Fibroblast Interferon Research Articles

Postoperative pain relief and hospital stay after total oesophagectomy

Macrophages were identified to be a major source of interferon produced in murine spleen cell cultures after intravenous injection of Corynebacterium parvum (C. parvum), strain CN 6134 or Bacille Calmette Guérin (BCG). Another strain of C. parvum, CN 5888, which lacks RES stimulating activity and adjuvant activity in vivo, was not effective when injected intravenously. Protein synthesis was required for interferon activity to be produced and protein synthesis was also required for the antiviral state to be expressed. The antiviral activity was relatively stable to pH 2 and neutralized by an antiserum against virus-induced fibroblast interferon, thus exhibiting some properties of type I interferon. In vitro only CN 6134, the biologically active strain, could induce small amounts of interferon in spleen macrophage cultures. Macrophages from CN 6134 or BCG-infected athymic nu/nu mice produced similar interferon titers as their controls. It is concluded that infection with certain immunomodulators can activate splenic macrophages via a predominantly T-cell independent mechanism. Interferon in turn may operate locally as a mediator of immunoregulation.

Poly(ADP-ribose) polymerase activity is inhibited by 2',5'-oligoadenylates in mouse L-cells

Down regulation of poly(ADP-ribose)polymerase (ADPRP) activity was observed in mouse LW-cells after treatment with 2'-5'oligoadenylates or with fibroblast interferon and poly(rI).poly(rC). The poly(rI).poly(rC)-induced inhibition of the enzymatic activity correlates with the observed increase of endogenous 2',5'-oligoadenylate cores which were reported to be potent inhibitors of ADPRP in vitro.

Regulation of muscle acetylcholine receptor-channel function by interferon

The effect of the antiviral agent interferon (IFN) on the function of the nicotinic acetylcholine receptor (AChR) channel, has been investigated in both mammalian cultured myotubes and adult fibres, using the single channel recording patch-clamp technique. Shortened AChR-channel lifetime, and occasionally reduced channel conductance and slowed opening frequency were seen with fibroblast IFN (IFN-beta) in the mouse myotubes, and with IFN-beta and leucocytes IFN (IFN-alpha), in the rat muscle fibres. These effects paralleled an increase in the cytosolic level of cAMP. This suggests that IFN exerts a regulatory action on AChR function. A similar regulatory action on other receptor may be responsible for some of the neurological side effects observed in patients treated with IFN.

Treatment of chronic non-A non-B hepatitis with human interferon β: a preliminary study

Twenty-four patients with chronic non-A non-B hepatitis were randomly assigned to receive either human fibroblast interferon (HuIFN-β) at doses of 1 or 3 million international units (MIU) per day for 4 or 12 weeks (12 patients) or to receive no therapy (12 patients), and were then compared with 5 patients with chronic type B hepatitis who were treated with HuIFN-β. Elevated serum aminotransferase levels decreased more rapidly during the treatment of chronic non-A non-B hepatitis than of chronic hepatitis B. Variations in serum aminotransferases were not observed in any of the untreated chronic non-A non-B hepatitis patients. In 3 of the 9 patients with chronic non-A non-B hepatitis who responded to HuIFN-β therapy, serum aminotransferase levels remained normal 15, 21 and 31 months after therapy was discontinued; liver biopsy specimens obtained after therapy from 2 patients showed marked histological improvement. In the six other patients aminotransferase activity levels became again elevated following cessation of interferon therapy. No response to HuIFN-β was seen in the remaining 3 patients with chronic non-A non-B hepatitis.

In vitro differentiation and antigenic changes in human melanoma cell lines.

Malignant transformation of melanocytes may be associated with changes in the expression of HLA antigens and melanoma-associated antigens (MAA). To determine whether these changes reflect the differential expression of HLA antigens and MAA by melanocytes at different stages of differentiation, we have studied the effect of the reversible induction of differentiation by fibroblast interferon (interferon beta) and/or 12-O-tetradecanoyl-phorbol 13-acetate (TPA) on the expression of HLA antigens and MAA by the melanoma cell lines DU-2, FO-1 and HO-1. The three melanoma cell lines differed in their sensitivity to the differentiating and antiproliferative activity of these two compounds and displayed an increased growth suppression and induction of differentiation, when incubated with the combination of TPA and interferon beta. Incubation of the three melanoma cell lines with interferon beta, TPA or their combination resulted in a differential modulation of the expression of membrane-bound high-molecular-mass melanoma-associated antigen, 115-kDa MAA, 100-kDa MAA, intercellular adhesion molecule 1, HLA class I antigens and gene products of the HLA-D region. Each melanoma cell line displayed a unique pattern of antigenic modulation when exposed to the two differentiating agents alone or in combination. No direct relationship was found between the effects of interferon beta and/or TPA on the growth and differentiation of the three melanoma cell lines and the expression of HLA antigens or the MAA evaluated in the present study. These findings argue against a direct role of any of the antigens tested in the reversible induction of human melanoma cell differentiation in the in vitro system.

