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Biomedical subjects

E Falcoff

Publications and source records attributed to E Falcoff.

At least 37 records · Page 2Linked to original sources
PubMed1987

Alpha-interferon in hairy cell leukaemia: direct effects on hairy cells or indirect cytotoxicity?

This report presents the results of a clinical trial on 53 patients with hairy cell leukaemia using low-dose alpha-interferon as therapy. Improvement of cytopenia and/or bone marrow hairy cell infiltration occurred in all but one patient. Often, blood and bone marrow improvements were dissociated and, after 7 or 13 months of therapy, complete remission was only observed in about 40% of patients. Recurrence of the disease was observed in some cases after cessation of therapy. A summary of the following results is presented: alpha-interferon receptor analysis, oncogene expression, study of the sensitivity of hairy cells to natural killer cells, and the effects of interferon on T-cell receptor gene rearrangement and on the function of T-cell clones. Results are also presented which show that myelofibrosis may be due to a release of platelet derived growth factor. The immunological findings and oncogene expression in 2 patients with a variant form of hairy cell leukaemia for which resistance to therapy was observed are also described. All the results show that interferon acts on hairy cells and are consistent with a direct effect by interferon in the treatment of hairy cell leukaemia.

Blood Platelets↗
PubMed1987

Treatment of metastatic malignant melanoma with recombinant interferon alfa-2b.

Twenty-six patients with histologically proven metastatic malignant melanoma were included in a phase II trial of interferon alfa-2b (Intron A; Schering-Plough). Patients were given 10 X 10(6) IU/m2 of interferon alfa-2b subcutaneously three times a week until major intolerance or progression of disease. General signs of intolerance were seen in all patients; hematological toxicity with leukopenia (below 1,800/mm3) and/or thrombocytopenia (below 600/mm3) was seen in six patients and therapy was interrupted in one patient. Mild liver toxicity was seen in most patients after two weeks of treatment. These manifestations disappeared 1-2 weeks after treatment was discontinued. Twenty-four patients were evaluable for response. There were two complete responses; one skin and one lymph node going into remission for 12 and 12.5 months respectively. A partial response was observed in five cases lasting 1, 1.8, 2, 3 and 5 months respectively. These results indicate a potential role for interferon alfa-2b in treating patients with metastatic malignant melanoma, however, further trials are required to determine the optimum dose and schedule of administration and use of interferon alfa-2b in combination with cytotoxic drugs.

Drug Evaluation↗
PubMed1987

Potentiation of antiproliferative activity by mixtures of human recombinant IFN-alpha 2 and -gamma on growth of human cancer nodules maintained in continuous organotypic culture.

Alveolar II pulmonary tumor cells (A549 cells) maintained in continuous tridimensional organotypic culture were used to evaluate the eventual potentiation effect of mixtures of recombinant human interferon-alpha 2 and -gamma on growth inhibition of the tumor nodules. A continuous 45 day treatment (interferon renewed three times a week) with 10, 10(2) or 10(3) U/ml of IFN-alpha 2 or -gamma combined with a fixed high dose (10(3) U/ml) of either IFN-alpha 2 or -gamma resulted in an additive or synergistic growth inhibition according to the doses used. There was a close dose-effect relation, the percentage of inhibition increasing proportionally to the variable IFN doses added to the fixed high dose; moreover, the growth inhibition effect occurred earlier with the mixtures than with IFNs used separately. Furthermore, the growth inhibition observed with 2000 U/ml of the mixture (1000 U/ml of each IFN) was greater than that induced by 2000 U/ml of IFN-alpha 2 or -gamma used alone. A 35-day treatment with IFN-alpha 2 1000 U/ml plus IFN-gamma 1000 U/ml led to a complete growth inhibition and necrosis of the nodules. These data demonstrate that IFN-alpha 2 and -gamma cooperate to potentiate the IFN antiproliferative activity.

Cell Division↗
PubMed1987

From old results to new perspectives: a look at interferon's fate in the body.

