Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemistry, biological activity, and pharmacokinetics of gamma-interferon and recombinant interferon gamma are reviewed, and the agent's clinical efficacy, adverse effects, and dosage and administration for the treatment of chronic granulomatous disease (CGD) and other disorders are described. Endogenous gamma-interferon is a 166-amino-acid protein encoded by a single gene on chromosome 12. Recombinant human interferon gamma is purified from Escherichia coli as a monomer containing 139 amino acids. Gamma-interferon has antiviral, immunomodulatory, and antiproliferative activity. Serum concentrations of recombinant interferon gamma increase in proportion to the dose. Clearance after i.m. or s.c. administration fits a two-compartment model. The half-life is 3.5-7.5 hours, and bioavailability is 89%. Evidence that recombinant interferon gamma can enhance phagocytic oxidative metabolism led to its evaluation for use in the treatment of CGD. Clinical studies showed that the agent decreases the frequency of serious infections in patients with CGD. Recombinant interferon gamma has shown only limited success in the treatment of metastatic renal cell carcinoma (RCC), both as a single agent and in combination with recombinant interferon alfa. Similarly, although interferons appear to be able to change cytogenetic abnormalities in some patients with Philadelphia chromosome-positive chronic myelogenous leukemia, therapy with recombinant interferon gamma has led to minimal success. However, the agent has produced some encouraging results in atopic dermatitis. The adverse effects of recombinant interferon gamma in patients with CGD usually consist only of fever, chills, headache, and erythema. The recommended dosage in CGD-afflicted children whose body surface area is greater than 0.5 sq m is 50 micrograms/sq m given by s.c. injection three times a week for life. Recombinant interferon gamma has given new hope to patients with CGD. Although the drug is very expensive, the cost may be offset by fewer hospitalizations to treat infection.
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PMID:Recombinant interferon gamma for treatment of chronic granulomatous disease and other disorders. 134 90

Juvenile chronic myelogenous leukemia (JCML) is a rare pediatric malignancy characterized by marked hepatosplenomegaly, leukocytosis with prominent monocytosis, elevated fetal hemoglobin, no Philadelphia chromosome, and generally a poor prognosis. In vitro, JCML peripheral blood granulocyte-macrophage progenitors (granulocyte-macrophage colony-forming units, CFU-GM) demonstrate the unique characteristic of "spontaneous" proliferation at very low cell densities in the absence of exogenous growth factors. The "spontaneous" CFU-GM proliferation can be abolished by prior adherent cell (monocyte) depletion, suggesting a paracrine mode of cellular proliferation. Although previous studies using a [3H]thymidine ([3H]TdR) incorporation assay suggested an important role for granulocyte-macrophage colony-stimulating factor (GM-CSF) in JCML, many non-growth factor-related reasons for [3H]TdR incorporation and the relatively low level of inhibition of [3H]TdR uptake left those conclusions open to question. Therefore, we performed clonal CFU-GM assays, which more specifically reflect cytokine effects on CFU-GM, using JCML peripheral blood mononuclear cells (PBMNC) and neutralizing antibodies against GM-CSF, granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating (M-CSF), interleukin 3 (IL-3), interleukin 1 alpha (IL-1 alpha), interleukin 1 beta (IL-1 beta), interleukin 4 (IL-4), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF alpha), and interferon gamma (IFN gamma). Cultures containing anti-GM-CSF alone inhibited "spontaneous" JCML CFU-GM by 87% +/- 9% (mean +/- standard error of the mean [SEM]). No other anti-cytokine antibody produced a significant inhibition of CFU-GM growth. Various combinations of antibodies, excluding anti-GM-CSF, failed to demonstrate any synergistic inhibitory effects upon CFU-GM. Because this apparent paracrine cellular stimulation could be due to excessive cytokine production, by monocytes or other accessory cells, we examined cytokine levels in conditioned media from various JCML cell populations using enzyme-linked immunosorbent assays (ELISAs). Monocytes from only a minority of JCML patients produced higher than normal quantities of GM-CSF, G-CSF, IL-1 beta, IL-6, and/or TNF alpha, but no obvious pattern could be discerned. Further, only 7 of 15 JCML monocyte-conditioned media (MCM) had elevated GM-CSF, and 6 of 15 JCML patients had normal levels of all nine cytokines tested. The monocyte depletion experiments and the inhibition experiments with anti-cytokine antibodies taken together demonstrate clearly that the "spontaneous" growth of JCML CFU-GM in vitro critically depends on at least one monocyte-derived growth factor, GM-CSF.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of monocyte-derived hemopoietic growth factors in the regulation of myeloproliferation in juvenile chronic myelogenous leukemia. 191 2