Human Fibroblast Interferon Adjuvant to CO2 Laser in the Treatment of Recurrent Juvenile Laryngeal Papillomatosis: Experience with 7 Cases

Preliminary results of adjuvant human fibroblasts interferon (IFN beta) given after CO2 laser excision in recurrent laryngeal papillomatosis in 7 adult patients are reported. Diagnostic procedure included histologic and immunohistochemical investigations to demonstrate the presence of viral cytopathic effect and for characterization of the virus. All patients underwent CO2 laser excision under general anesthesia followed by administration of IFN beta intramuscularly at the dose of 4 x 10(6) IU/day for 10 consecutive days. In the presence of complete remission, patients were followed without further therapy; in the presence of partial remission, a new combined treatment was established. All patients had a complete remission after combined treatment, but 4 subsequently developed recurrences. Treatments were always well tolerated; even cirrhotic patients showed no side effects.

Effect of absorption promoters in intranasal administration of human fibroblast interferon as a powder dosage form in rabbits.

The utility of the absorption promoters, sodium glycocholate (GC-Na), ethylenediamine dihydrochloride (EDTA-2Na), sodium caprylate (Cap-Na) and sodium salicylate (Sal-Na), in the intranasal administration of human fibroblast interferon-beta (HuIFN-beta) in rabbits was investigated. The optimal amount of added EDTA-2Na, Cap-Na and Sal-Na with respect to HuIFN-beta was examined for nasal absorption in the powder dosage form. Formulations of HuIFN-beta with GC-Na showed greatly enhanced intranasal HuIFN-beta absorption, as compared to the other absorption promoters. The results of a stability study on HuIFN-beta in homogenates of nasal mucosa suggested that GC-Na behaved as a hydrolysis inhibitor in the nasal mucosa and maintained the activity of HuIFN-beta.

ヌードマウス可移植性肝細胞癌に対するインターフェロン‐βと徐放性制癌剤の単独及び併用効果 腫よう内直接投与による実験的検討

インターフェロン(IFN)の肝細胞癌に対する有用性を探るため,ヌードマウス可移植性肝細胞株PLC/PRF/5に対し,IFN-β単独及びマイトマイシンC (MMC),アドリアマイシン(ADM)含有徐放性制癌針(放出期間;約1カ月)との併用による腫瘍内直接投与効果を検討した.IFN-βの各々6×104IU, 3×105IUを週2回,5週間投与したが,非治療群に比し腫瘍重量やAFP値に有意の抑制効果は認められなかった.MMC 1.0mg, MMC, ADMの各0.5mg含有針は単独でも有意の抑制効果を示し,MMCでは用量依存性であった.一方MMC, ADM 0.5mg針とIFN-βを併用したところ,MMC+3×105IUでは腫瘍重量及びAFP値が,ADM+3×105IUではAFP値が,それぞれ制癌針単独に比し有意に抑制された.以上より肝細胞癌においてIFN-βの腫瘍内直接投与は単独では無効であったが,作用機序の異なる制癌剤との併用により,制癌剤の有する抗腫瘍活性を増強させる可能性が推測された.

Opposite effects of murine interferons on erythroid differentiation of friend cells

Interferons (IFNs), in addition to inducing an antiviral state in uninfected cells, are able to affect cell physiology, including cell differentiation. In this respect hematopoiesis is certainly the area in which most data have accumulated. In general IFN-α or-β inhibit cell growth of normal progenitors of hematopoietic lineages. In leukemia cell cultures IFNs may either stimulate or inhibit cell growth and differentiation. We report here different biological effects of murine (mu) IFN- α 1, -β and -γ species on the erythroid differentiation of dimethyl sulfoxide (DMSO)-induced Friend leukemia cells. Treatment with mu recombinant IFN-β enhances DMSO-induced FLC differentiation, whereas treatment with IFN- α 1 species as well as with natural and recombinant mu IFN-γ preparations only inhibits it. All these observed effects are neutralized by monoclonal antibodies against IFN-α, -β and -γ species. When mu fibroblast IFN (a mixture of α and β species) was used, the inhibitory effect attributable to IFN-α was partly overshadowed by the simultaneous presence of a majority of IFN-β molecules exerting the opposite effect. This is in agreement with data obtained neutralizing fibroblast IFN preparations with excess amounts of monoclonal antibodies against IFN-β (G. B. Rossi etal., 1988, “The Status of Differentiation Therapy of Cancer,” Raven Press, New York) and with our previous reports indicating that mu fibroblast IFN can either enhance or inhibit DMSO-induced differentiation when administered at low (<500 U/ml) or high (>5000 U/ml) doses, respectively. The inhibitory effect of IFN- α 1 on cell differentiation is not linked to any inhibitory effect on cell growth. Results obtained analyzing the effect of IFN- α 1 and -β on various IFN-resistant FLC clones indicate that different mechanisms underlie the stimulatory effect of IFN-β and the inhibitory effect of IFN- α 1. These results shed light on possibly distinct physiological roles of the various species of IFNs.