In a previous report, we presented preliminary data on interferon-alpha A (IFN-alpha A) pharmacokinetics through the simultaneous study of distribution of the radiolabeled protein by numerical dynamic scintigraphy and the trichloroacetic acid (TCA)-precipitable radioactivity in whole blood and serum, as well as the radioactivity linked to blood mononuclear cells. The interferon preparation then used was contaminated with free iodine which gave parasite images and counts. Here we present further analysis of those data, enlightened by additional information collected in new studies with interferon preparations without free iodine. Interferon uptake by the kidneys, liver, and heart was a consistent finding. On the contrary, images in stomach and duodenum seem mostly related to their well-known iodine uptake. At present, whether interferon is present in saliva and nasal secretion is unclear. The extent to which blood radioactivity corresponded to blood cells or plasma was analyzed. TCA-precipitable radioactivity measured after administration of filtered radiolabeled interferon was mainly confined to serum. The marginal amount bound to cells seemed to be in leukocytes. Current research points to compare the pharmacokinetic profiles of IFN-alpha and IFN-gamma.

Humans↗
PubMed1987

Proliferative response of hairy cells to B cell growth factor (BCGF): in vivo inhibition by interferon-alpha and in vitro effects of interferon-alpha, -beta, and -gamma.

Hairy cell leukemia (HCL) is a pre-plasma B cell tumor which responds to interferon (IFN)-alpha therapy. In vitro, B cell growth factor (BCGF) can induce proliferation of hairy cells. We have investigated the effect of in vitro and in vivo treatments with different recombinant IFN on the capacity of hairy cells to proliferate in response to human BCGF. In vitro treatment of leukemic cells from HCL patients with recombinant IFN-alpha-2 (5/5 cases) or IFN-beta (4/5 cases) resulted in a marked inhibition of the BCGF-dependent response. This suppressive effect was obtained with IFN concentrations of 1000, 100 IU/ml, and even occasionally 10 IU/ml. In contrast, no such inhibition was observed with IFN-gamma, despite the presence of specific IFN-gamma receptors on hairy cells at densities similar to receptors for IFN-alpha/beta. The IFN-alpha-induced suppression of the proliferative response of hairy cells to BCGF was also observed in vivo in two patients within 6-12 hr after administration of single doses of IFN-alpha. When hairy cells were maintained in culture for 1 week, they recovered their capacity to be stimulated by BCGF. This reversion was also shown in vivo in hairy cells isolated 1 week after IFN administration. Since in vivo growth of hairy cells could possibly result from the autocrine secretion of BCGF, we propose that the therapeutic effect of IFN-alpha on HCL may be due in part to an inhibition of such autocrine loop.

2',5'-Oligoadenylate Synthetase↗
PubMed1986

Clinical phase II trial of recombinant DNA interferon (interferon alpha 2b) in patients with metastatic malignant melanoma.

Twenty-four patients with histologically proven metastatic malignant melanoma were included in a Phase II trial of human DNA recombinant interferon (rDNA IFN alpha 2). They were given 10 X 10(6) IU of IFN alpha 2 subcutaneously three times a week until progression of disease or major intolerance developed. Twenty-two patients were evaluable for toxicity and response. General manifestations of intolerance were seen in all the patients. Hematologic toxicity was seen in six patients and therapy had to be interrupted in one patient. Mild liver toxicity was seen in most patients after 2 weeks of treatment. These manifestations disappeared within 2 weeks after treatment was discontinued. A partial response was seen in four cases lasting 2, 4, 4, and 5 months, respectively. There were two complete responses (one skin, one lymph node metastasis) lasting 20 and 6 weeks, respectively. These results indicate a potential role for rDNA IFN alpha 2 in treating patients with metastatic malignant melanoma. However, further trials are required to determine the optimal dose and schedule of administration and modalities of combination.

Adult↗
PubMed1986

Interferon alpha in the treatment of hairy cell leukemia.

Fifty-four patients with hairy cell leukemia were treated for 7 months with three types of subcutaneously injected interferon: recombinant interferon alfa-2a from Hoffmann-La Roche (3 X 10(6) U daily); recombinant interferon alfa-2b from Schering (2 X 10(6) U/m2, three times per week); and partially purified human leukocyte interferon alpha from the Finnish Red Cross (3 X 10(6) U daily). After 4 months, in 27 patients hairy cells decreased dramatically (P less than 0.01) while platelets (P less than 0.05), monocytes (P less than 0.01), polymorphonuclear leukocytes (P less than 0.01) and hemoglobin (P less than 0.01) increased (in this order) as treatment progressed. Morphometric parameters were used to estimate the relative volume of hairy and myeloid cells present in bone marrow. Biopsies were performed at the beginning of the study and in the second, fourth, and seventh months thereafter. Bone marrow disorders were slower to improve as compared with blood. Six severe cases of hairy cell leukemia were responsive to treatment, but required special monitoring during the first 2 months. All three interferons studied are efficient. Interferon receptors, oncogene (mRNA levels) expression, and the relationship between PDGF and fibrosis in hairy cell leukemia are under investigation.

