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)

Granulocyte colony-stimulating factor (G-CSF) is known to act on the neutrophilic granulocytes from chronic myelogenous leukemia (CML) patients to induce neutrophil alkaline phosphatase (NAP) activity. Gamma-interferon (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been reported to suppress NAP induction with G-CSF. We confirmed that this inhibitory effect of GM-CSF is accompanied by the decrease of the NAP mRNA level. Moreover, we found that the simultaneous addition of retinoic acid completely neutralized this inhibitory effect of GM-CSF. Recovery of the NAP activity brought about by the retinoic acid was also accompanied by the increase of NAP mRNA level. These results indicate that retinoic acid neutralizes the inhibitory effect of GM-CSF on the induction of NAP activity through the change of the NAP mRNA level.
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PMID:Retinoic acid acts to neutralize the inhibitory effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on alkaline phosphatase activity of neutrophils that is induced by granulocyte colony-stimulating factor (G-CSF). 137 89

Activity of the interferon-induced enzyme 2'-5' oligoadenylate synthetase (2-5 OAS) was measured in peripheral blood mononuclear cells (PBMCs) and serum of patients with chronic phase Ph'-positive chronic myelogenous leukemia (CML) treated with interferon-alpha (IFN-alpha) (4 x 10(6) IU/m2) alone or in combination with 50 micrograms IFN-gamma. At the beginning of IFN therapy, marked elevation of 2-5 OAS titers was detected in PBMCs (pretreatment 0.03-1.62, median 0.2; during treatment 0.8-13.14, median 4.31; 22 patients studied) and in serum (pretreatment 21-156 pmol/dl, median 62; during treatment 532-1740 pmol/dl, median 800; eight patients studied). However, 2-5 OAS titers were not related to clinical outcome or IFN therapy and also during IFN resistance elevated 2-5 OAS activity in PBMCs (median 3.45; range 1.05-13.14; 11 patients studied) were detected. These data argue against direct involvement of the 2-5 OAS system in the therapeutic effect of IFN in CML. However, 2-5 OAS titers in PBMCs or serum appear to be a reliable control of biologically active IFN therapy.
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PMID:Induction of 2'-5' oligoadenylate synthetase during interferon treatment of chronic myelogenous leukemia. 138 Nov 90

Symptoms of autoimmune disease were evaluated in 125 patients with chronic myelogenous leukemia (CML) and in 12 patients with essential thrombocythemia undergoing treatment with recombinant interferon (IFN)-alpha-2b plus/minus low-dose recombinant IFN-gamma. Twenty-seven of 137 patients (20%) developed rheumatoid symptoms. Furthermore, the incidence of antinuclear antibody (ANA) formation was studied. Elevated ANA titers were found in 5/19 (26%) of CML patients at the time of diagnosis and in 3/18 (17%) of patients treated with hydroxyurea or busulfan. During IFN treatment, 18 of 25 tested patients (72%) had elevated ANA titers. In 15 of these ANA-positive patients, clinical signs of autoimmune disease appeared. All these patients were under long-term IFN treatment and were in remission of disease. In three patients criteria for systemic lupus erythematosus were fulfilled. Severity of side effects had led to the discontinuation of IFN treatment in these patients. The data indicate that IFN-alpha and IFN-gamma can induce ANA associated with autoimmune disease in patients with myeloproliferative disorders.
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PMID:Lupus-like autoimmune disease induced by interferon therapy for myeloproliferative disorders. 138 10

The effects of various compounds which modulated the intracellular signal transduction on the induction of class I major histocompatibility complex (MHC) antigens by recombinant human interferon-gamma (rIFN-gamma) were investigated using K562, chronic myelogenous leukemia cells. Class I or class II MHC antigens were not expressed in untreated K562 cells and rIFN-gamma (600 units/ml) weakly induced class I antigens on the cells. Among the compounds tested, verapamil but not the calcium ionophore A23187 enhanced the rIFN-gamma-induced class I antigen expression at both the surface molecule and mRNA levels and enhancement by verapamil occurred in a dose-dependent manner at non-toxic concentrations examined (approximately 50 microM). Verapamil alone had no inducible effect on MHC antigen expression. Deprivation of Ca2+ in culture medium by ethylene glycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) could not cause an enhancement of class I antigen induction by rIFN-gamma. Simultaneous exposure of K562 cells to rIFN-gamma (600 units/ml) and recombinant human tumor necrosis factor (rTNF; 1000 units/ml) in combination with verapamil (50 microM) resulted in a further increase of class I antigens in the cells. The expressions of c-myc oncogene in K562 cells were not changed when the cells were treated with rIFN-gamma (600 units/ml) or verapamil (50 microM), either alone or in combination. These results indicate that verapamil synergistically interacts with rIFN-gamma on the class I antigen induction in K562 cells irrespective of c-myc gene expression and that class I antigen induction in this cell line may not be relevant to calcium influx triggered by IFN-gamma.
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PMID:Effect of verapamil on the class I major histocompatibility complex antigen expression in K562 chronic myelogenous leukemia cells treated with recombinant human interferon-gamma. 151 24