Resolution of cutaneous lesions of granuloma annulare by intralesional injection of human fibroblast interferon

Resolution of cutaneous lesions of granuloma annulare by intralesional injection of human fibroblast interferon

Resolution of Cutaneous Lesions of Granuloma Annulare by Intralesional Injection of Human Fibroblast Interferon

<h3>To the Editor.—</h3> We report a successful clinical trial of interferon beta-1 for the treatment of granuloma annulare. Although the cause of granuloma annulare still remains unknown, by histochemical and electron microscopic studies, Umbert and Winkelmann¹have observed activated macrophages in the lesion and have presumed that activation of mononuclear phagocytes may be the central event in an inflammatory process of granuloma annulare. Lee and Epstein²report that interferon beta inhibits maturation of monocytes to macrophages, and we found that interferon beta inhibited activation of monocytes.³These findings prompted us to study the effect of interferon beta on granuloma annulare. Human interferon beta-1 was a product of human fibroblasts stimulated with Poly I:C. Since human serum albumin was added, as a stabilizer, into a vial of interferon beta-1, a placebo vial, which contained only the same amount of human serum albumin, was also prepared (Toray Industries, Tokyo). A vial of interferon beta-1 was

Monoclonal antibodies anti-murine interferon (IFN) β neutralize the stimulation of erythroid differentiation induced by treatnent of friend cells with dimethylsulfoxide and murine fibroblast IFN

Monoclonal antibodies anti-murine interferon (IFN) β neutralize the stimulation of erythroid differentiation induced by treatnent of friend cells with dimethylsulfoxide and murine fibroblast IFN

Organ distribution of interferon after intravenous injection into active and hibernating spotted susliks.

Spotted suslik fibroblast interferon (SuIFN-beta) was given intravenously to animals active in summer and hibernating in winter. In both groups, most IFN was detectable in the serum 1 min after injection; in hibernating susliks, in spite of their arousal from hibernation, IFN remained detectable for a longer period in the serum. IFN was also detected in lungs, liver, spleen, and kidneys and in peritoneal washings. IFN levels in the organs were lower in hibernating susliks than in active ones, but, particularly in the spleen and kidneys, IFN remained detectable for longer in hibernating animals than in active susliks.

Local Administration of Human Fibroblast Interferon (Hu IFN-β) for Metastatic Brain Tumor

Twelve patients with intracranial metastatic tumors were given local treatment with human fibroblast interferon (Hu IFN-β). Following tumor removal, the IFN was injected into the tumor removed cavity through an Ommaya's reservoir. When serial computed tomographic scans suggested recurrence, whole brain irradiation was started. The results demonstrated that local administration of Hu IFN-β was an important addition to surgical excision and whole brain irradiation when there were no extracranial metastases from the primary lesion and T lymphocyte transformation to phytohemagglutinin and concanavalin A was relatively normal. However, IFN was not effective in preventing the appearance of other intracranial metastases beyond the site of injection.

Enzyme immunoassay of human fibroblast interferon after intranasal administration with several excipients in rabbits.

Human interferon-β (HuIFN-β) titer after intransal administration was determined by enzyme immunoassay (EIA), substituting for bioassay. The intranasal absorption was linearly related to HuIFN-β dose. Compared with intravenous administration, the mean bioavailability of intranasal HuIFN-β was 3%. The effects of several excipients, human serum albumin (HSA), polyethylene glycol, diethylaminoethyl-dextran, carboxy polymethylene, α-cyclodextrin and cholesteryl stearate, on the absorption of HuIFN-β were examined with the powder dosage form. Among these excipients, HSA and α-cyclodextrin gave the highest HuIFN-β concentrations in plasma. The area under the plasma concentration-time curve (AUC) decreased as the molecular weight of excipients was increased.