Adult↗
PubMed1986

Binding and cross-linking of recombinant mouse interferon-gamma to receptors in mouse leukemic L1210 cells; interferon-gamma internalization and receptor down-regulation.

Recombinant E. coli-derived murine IFN-gamma (Mu-rIFN-gamma; 5 X 10(7) U/mg) was radiolabeled with 125I by the chloramine-T method without loss of its antiviral activity. The 125I-Mu-rIFN-gamma showed specific binding to L1210 cells. Scatchard analysis indicates about 4000 binding sites per cell and an apparent Kd of 5 X 10(-10)M. Binding of 125I-Mu-rIFN-gamma to cells was inhibited by both natural (glycosylated) and rIFN-gamma, but not by IFN-alpha/beta. Receptor-bound 125I-Mu-rIFN-gamma was rapidly internalized when incubation temperature was raised from 4 degrees C to 37 degrees C. On internalization, almost no IFN-gamma degradation was observed during 16 hr incubation. 125I-Mu-rIFN-gamma binding capacity decreased in cells preincubated with low doses of unlabeled Mu-rIFN-gamma, but not with IFN-alpha/beta. This receptor down-regulation was dose-dependent: 90% reduction of 125I-Mu-rIFN-gamma binding was observed after preincubation with 100 U/ml. After removal of IFN-gamma from the culture medium, the binding capacity increased with time. However, reappearance of receptor was completely blocked by cycloheximide or tunicamycin, suggesting that re-expression of receptors is not due to recycling but to the synthesis of new receptors, and that the receptor is probably a glycoprotein. Cross-linking of 125I-Mu-rIFN-gamma to surface L1210 cell proteins by using bifunctional agents yielded a predominant complex of m.w. 110,000 +/- 5000. Thus, assuming a bimolecular complex, the m.w. of the receptor or receptor subunit would be close to 95,000 +/- 5000. The formation of such a complex appeared highly specific on the basis of the following criteria: it could be inhibited by the addition of Mu-rIFN-gamma but not by Mu-rIFN-alpha/beta, it was not obtained in cells pretreated with IFN-gamma to induce down-regulation of IFN-gamma receptors, and it was also identified in the IFN-alpha/beta-resistant L1210R cell line, known to be sensitive to IFN-gamma and which we have recently shown to express IFN-gamma receptors.

Animals↗
PubMed1986

Effects of human recombinant interferons-alpha 2, -beta and -gamma on growth and survival of human cancer nodules maintained in continuous organotypic culture.

Alveolar II pulmonary tumor cells (A549 cells) maintained in continuous tridimensional organotypic culture were used to test the effects of recombinant human interferons -alpha 2, -beta and -gamma on growth inhibition and survival of the tumor nodules. The organotypic culture method has several advantages: the three-dimensional structures of the cells as well as some cell differentiation are maintained and the extremely low traumatizing culture conditions offer injured cells the maximum chance of survival. A continuous treatment lasting 65 days (three weekly interferon changes) with 10, 10(2), 10(3) and 10(4) U/ml doses of the three interferons led to growth inhibition and necrosis only in the presence of the two highest doses (10(3) and 10(4) U/ml) of IFN-alpha 2 and -gamma. IFN-beta had no inhibitory effect. Some nodules, especially at the lower dose levels (10(2) U/ml), showed enhanced growth in presence of the three types of interferons. After stopping the treatments, all the necrotic and disintegrating nodules resumed growth. Growth of the recovered nodules was followed in the absence of interferon for another period of 70 days. The growth rate of IFN-beta and -gamma-treated nodules was similar to that of the controls, but was slowed down for the regenerated IFN-alpha 2-treated nodules. Hence, in A549 organotypic cancer nodules and under our experimental conditions, only high doses of IFN-alpha 2 and -gamma appeared to have a partial cytolytic, but finally no tumoricidal action; IFN-beta was inactive. At the lower doses growth stimulation was found during the treatments with the three interferons.

