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PubMed1990

Analysis of interferon-inducible genes in cells of chronic myeloid leukemia patients responsive or resistant to an interferon-alpha treatment.

Recombinant human interferon-alpha (IFN-alpha) can induce a hematologic remission in patients with chronic myeloid leukemia. However, some patients are resistant and others develop late resistance to the IFN-alpha treatment. To understand the molecular mechanism of this resistance, we have analyzed the expression of 10 IFN-inducible genes in the cells of three resistant patients, two responsive patients, and six healthy controls. Northern blot hybridizations showed that all the genes were induced in in vitro IFN-alpha treated peripheral blood cells of the patients and healthy controls. These genes were also inducible in peripheral blood and bone marrow cells of two out of two resistant patients administered an injection of IFN-alpha. We conclude that the resistance to the IFN-alpha treatment of the chronic myeloid leukemia patients we studied is not due to (1) the absence of induction of any of the 10 IFN-inducible genes we studied, including the low-molecular-weight 2'-5'oligoadenylate synthetase; (2) the presence of an antagonist of IFN-alpha in the peripheral blood or bone marrow cells; and (3) the presence of neutralizing anti-IFN-alpha antibodies.

2',5'-Oligoadenylate Synthetase↗
PubMed1991

alpha-Interferon down-regulates epidermal growth factor receptors on renal carcinoma cells: relation to cellular responsiveness to the antiproliferative action of alpha-interferon.

The CaKi-I line of renal carcinoma (RC) cells is highly sensitive to the antiproliferative effect of human leukocyte interferon (IFN-alpha). These RC cells express high numbers of cell surface receptors for epidermal growth factor (EGF), and EGF stimulates their proliferation. IFN-alpha blocks EGF-stimulated proliferation of these cells and down-regulates EGF receptors (EGFR) by inhibiting EGFR synthesis. Although EGF stimulates the proliferation of RC cells resistant to the antiproliferative action of IFN-alpha, IFN-alpha treatment does not block the EGF-stimulated proliferation of these cells and has no effect on EGFR expression. Thus, the down-regulation of EGFR is specific for RC cells sensitive to IFN-alpha. While IFN-alpha does not affect the level of total cellular message or total polyadenylated message for the EGFR, IFN-alpha treatment decreases the level of cytoplasmic EGFR message. Analysis of polysome distribution of cellular mRNAs indicates that IFN-alpha treatment results in an accumulation of EGFR mRNA in lighter polysome fractions, consistent with a partial block in translational elongation. Thus, IFN-alpha regulates the expression of EGFR and possibly other growth-related proteins by post-transcriptional mechanisms, which may play an important part in the complex inhibitory action of IFN-alpha on RC proliferation.

Carcinoma, Renal Cell↗
PubMed1991

[Human fibroblast interferon therapy alone and human fibroblast interferon combined with thymostimulin in genital papillomavirus infection associated with cervical intraepithelial neoplasia].

Eighteen patients suffering for HPV infections associated with CIN were treated using human fibroblast interferon, via an intramuscular route, with positive results. Five cases of recurrent HPV within nine months of treatment received thymostimulin therapy, via an intramuscular route, with positive results.

Adult↗
PubMed1991

[Clinical trial of alpha-interferon (human lymphoblastoid interferon) in combination with VCAP chemotherapy in multiple myeloma].

We compared the effect of combined natural interferon-alpha (HLBI)/VCAP chemotherapy with VCAP chemotherapy alone on multiple myeloma. Sixteen previously untreated patients with multiple myeloma were treated with a combination of IFN-alpha and VCAP chemotherapy; nine of them were treated with HLBI-VCAP (I) regimen (HLBI 3 x 10(6) units/day, daily, 56 days) only for induction chemotherapy, and seven with continuous HLBI-VCAP (II) regimen (HLBI 3 x 10(6) units/day, twice a week) both for induction and maintenance chemotherapy. Thirty-one control patients were treated with a VCAP regimen only. HLBI-VCAP (II) regimen exhibited an 85.7% (6/7) response rate, while VCAP and HLBI-VCAP (I) regimen showed 74.2% (23/31) and 77.8% (7/9) response rates, respectively. The median duration of survival was 43 months in the control group, greater than 44 months in HLBI-VCAP (I) group and greater than 45 months in HLBI-VCAP (II) group. No significant difference in survival duration has yet been observed between the VCAP group and HLBI-VCAP groups. We conclude that continuous, long-term combination therapy with HLBI and VCAP regimen for induction and maintenance therapy may be most effective, and found that intensive HLBI-VCAP regimen, for only remission induction therapy, was not more effective than VCAP regimen alone.

Adult↗
PubMed1991

Effective natural interferon-alpha therapy in recombinant interferon-alpha-resistant patients with hairy cell leukemia.