Six chronic and four advanced patients with Ph1 positive chronic myelogenous leukemia (CML) received autologous bone marrow transplantation (ABMT) using bone marrow treated ex vivo with recombinant human interferon gamma (rIFN gamma). In three cases 100% Ph1 negative bone marrow hematopoiesis was demonstrated 4 to 8 weeks after ABMT. In three additional cases, a maximum of 40-45% bone marrow metaphases were Ph1 negative 2 to 12 weeks following ABMT. In four cases, no or minimal evidence of Ph1 negative hematopoiesis could be demonstrated posttransplant. Seven patients survive in chronic phase at a median of 375 days (range 100-495 days). Five patients have not required therapy, while two patients receive low doses of rIFN alpha to control peripheral blood counts. Ex vivo treatment of CML bone marrow with rIFN gamma followed by ABMT in patients dependent upon or refractory to therapy prior to transplantation is associated with transient complete or partial Ph1 negative bone marrow hematopoiesis in the majority of patients post-transplant and with return of a chronic phase characterized by no need for therapy or by response to low doses of rIFN alpha. Modification of the ABMT procedure and efforts to maintain cytogenetic and hematologic remission following ABMT may lead to prolonged survival or cure.
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PMID:Autologous transplantation for CML using marrow treated ex vivo with recombinant human interferon gamma. 211 38

Alpha- and gamma-interferons have been shown to actively suppress hematopoiesis in patients in the chronic phase of chronic myelogenous leukemia in vitro and in vivo. Since both interferons act through different receptors on their hematopoietic target cells, they are expected to be capable of independently inhibiting abnormal blood cell development in patients with chronic myelogenous leukemia. We have utilized recombinant human interferon alfa-2c to treat 11 patients with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase, who were resistant to previous interferon gamma therapy. Ten of the patients were evaluable for hematologic, cytogenetic and molecular-genetic response following interferon alfa-2c therapy for 6 to 30 months. In 5 patients, IFN alfa-2c treatment failed due to lack of hematologic response. A complete hematologic or partial hematologic response was achieved in the remaining 5 patients. Three of these experienced cytogenetic improvement with reappearence of 100% diploid hematopoietic cells and disappearence of c-abl/bcr rearrangement in one patient. In two patients interferon alfa-2c did not prevent transformation of the disease into an accelerated state or blast crisis, respectively. We conclude that recombinant human interferon alfa-2c may also control hematopoiesis in interferon-gamma resistant chronic myelogenous leukemia patients, although the long-term response will need to be elucidated in further studies.
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PMID:Interferon alfa-2c in chronic myelogenous leukemia (CML): hematologic, cytogenetic and molecular-genetic response of patients with chronic phase CML previously resistant to therapy with interferon gamma. 212 Dec 99

We report a case of a 33-year-old woman who developed episodes of palpitation while receiving weekly alternating doses of daily intramuscular recombinant interferon alpha-2a (rIFN alpha-2a) and recombinant interferon gamma (rIFN gamma) for Philadelphia chromosome-positive chronic myelogenous leukemia. The electrocardiogram (ECG) and ambulatory Holter monitoring showed first-degree atrioventricular (A-V) block and episodes of junctional tachycardia. The ECG abnormality and palpitation disappeared after discontinuation of therapy. On rechallenge with recombinant interferon alpha-2b (rIFN alpha-2b) alone, there was recurrent palpitation and first-degree A-V block. Subsequent treatment with various doses of rIFN alpha-2b established a dose-response relationship between rIFN alpha-2b and palpitation in our patient. In view of increasing use of rIFNs in the clinical setting, this potential, albeit uncommon, toxicity requires attention and further investigation.
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PMID:Cardiac arrhythmia in a CML patient treated with interferons. 249 75