Cell Survival↗
PubMed1986

Treatment of hairy cell leukemia with recombinant alpha interferon: II. In vivo down-regulation of alpha interferon receptors on tumor cells.

Interferons (IFNs) initiate their effects by interacting with specific high-affinity cell surface receptors, but little is known about the physiology of IFN receptor interaction in vivo. Treatment of patients suffering from hairy cell leukemia (HCL) with human recombinant alpha IFN results in significant tumor regression, with clinical improvement in a high percentage of cases. To investigate a possible relevance of binding parameters as response markers, IFN receptor interaction on tumor cells responsive to IFN in vivo was studied. Binding of human alpha 2 IFN to circulating hairy cells was analyzed before and during IFN therapy in ten patients selected on the basis of high numbers of peripheral hairy cells. Binding experiments were carried out on Ficoll-Paque fractionated peripheral cell samples containing a majority of hairy cells. All patients reacted to recombinant alpha IFN treatment with a striking decrease in binding capacity within 12 hours after the first injection. As demonstrated by using a monoclonal antibody able to recognize alpha 2 IFN bound to its receptor, this decreased binding capacity was not due to blocking by circulating IFN but rather to a decrease in receptor number. This receptor "down-regulation" was partially reversible after the first IFN injection. However, upon prolonged IFN therapy, all patients displayed a stable state of decreased receptor expression. Down-regulation of IFN receptors can be regarded as a response marker to IFN treatment. This response marker, however, was not correlated with the clinical response within the first months of IFN therapy.

Animals↗
PubMed1986

Treatment of hairy cell leukemia with recombinant alpha interferon: I. Quantitative study of bone marrow changes during the first months of treatment.

Seventeen patients with hairy cell leukemia (HCL) were treated with low doses of recombinant alpha interferon (IFN) for over 4 months. Marked improvement was observed in peripheral blood and bone marrow in 15 of 17 patients. Comparison of pretreatment values and hemograms obtained after 4 months of treatment showed a marked decrease in circulating hairy cells (P less than .01), a decrease in the number of lymphocytes (P less than .01), a rise in the number of platelets (P less than .05), granulocytes (P less than .05), and monocytes (P less than .01), and a rise in the hemoglobin level (P less than .01). Transient reduction in the number of granulocytes was noted during the first month. Correction of thrombocytopenia often appeared within 2 months and usually preceded improvement of anemia, monocytopenia, and neutropenia. Bone marrow biopsy specimens were taken before treatment and 2, 4, and 7 months after its initiation. The volumes occupied by hairy cells, cells of the myeloid lines, and adipocytes were studied by stereological analysis of semithin sections. Decrease in the volume occupied by hairy cells was seen after 4 months of treatment (P less than .01), and the volume continued to decrease at the seventh month (P less than .05). Hairy cells were no longer detected on bone marrow biopsies of 4 of 17 patients by the fourth month and in 3 of 8 additional patients by the seventh month. A rise in the volume occupied by normal myeloid cells was visible by the second month of treatment (P less than .01). Nevertheless, the volume occupied by granulocytes remained lower than in the normal controls (P less than .01). After an initial increase during the first 2 months of treatment (P less than .01), the overall cellularity remained unchanged at 4 months and decreased significantly (P less than .05) at 7 months. Except for biopsies at 2 months, mean cellularity was below that of control biopsies (P less than .01).

Biopsy↗
PubMed1985

125I-labelled human interferons alpha, beta and gamma: comparative receptor-binding data.

Binding of 125I-labelled human recombinant DNA interferons (IFNs) alpha-2, beta and gamma was compared on various human lymphoid cells and embryonic fibroblasts. While binding constants were within an order of magnitude for all three interferons (10(-10) to 10(-9) M), no competition was observed between IFN-gamma on the one hand and IFN-alpha 2 and IFN-beta on the other. However, consistent with previous reports, IFN-alpha 2 and IFN-beta competed for presumably common receptors. Depending on the cell type, binding sites for IFN-gamma were expressed in different numbers compared to those for IFN-alpha 2 and IFN-beta. These direct comparative binding studies support the hypothesis that the receptor system for IFN-gamma is unrelated to the IFN-alpha/beta system.