To explore the relationship between anti-interferon-alpha (anti-IFN-alpha) antibodies and loss of clinical responsiveness to IFN-alpha treatment, we examined sera from 59 patients with hairy cell leukemia who responded to therapy with recombinant IFN-alpha-2a (rIFN-alpha-2a). During the first 2 years of therapy, 10 patients developed rIFN-alpha-2a-neutralizing and 15 rIFN-alpha-2a-binding antibodies. Nine of the 59 initially responding patients became resistant to rIFN-alpha-2a and suffered a relapse of the disease at 7 to 24 months of treatment. All nine relapsing patients tested positive for both neutralizing and binding antibodies with titers above 400 INU/mL, while none of the antibody-negative patients relapsed. Six patients with detectable binding antibody titers below 400 INU/mL continued to respond to treatment. By measuring the IFN kinetics and the levels of the IFN-induced Mx-homologous protein in mononuclear cells after a single injection each of rIFN-alpha-2a and nIFN-alpha the IFN antibodies of eight of the nine resistant rIFN-alpha patients were found to be highly specific for rIFN-alpha-2a. Therefore, these eight patients were switched to natural IFN-alpha (nIFN-alpha) therapy at doses of 3 million IU, three times a week. All eight patients responded to treatment with nIFN-alpha, achieving durable objective responses similar to those obtained previously with rIFN-alpha-2a. These data clearly demonstrate that rIFN-alpha antibody-positive patients can effectively be treated with nIFN-alpha.

Adult↗
PubMed1990

[Sizofiran and recombinant interferon gamma stimulate peritoneal macrophages obtained from patients with gynecologic malignancies--increased secretion of tumor necrosis factor, IL-1 and interferon-gamma].

TNF, IL-1, IFN-gamma and PGE2 secretion of peritoneal macrophage obtained by peritoneal washing at the first day after laparotomy from 19 patients with cervical cancer and 19 with ovarian cancer, who were treated with sizofiran (SPG) intramuscularly before laparotomy or with recombinant interferon gamma (rIFN) intraperitoneally at the day of laparotomy, were studied. Treatment with SPG and rIFN significantly increased the number and secretion of TNF, IL-1 and IFN-gamma (p less than 0.05) but not that of PGE2. A high correlation between secretion of TNF and IFN-gamma (r = 0.99, p less than 0.01) was observed. These data suggest that potent tumoricidal activity of peritoneal macrophage obtained from the patients with gynecological malignancies could be expected by the treatment with SPG and rIFN due to the increased secretion of TNF, IFN-gamma and IL-1 and inhibition of increased secretion of PGE2.

Dinoprostone↗
PubMed1985

Mechanism of interferon action. The interferon-induced phosphoprotein P1 possesses a double-stranded RNA-dependent ATP-binding site.

Protein P1, the interferon-induced protein phosphorylated in the presence of dsRNA in human amnion U-cells, was covalently labeled with [alpha-32P]ATP following ultraviolet irradiation. The photoaffinity labeling of protein P1 was dependent upon double-stranded RNA. Antibody prepared against phosphorylated protein P1 immunoprecipitated the double-stranded RNA-dependent photoaffinity-labeled product. The extent of photoaffinity labeling was significantly decreased by the addition of unlabeled ATP, GTP, or AMP; adenosine had little effect on the photoaffinity labeling of protein P1. These results suggest that protein P1 possesses a site capable of binding an adenine nucleotide in a double-stranded RNA-dependent manner.

Adenosine Triphosphate↗
PubMed1985

Studies on interferon-sensitive cells derived from the interferon-resistant NIH 3T3 clone 1 line.

From the NIH 3T3 clone 1 line which is normally unprotected by interferon (IFN) against lytic virus infection we have selected subclones which show high sensitivity to IFN. The selection procedure was based on encephalomyocarditis virus (EMCV) as selection agent. In the IFN-sensitive subclones thus obtained EMCV replication was inhibited by IFN to a similar degree as observed in L929 cells. Like in the original NIH 3T3 clone 1 line, however, replication of vesicular stomatitis virus (VSV) and cell multiplication were only marginally affected by IFN. We measured the levels of known IFN-induced enzymes (2-5A-synthetase, dsRNA protein kinase and 2-5A-dependent RNase) in a number of subclones and found no consistent differences to the original population. Thus, the newly acquired IFN-dependent protection against EMCV may be mediated by a different antiviral mechanism.

2',5'-Oligoadenylate Synthetase↗
PubMed1988

The physiological interferon response. IX. Interferon activity in rabbit lymph after intraduodenal administration of alimentary lectins.