The therapeutic potential of recombinant interferon gamma (IFN gamma) alone or in combination with two cytotoxic drugs - 5-fluorouracil (5-FU) and cytosine arabinoside (Ara-C) - was studied in vitro on two myeloid leukemia systems: HL60 promyelocytic cell line and chronic granulocytic leukemia (CGL) progenitor cells. When applied individually, IFN gamma and the drugs inhibited in a dose-dependent manner HL60 cell colony formation in semisolid culture. Moreover, IFN gamma or the cytotoxic drugs dose-dependently reduced the colony formation of CGL progenitor cell in agar. When added in combination, IFN gamma potentiated synergistically the inhibitory action of 5-FU in both systems. The most pronounced potentiation was detected at concentrations of 0.5 microgram/ml 5-FU and 50 U/ml IFN gamma. On the contrary, the antiproliferative effect of Ara-C was enhanced only subadditively when combined with IFN gamma. In view of the present findings, which are supported by new evidence from the literature, the use of 5-FU in leukemia should be reconsidered. The results further imply the potential value of combined treatment of 5-FU and IFN gamma in leukemia.
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PMID:New combination of 5-fluorouracil and interferon-gamma effective against human myeloid leukemia in vitro. 251 May 79

Chronic myelogenous leukemia (CML) granulo-monocyte committed progenitors (CFU-GM) are markedly less sensitive than normal progenitors to the inhibitory action of prostaglandin E (PGE). This phenomenon has been ascribed to their abnormal expression of HLA class II (mainly DR) determinants. Since interferon gamma (IFN-gamma) is a potent inducer of the expression of HLA class II (DR and to a lesser extent DQ) antigens, we have sought to determine the extent to which this agent can modulate both the antigenic pattern of normal and leukemic progenitors and their sensitivity to PGE 1. 72-h preincubation of normal and CML bone marrow cells with or without IFN-gamma does not significantly change DR and DQ expression by CFU-GM. Pre-incubation for 72 h with and without IFN-gamma produces the following changes in PGE 1 sensitivity: (1) normal CFU-GM lose some sensitivity to PGE 1. This is only marginally counteracted by the presence of IFN-gamma. (2) CML CFU-GM, preincubated with IFN-gamma regain a significant sensitivity to high concentrations of PGE 1. Our data confirm the expression of DR molecules on normal and leukemic progenitors. They also show that, although incubation with IFN-gamma for 72 h in a liquid culture system does not significantly affect the expression of HLA class II molecules by progenitor cells, it may increase their sensitivity to PGE, particularly in the case of CML CFU-GM. Thus expression of HLA class II antigens and sensitivity to PGE may be dissociated.
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PMID:Effect of interferon-gamma on HLA class II antigen expression and sensitivity to prostaglandin E1 by normal and leukemic myeloid progenitors. 313 93

We treated 11 patients who had Philadelphia-chromosome-positive chronic myelogenous leukemia with natural interferon alpha (human lymphoblastoid interferon; HLBI). HLBI was given at 6-12 X 10(6) u/day i.m. or i.s.c. during induction therapy. Nine patients responded to the treatment, of whom 7 had hematologic remission and 2 had partial remission. Six patients with MDS or hypoplastic leukemia, and 3 patients with overt leukemia from MDS were treated with recombinant interferon gamma (GI-3). GI-3 was given at 0.4 X 10(6) u/m2 of body-surface area per day i.s.c. or i.v. for 4-6 weeks. In 2 patients with RAEB and hypoplastic leukemia, the blast cell count in bone marrow decreased from 8-16% to 2-3% after 4 weeks of administration. In another patient with hypoplastic leukemia, blast cells in the marrow did not decrease, but anemia was improved without transfusion, increasing the bone marrow NCC and erythroblast count. In patients with overt leukemia and CMML, no clinical effect was obtained. Interferons can therefore be offered to patients in a preleukemic state.
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PMID:[Clinical investigation of interferons in the preleukemic state (CML and MDS)]. 313 93