Binding Sites↗
PubMed1985

[Demonstration of 2-5A synthetase in human circulating mononuclear cells after oral administration of an interferon inducer isolated from a fraction of Escherichia coli and Klebsiella pneumoniae].

Evaluation of the activity of an enzyme activated by interferon (2'-5' oligo-isoadenylate synthetase or 2-5A synthetase) has been used to determine, in man, the interferon inducing capacity of a fraction isolated from Escherichia coli and Klebsiella pneumoniae, SL04, an immunomodulating agent administrated per os. An increase of the activity of this enzyme has been shown in four out of five volunteers following a single oral administration of 100 mg of SL04. This activation demonstrated in humans confirms the pharmacological results of the interferon induction obtained with SL04 in vivo in mice and in vitro in human cell cultures.

2',5'-Oligoadenylate Synthetase↗
PubMed1984

Synergistic protection by specific antibodies and interferon against infection by Trypanosoma cruzi in vitro.

Trypanosoma cruzi infects many mammalian cell types in vitro, including fibroblasts and macrophages. We have analyzed and compared the infection of mouse 3T3 fibroblasts and J774 macrophage-like tumor cells by cloned Y-A1.2 T. cruzi trypomastigotes. The effects of T. cruzi-specific antibodies and of interferon (IFN) on infection were considered. Specific antibodies protected 3T3 fibroblasts from infection by T. cruzi, but increased the relative infectivity for J774 cells due to binding of the opsonized parasite to J774 Fc receptors. It was also apparent that IFN-alpha, beta (produced by fibroblasts) and IFN-gamma (produced by T lymphocytes) activated trypanocidal activities in both 3T3 and J774 cells, although IFN-gamma was 100 to 2000 times more effective than IFN-alpha, beta on the basis of IFN antiviral units added per culture. When anti-T. cruzi antibodies and IFN-alpha, beta or IFN-gamma were used jointly, a synergistic protective effect was observed with both 3T3 fibroblasts and J774 cells. These results suggest that B and T lymphocytes might collaborate in vivo in the protection against T. cruzi infections by the production of anti-trypomastigote antibodies and IFN-gamma, respectively.

Animals↗
PubMed1984

Studies on purification of human gamma interferon: chromatographic behavior of accompanying IL2 and B-cell helper activity.

Gamma interferon (gamma IFN) was produced in human lymphocyte cultures stimulated by PHA. Titers were in the range of 10,000-30,000 U/ml. Crude gamma IFN was adsorbed on silicic acid, from which the antiviral activity was eluted by a buffer containing a high salt concentration and ethylene glycol. This treatment allowed quantitative recovery of gamma IFN with a specific activity of 5 X 10(5)-1 X 10(6) U/mg of proteins. IL2 and B-cell helper activities were adsorbed and eluted from silicic acid together with the antiviral activity. This finding might be of practical interest for the purification of these lymphokines, particularly IL2. Gamma interferon was further purified on Blue Sepharose to a specific activity of 2 X 10(7) U/mg. The resulting preparations still contained IL2 and B cell helper activities. However, taking advantage of the differences in apparent hydrophobicity and in isoelectric point, we were able to dissociate antiviral activity from lymphokines. Such dissociation should facilitate the study of the biological properties of human natural gamma IFN.

Adsorption↗
PubMed1984

Endogenous interferon in Argentine hemorrhagic fever.

The induction of endogenous interferon (IFN) was studied in 28 cases of Argentine hemorrhagic fever (AHF), a severe systemic disease caused by Junin virus. Serum samples were taken daily during the acute period, both before and after administration of immune plasma. This form of treatment has been found to reduce mortality when given early in the course of AHF. High titers of circulating IFN were present in the serum samples taken before treatment. IFN titers drastically dropped after transfusion of immune plasma. The antiviral activity was stable at pH 2 and was completely neutralized only by antibodies against IFN-alpha. Thus, we concluded that circulating endogenous IFN in patients with AHF can be considered as typical IFN-alpha. Fever, chills, and backache were associated with the higher levels of IFN. An inverse correlation between days of evolution of the disease and IFN activity was also observed.

Back Pain↗