The physiological interferon (IFN) response involves the production of little amounts of IFN in localized lymphoid microenvironments upon induction of exogenous and endogenous inducers. The aim of this work was to demonstrate whether dietary antigens and/or alimentary lectins could induce IFN in vivo after intraduodenal administration in rabbits. For this purpose we have collected simultaneously the abdominal lymph and plasma during the experiments for about 12 hours. The results show that while both onion' (Allium cepa) and cucumber' (Cucumis sativum) homogenates are ineffective, the hydrolysate of the latter induces a marked increase of IFN in the lymph suggesting that preliminary digestion (and probably gastric digestion) is crucial for the activation of IFN inducers. The maximum IFN activity occurs 7 hours after the administration and there is no concomitant activity in the plasma. Addition of bile salts to either the homogenates or the hydrolysates in unable to modify the pattern of the response. Preliminary characterization of the IFN activity has shown it to be trypsin-sensitive acid- and heat-stable and species-specific.

Animals↗
PubMed1988

Interferon production in myelo- and lymphoproliferative diseases. I. Spontaneous interferon production in acute and chronic leukaemias.

Blood plasma interferon (IFN) of patients with acute myeloid (AML) and chronic granulocytic (CGL) and with acute and chronic lymphoid leukaemia (ALL and CLL) was measured by bioassay and characterized by neutralization with anti-human-IFN-alpha treatment. Elevated IFN-alpha level (60-125 IU/ml) was found in the quiescent phase of CGL as compared to the control samples (15 +/- 10 IU/ml). No significant differences could be found between plasma IFN of patients suffering from the blastic crisis of CGL and control persons. Analogous results were obtained in experiments with plasmas of AML patients, regardless the stage of the disease. Elevated IFN-alpha production (60-100 IU/ml) was found in patients being in the remission phase of T-cell ALL but only in one case in the progressive phase of the disease. No significant elevation of plasma IFN level was demonstrated in patients with O-cell ALL and B-cell CLL, as compared to the control samples.

Blast Crisis↗
PubMed1987

Resistance of vaccinia virus to interferons: modulation of the 2-5A system in interferon-treated, vaccinia virus infected cells.

In this study we have examined if resistance of vaccinia virus to interferon (IFN) correlates with virus-induced alterations of the 2-5A system. We have shown that in various IFN-treated vaccinia virus infected cells of mouse, monkey and human origins, the intracellular levels of 2-5A are low early in infection but exhibit a sharp rise late in infection. In spite of the presence of 2-5A, activation of the 2-5A dependent RNase, as measured by the rRNA cleavage assay, does not occur or is delayed in the course of virus infection. However, when cycloheximide, an inhibitor of protein synthesis is added at the time of virus infection, extensive cleavage or rRNA is observed in IFN-treated, infected cells. If cycloheximide is added at various times after virus infection, rRNA cleavage is gradually prevented and a virus-induced inhibitor of the 2-5A system can be detected between 1-2 hr post infection. A function encoded by a ts 22 mutant of vaccinia virus blocked rRNA cleavage. Restriction of rRNA cleavage during virus infection correlated with dephosphorylation of 2-5A. Our findings suggest that modulation of the 2-5A system by vaccinia virus involves the production of an activator and simultaneous synthesis of an inhibitor(s). Viral ds-RNA is likely to be the activator while a function encoded by ts 22 mutant is involved in inhibition of the 2-5A system. Other viral functions (ATPase and phosphatase) may also be involved in modifications of the 2-5A system by regulating 2-5A levels and altering the integrity of 2-5A. Modifications of the 2-5A system, during vaccinia virus infection might contribute to the resistance of this cytoplasmic DNA virus to IFN.

2',5'-Oligoadenylate Synthetase↗
PubMed1986

Interferons: from molecular biology to man. Part 3. Interferons and disease.

The previous two articles described how the interferons (IFNs) bring about a number of specific molecular changes in the cell which result in functional alterations. IFN-treated cells enter an antiviral state which renders them resistant to a broad spectrum of viruses. They show enhanced differentiated behaviour, significant alterations in cell membrane proteins and slower progress through the cell cycle. This third (and final) article discusses the relevance of the IFN system to the whole animal, both as part of the natural defence against disease and as part of a new series of therapeutic agents collectively called biological response modifiers.

Animals↗
PubMed1989

Modulation of major histocompatibility complex (MHC) class I genes in adenovirus 12 transformed cells: interferon-gamma increases class I expression by a mechanism that circumvents E1A induced-repression and tumor necrosis factor enhances the effect of interferon-gamma.