Central Nervous System Toxicity of Local Interferon-β Therapy

Interferon-β (IFN-β) is considered remarkably nontoxic compared with other anticancer drugs. Central nervous system toxicity, in particular, is very rare, only three cases having been reported (seizure in one case and deterioration of consciousness in two cases). In this study, human fibroblast interferon (Hu IFN-β with a specific activity of 2.0 × 108 IU/mg protein) was administered to three patients who were marginally functioning with malignant brain tumors (two glioblastoma multiforme and one grade 2 astrocytoma with intracerebral seeding) by intraventricular and/or intratumoral injection. Deterioration of the highest integrative functions, such as spontaneity, interaction with the environment, and orientation to time, place, person, and situation were then observed. Drowsiness and deterioration of consciousness were observed in two cases. One patient, to whom IFN-β was administered through an Ommaya's reservoir into a left parietal tumor cavity, developed complete sensory aphasia. The mechanisms of these central nervous system reactions to IFN-β are unclear. Deterioration of high integrative functions and consciousness disturbance are considered to reflect global suppression of cerebral function by IFN-β access to the subarachnoid space or ventricular system. Sensory aphasia is regarded as a result of direct, local suppression of cerebral function. It is suggested that IFN-β-induced central nervous system toxicity tends to occur in patients whose cerebral function is tenuous. The possibility of central nervous system toxicity should be kept in mind when IFN-β is administered locally.

Natural human interferon-beta in metastatic malignant melanoma. A phase II study.

A phase II trial of natural human fibroblast interferon (HuIFN-beta) in 15 previously untreated patients with advanced metastatic malignant melanoma is reported. It was given as out-patient treatment by 30 min i.v. infusion of 60 x 10(6) U/m2/day on 4 consecutive days each week. Systemic toxicity was acceptable to all patients except one who declined further treatment. Performance status of treated patients was good. Three patients had a partial response and 3 patients had stable disease. The median time to response was 13.3 weeks and the duration of response was 22.6 weeks. Responses were seen in lungs and soft tissues only and relapses were seen particularly in the central nervous system and the liver. Overall survival of the patients was only 20.7 weeks. Those who achieved a partial remission had a median survival of 34.7 weeks and those with disease stabilisation a survival of 22.0 weeks. HuIFN-beta is shown to have anti-tumour activity in advanced metastatic melanoma, although the unit dose of HuIFN-beta is much larger than that required to achieve similar anti-tumour activity with interferon-alpha.

An unusual case of renal cancer showing mixed tumor response to interferon

A patient with renal cell carcinoma, recurrent in the renal bed and metastatic to the lung parenchyma, hilar lymph nodes, and ilium bone, showed a complete response to 12 months of treatment with human diploid fibroblast interferon. However, concurrently with clinical and pathologic resolution of the metastatic and recurrent tumor at known sites, a brain metastasis developed, which was not clinically or radiologically apparent during his lifetime. At autopsy, there was no evidence of metastatic renal cell carcinoma at the known sites of disease. In the brain, there was a massive fresh intracerebral hemorrhage originating in a small focus of metastatic renal cell carcinoma. Possible explanations for these mixed responses to interferon and this curious phenomenon are discussed.

Interferon-β Treatment of Metastatic Prostate Cancer

A limited clinical trial of Interferon-beta (Human Fibroblast Interferon) in the treatment of advanced, hormone-refractory prostate cancer was conducted by the National Prostate Cancer Project (NPCP Protocol 2100). Sixteen patients with metastatic prostate cancer who had failed prior hormone therapy were entered into the study. Treatment consisted of 6 X 10(6) units of Interferon-beta intravenously three times per week for 12 weeks. Chills and fever were seen in ten of the 16 patients (62.5%), and mild hematologic toxicity occurred in four patients. No complete or partial responses were observed. Three patients had stable disease by NPCP criteria for a mean duration of 6.3 months. Progression of disease was seen in 13 of the 16 patients, eight of whom progressed during therapy. The results of this study suggest that Interferon-beta has limited efficacy in the treatment of advanced, hormone-refractory prostate cancer.

Effect of human fibroblast interferon on normal human monocyte activation induced by a factor found in sarcoidosis sera.

AbstractEffect of human fibroblast interferon (IFN‐β) on normal human monocyte activation induced by the monocyte activating factor found in sarcoidosis sera was studied. Spreading was used as one indicator of monocyte activation. IFN‐β was shown to inhibit spreading of normal human monocytes induced by the activating factor. The inhibitory activity of IFN‐β against monocyte spreading was adsorbed with monoclonal antibody to human IFN‐β‐Sepharose beads. Increases in phagocytosis and glucose consumption of normal human monocytes induced by the activating factor was also inhibited by IFN‐β. Recombinant IFN‐β also showed similar inhibitions.