In vitro data suggest a synergistic antiproliferative effect of different cytokines. In four clinical studies chronic myelogenous leukemia (CML) patients were treated with interferon (IFN)-alpha alone or IFN-alpha combined with either low-dose IFN-gamma or tumor necrosis factor (TNF)-alpha. The best response was achieved in previously untreated patients with good prognostic factors and highest tolerable IFN dose for maintenance treatment. Breakpoint localization within the major breakpoint cluster region did not correlate with response to IFN. In a randomized study of IFN-alpha versus IFN-alpha combined with IFN-gamma, no differences in response rates were observed. Patients with primary or secondary resistance to these treatment modalities received a combination therapy with IFN-alpha and TNF-alpha. In these patients, a decrease in leukocyte counts was noted, but no cytogenetic improvement occurred.
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PMID:Treatment of chronic myelogenous leukemia with different cytokines. 155 80

We investigated the effect of recombinant human interleukin-4 (rhIL-4) on the in vitro growth of human leukemia cells in liquid culture and 3H-thymidine incorporation and found inhibitory effects on the growth of leukemic cells from patients with Ph1-positive acute lymphoblastic leukemia (Ph1 ALL) and three Ph1 ALL cell lines. However, no inhibitory effects were seen in Ph1-positive leukemic cell lines derived from patients with chronic myelogenous leukemia in blast crisis and various types of Ph1-negative leukemia cells, including B-lineage leukemia cells. In a flow cytometry assay of IL-4 receptor (IL-4R), all three Ph1-positive ALL cell lines showed the presence of IL-4R on their cell surfaces, and the IL-4-dependent inhibition on the growth of Ph1-positive ALL cells was abrogated by the addition of either monoclonal or polyclonal antibodies against rhIL-4. Other cytokines, including IL-2, IL-3, granulocyte-macrophage colony-stimulating factor (CSF), granulocyte-CSF, and IL-6, showed no inhibitory effects on the growth of Ph1-ALL cells, but tumor necrosis factor-alpha (TNF-alpha) and interferon (IFN)-alpha, -beta, and -gamma displayed slight inhibitory effects in a high concentration. The growth inhibition induced by rhIL-4 in the Ph1-positive ALL cells was not abrogated by the addition of antibodies against either IFN-gamma or TNF-alpha. Furthermore, these cells showed no significant production of IFN-alpha, -beta, or -gamma or TNF-alpha after exposure to rhIL-4, thus indicating that the growth inhibition of Ph1-positive ALL cells by rhIL-4 is not associated with IL-4-stimulating production of these factors. rhIL-4 caused significant inhibition of the tyrosine kinase activity in these Ph1-positive ALL cells, similar to Herbimycin A, an inhibitor of tyrosine kinase that inhibited the tyrosine kinase activity in these cells. Our finding suggests that the clinical evaluation of rhIL-4 may offer promising therapeutic possibilities for patients with Ph1-positive ALL.
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PMID:Inhibitory effect of interleukin-4 on the in vitro growth of Ph1-positive acute lymphoblastic leukemia cells. 188 23