The protein products of the E1A gene of adenovirus type-12 (Ad12) block transcription of major histocompatibility (MHC) class I genes in both rodent and human transformed cells and interferon-gamma (IFN-gamma) is able to override this repression. Although IFN-gamma is known to stimulate class I transcription, we investigated whether its dominance over E1A repression could alternatively result from the ability of this cytokine to induce antiviral mechanisms. We show that this is not so, since the accumulation of Ad12 E1A mRNA and protein are unabated in the presence of IFN-gamma. Also, tumor necrosis factor (TNF) was shown to act synergistically with IFN-gamma to enhance class I antigen levels, although it had little effect alone. These results suggest that the normal pathway by which IFN-gamma acts to enhance the level of class I mRNAs, circumvents the block by which E1A represses class I transcription.

Adenovirus Early Proteins↗
PubMed1989

Tumor necrosis factor acts synergistically with autocrine interferon-beta and increases interferon-beta mRNA levels in human fibroblasts.

Medium of untreated human FS-4 foreskin fibroblasts contained a factor which, upon the addition of exogenous tumor necrosis factor (TNF), inhibited encephalomyocarditis virus replication when neither medium alone nor TNF alone were effective. This antiviral activity was abolished by a monoclonal antibody to human interferon (IFN)-beta, suggesting that the active component in the medium from untreated FS-4 cells was IFN-beta, present at subeffective concentrations. In addition, we show that untreated FS-4 cells contain IFN-beta mRNA, demonstrable by the highly sensitive polymerase chain reaction after reverse transcription. Treatment of FS-4 cells with TNF produced an approximately 16-fold increase in the steady-state level of IFN-beta mRNA. Our results support the conclusion that autocrine IFN-beta is secreted by untreated normal fibroblasts and that TNF can enhance the production of autocrine IFN-beta by increasing the level of IFN-beta mRNA. Our study also demonstrates that subeffective concentrations of autocrine IFN-beta, which escape detection in conventional assays, are sufficient to produce a strong synergistic action with TNF.

Antibodies, Monoclonal↗
PubMed1985

The physiologic interferon response. VI. Interferon activity in human plasma after a meal and drinking.

Interferon activity in plasma was found negligible in the morning and slightly increased in the afternoon. However, because of the wide variability of the results, the difference was not statistically significant even though the existence of a circadian rhythm appears possible. The afternoon increase of IFN activity could be at least in part due to increased abdominal lymphatic drainage following digestion and absorption. In fact, it has been shown that there is a significant transient increase in IFN plasma level 2 hours after a fat-rich meal or drinking 700 ml of water. IFN activity was due to acid-labile IFN-alpha. This is another, yet indirect, indication of the existence of the physiologic IFN response that entails a localized production of lymphomonokines with limited spillover in the circulation.

Adult↗
PubMed1989

Interleukin 6 (interferon beta 2) and interferon alpha/beta present in postendotoxin serum induce differentiation of murine M1 myeloid leukemia cells.

Serum from lipopolysaccharide-treated mice (postendotoxin serum, PES) induces the differentiation of M1 myeloid leukemia cells into mature macrophages, as well as supporting the proliferation of the interleukin 6 (IL6)-dependent B9 hybridoma cells. The kinetics of appearance of these two activities in PES were identical. To determine whether these two activities are due to the presence of the same substance, we tested whether anti-IL6 antibodies could neutralize the differentiation-inducing activity of PES. We found that anti-IL6 antibodies completely neutralized the proliferation of B9 cells and resulted in a 60% neutralization of the differentiation-inducing activity of PES. Anti-interferon alpha/beta (INF alpha/beta) antibodies neutralized 70% of the differentiation-inducing activity of PES. These data suggest that the differentiation-inducing activity of PES is not limited to IL6, and that PES contains additional factors such as INF alpha/beta that are capable of inducing differentiation of M1 cells.

Animals↗
PubMed1987

Mechanism of interferon action. II. Induction and decay kinetics of the antiviral state and protein P54 in human amnion U cells treated with gamma interferon.

The kinetics of induction and decay of the antiviral state and polypeptide p54 expression induced by recombinant human interferon gamma (rIFN-gamma) were examined in human amnion U cells. The kinetics of induction of the antiviral state, as measured by the single-cycle yield reduction of vesicular stomatitis virus, were first order over the period of about 6-12 h following a lag of about 2-4 h. The induction of p54 synthesis by rIFN-gamma slightly preceded the induction of the antiviral state. The kinetics of p54 induction were first order over a period of about 2-8 h after a lag of about 1 h. The rate of polypeptide p54 synthesis induced by rIFN-gamma decayed significantly within 1 day after the removal of IFN. However, polypeptide p54 was comparatively stable, displaying a half-life of about 3 days. The antiviral state likewise decayed significantly within 3-4 days following removal of IFN-gamma, and by 5-8 days, the virus yields were comparable to those of untreated control cell cultures. These results suggest that polypeptide p54 may play an important role in the antiviral action of rIFN-gamma in human amnion U cells.

Cell Line↗