HLA-identical bone marrow transplantation (BMT) is associated with both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) reactivity. Different T-cell subsets from the bone marrow (BM) graft may be responsible for GVHD and GVL reactivity after BMT. In the etiology of GVHD, not only CD8+ but also CD4+ donor T lymphocytes may play an important role. Here we report a patient with chronic myeloid leukemia (CML) who was transplanted with the BM from his HLA-genotypically identical sister. After BMT there was complete engraftment, but the patient died because of acute GVHD grade III-IV in complete remission. Cytotoxic T-lymphocyte (CTL) lines were generated after BMT using the irradiated leukemic cells from the patient as stimulator cells and the donor-originated peripheral blood mononuclear cells, procured from the patient after BMT, as responder cells. The generated CTL lines showed specific lysis of the recipient lymphocytes and leukemic cells in a 51Cr release assay. Two types of CTL clones could be established from these CTL lines, both phenotypically CD4+. Clone type I showed male-specific HLA-DQ5-restricted lysis of the recipient lymphocytes, but not of the circulating relatively mature leukemic cells from the patient. This may be explained by the low HLA-DQ5 expression of the more mature CML cells. Clone type II showed HLA-DR2-restricted minor histocompatibility antigen-specific lysis of the recipient lymphocytes and leukemic cells. Both types of CTL clones showed antigen-specific cell-mediated growth inhibition of the recipient clonogenic leukemic precursor cells. These CD4+ CTL clones produced several activating cytokines including tumor necrosis factor alpha, interferon gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage CSF. Our results illustrate that these CD4+ CTL clones may have induced GVHD directly by cytolysis and indirectly by activating cytokines. Because both types of CTL clones recognized the recipient leukemic progenitor cells, they may also contribute to GVL reactivity after BMT.
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PMID:Generation of CD4+ cytotoxic T-lymphocyte clones from a patient with severe graft-versus-host disease after allogeneic bone marrow transplantation: implications for graft-versus-leukemia reactivity. 767 Jan 18

In the present in vitro study we investigated the influence of 2-chlorodeoxyadenosine (2-CdA) and interferon gamma (IFNgamma) on the clonal growth of granulocyte macrophage progenitor (CFU-GM) cells from 10 normal individuals and from 10 patients with chronic myeloid leukemia (CML) and on CFU-L blasts from 10 patients with acute myeloid leukemia (AML). 2-CdA was added to the culture medium at 20nM/l, 40nM/l and 80nM/l concentrations and IFNgamma at concentrations of 10(2)U/ml, 10(3)U/ml and 10(4)U/ml. Both agents were used alone and in combination with these different concentrations. We observed a decrease in the number of colonies formed by CML CFU-GM as well as by AML CFU-L in a dose-dependent manner. The drugs used alone inhibited to a higher degree the growth of CML than of normal CFU-GM progenitors. 2-CdA and IFN gamma showed the greatest additive effect on the growth of CFU-L blasts at the concentrations of 80nM/l and 10(4)U/ml, respectively. We compared our results with previous in vitro studies in which we have demonstrated the synergistic inhibitory effect of 2-CdA and IFN alpha on both normal and leukemic hematopoiesis. We suggest that the greatest inhibitory effect is observed when 2-CdA and IFN alpha at the highest concentration are added together to the culture of AML CFU-L blasts.
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PMID:The comparison of 2-chlorodeoxyadenosine (2-Cd A) in combination with interferon alpha (IFN alpha) or interferon gamma (IFN gamma) on granulocyte-macrophage progenitor cells (CFU-GM) and clonogenic blasts in (CFU-L) in vitro cultures. 890 84


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