-2b and ribavirin. However, our study results and others suggest that standard-dose interferon and ribavirin for 48 weeks should be considered for selected patients who did not respond to previous interferon therapy.

Adult↗
PubMed1983

Binding of human interferon alpha to cells of different sensitivities: studies with internally radiolabeled interferon retaining full biological activity.

The characteristics of interferon binding to various cells with different interferon sensitivity were studied by using [3H]leucine-labeled, pure human interferon alpha from Namalwa cells. Scatchard analysis of the binding data on cells sensitive to interferon alpha (human FL and fibroblasts and bovine MDBK) indicated the presence of two kinds of binding sites with high and low affinities. The binding constants of the high-affinity sites in these cells were similar (4 X 10(10) to 11 X 10(10) M-1). Cells insensitive to human interferon alpha (human HEC-1 and mouse L cells) were shown to have only low-affinity sites, suggesting that high-affinity binding sites are indispensable for interferon sensitivity and represent interferon receptors. However, the number of sites in three human diploid fibroblast strains and one strain trisomic for chromosome 21 were not proportionally correlated to the interferon sensitivity of the cells. The high-affinity binding to human cells was completely inhibited by both nonradioactive human interferons alpha and beta in a similar manner, but binding to bovine MDBK cells, on which human interferon beta is practically inactive, was inhibited effectively only by interferon alpha and not by beta. These results suggest that the receptor for human interferon alpha is common to human interferon beta in human cells, whereas the receptor on bovine cells binds only human interferon alpha.

Animals↗
PubMed1984

[Prevention of 5-FU induced toxicity in C3 H/HE mice with interferon or with interferon inducers (poly 1: C, OK-432, Lentinan)].

It is well known that all cell lines, normal as well as malignant, have a sensitivity to the growth-inhibitory effect of Interferon, or Interferon inducers. 5-FU is a widely used anticancer drug considered to be a cell cycle-specific agent. We speculated that the antiproliferative effect of Interferon or Interferon inducers might affect the activity of 5-FU and diminish the uncomfortable side-effects of this agent. Initially this experiment, we observed the mortality rate in mice after administration of 5-FU alone, or 5-FU plus Interferon (alpha inducers). We then carried out cytofluorometric observation of bone marrow cells, and finally studied the influence of Interferon (or inducers) on the anticancer effects of 5-FU against MM48 tumors in C3/He mice. Findings were as follow: 1) Administration of beta-type Interferon for 2 days, following the administration of a toxic dose (140 mg/kg/w) of 5-FU, revealed significant protection from mortality in C3H/He mice. This effect was also observed when Interferon inducers (Poly I: C, OK-432, Lentinan) were administered with 5-FU. Body weight loss was 10.4% at nadir in mice treated with 5-FU alone, while there was a body weight gain of 36.3% in mice treated with 5-FU plus Interferon. 2) Cytofluorometry of bone marrow cells obtained from mice femur at timed intervals after the administration of OK-432, or Lentinan indicated that these drugs inhibited the entry of cells into the S-phase, causing then to accumulated in the G0.G1-phase during the first 48 hours. 3) Histological findings of intestinal mucosa in mice showed prominent destruction after bolus injection of 350 mg/kg of 5-FU alone, while these findings were not observed in mice after the bolus injection of 350 mg/kg of 5-FU combined with Interferon. 4) The tumor volume ratio (T/C) was significantly reduced in the group treated with 5-FU alone as well as that treated with 5-FU combined with Interferon (or inducers) in C3H/He mice bearing MM48 tumors. All mice were dead about 2 weeks after administration of 5-FU alone, while all mice treated with 5-FU plus Interferon (or inducers) were alive in the same period. From these results, we speculate that Interferon, or Interferon inducers play an important role in the prevention of side effects of cell cycle-specific cytotoxic drugs like 5-FU, without decreasing their anticancer activity.

Animals↗
PubMed1982

Interaction of interferon with cellular receptors. Internalization and degradation of cell-bound interferon.

Human interferon alpha A, produced in Escherichia coli by recombinant DNA technology, was labeled with 125I to study its binding to receptors on human lymphoblastoid Daudi cells. This binding showed a marked temperature dependency, with maximum binding obtained at 30-37 degrees C. About 60% of the cell-bound radioactivity was released upon subsequent addition of unlabeled interferon, indicating that only part of the cell-bound interferon could be displaced by competitor. Moreover, about 30-50% of cell-bound interferon was not released by treating the cells with 0.2 N acetic acid, a procedure which removes polypeptide hormones on the cell surface, indicating that part of the interferon bound at 37 degrees C was internalized. This interferon was slowly degraded to acid-soluble products, which were released into the culture medium. Treatment of DAudi cells with the lysosomotropic amines chloroquine and methylamine inhibited the degradation of interferon. Methylamine, however, also inhibited the internalization of interferon. Daudi cells treated with interferon in the presence of chloroquine showed an increase in the interferon-induced enzyme 2',5'-oligo(A) polymerase comparable to that of cells treated with interferon alone. This enzyme increased to a similar extent in cells treated with interferon and cytochalasin, a drug which inhibited internalization of interferon by 50%. These results suggest that degradation and possibly internalization of interferon are not required for at least some of its biological activities.

Biological Transport↗