We have previously shown that a factor termed NAP-IF has the capacity to induce neutrophil alkaline phosphatase (NAP) in postmitotic granulocytes (PMGs). Recently, this factor found in cystic fluid of a human squamous cell carcinoma was shown to be identical to granulocyte colony-stimulating factor (G-CSF). In this study we examined whether NAP activity inducible with G-CSF could be modulated by other factors that are present in vivo or those that are known to induce differentiation of hemopoietic cells. Purified natural and recombinant G-CSF (nG-CSF and rG-CSF) induced NAP in PMGs from both normal individuals and patients with chronic myelogenous leukemia. Interferons (IFNs) suppressed expression of NAP by G-CSF. IFN-gamma was a potent inhibitor of G-CSF stimulation: IFN-gamma at 100 U/ml inhibited by greater than 90% the induction of NAP by G-CSF. In contrast, retinol (10(-6) M, a nearly physiological concentration) or all-trans-retinoic acid (10(-6) M) significantly enhanced NAP activity in vitro. Furthermore, the simultaneous addition of 10(-6) M retinol partially reversed the inhibitory action of IFN-gamma on the NAP induction by G-CSF. Our results suggest that NAP activity, which is often abnormal in a variety of diseases, may reflect G-CSF levels in vivo perhaps in concert with a number of other factors including IFNs and retinoids.
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PMID:Modulation by retinoids and interferons of alkaline phosphatase activity in granulocytes induced by granulocyte colony-stimulating factor. 246 68

Tumor necrosis factor alpha (TNF-alpha) and gamma-interferon (IFN-gamma) have been shown to suppress clonogenic growth in cultures containing blast cells obtained from patients with acute myeloid leukemia. We report that recombinant human TNF-alpha and IFN-gamma are also able to induce functional and morphological maturation in fresh myeloid leukemic cells in vitro. Assessing suspension cultures containing cells from patients with acute myeloid leukemia (11 patients) or myeloid blast crisis of chronic myeloid leukemia (5 patients), it was found that recombinant human TNF-alpha and IFN-gamma significantly enhanced the number of cells reducing nitroblue tetrazolium, as compared to control cultures containing no cytokine (P less than 0.001 and P less than 0.001, respectively). Cells from responders showed alterations characteristic of monocyte/macrophage differentiation, adherence to plastic surfaces, development of positive staining for alpha-naphthyl acetate esterase, typical morphology, and expression of cell surface antigens detected by the monoclonal antibodies Mo-1, Mo-2, and My-4. Both cytokines decreased the number of viable cells, the number of blast cells, and the number of cluster-forming units in suspension culture, suggesting inhibitory actions on the growth capacity of leukemic cells. Compared to the maximum effects of either factor alone, the combination of recombinant human TNF-alpha and IFN-gamma significantly increased the extent of growth inhibition and cell adherence but did not result in further increases in nitroblue tetrazolium reduction. The presence of Auer rods in IFN-gamma or TNF-alpha differentiation-induced macrophages with cells from a patient with M5 acute myeloid leukemia demonstrates that these cytokines can induce differentiation of a leukemic clone in primary cells from patients with leukemia.
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PMID:Differentiation-inducing effect of recombinant human tumor necrosis factor alpha and gamma-interferon in vitro on blast cells from patients with acute myeloid leukemia and myeloid blast crisis of chronic myeloid leukemia. 249 71

The effects of recombinant human interferon (IFN) alpha-2b and gamma on the bone marrow megakaryocyte progenitors (CFU-Meg) were compared between eight patients in the chronic phase of Ph1-positive chronic myelocytic leukemia (CML) and five hematologically normal patients. CFU-Meg was assayed in plasma clot culture added with phytohemagglutinin-stimulated leukocyte-conditioned medium as a source of colony stimulating activity. The average count of CFU-Meg colonies formed from the bone marrow of CML patients was 5.5 times that of normal controls. Spontaneous CFU-Meg colonies were grown in seven of eight CML patients, but in none of five controls. Colony formation by CFU-Meg in CML as well as normal bone marrow was suppressed by the two preparations of IFN in a dose dependent fashion. Their suppressive influence on colonies from CFU-Meg was comparable between CML and normal bone marrow at lower concentrations, but was less marked for CML than normal bone marrow at higher concentrations. The formation of CFU-Meg colonies from CML bone marrow was more severely suppressed by IFN-gamma than IFN-alpha-2b. Depletion of either T lymphocytes or adherent cells from the CML bone marrow cells diminished the suppressive effects of IFN-gamma, but had no influence on the effects of IFN-alpha-2b.
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PMID:[Effects of recombinant human alpha-2b and gamma interferons on bone marrow megakaryocyte progenitors (CFU-Meg) from patients with chronic myelocytic leukemia]. 251 97

Natural and recombinant interferons (IFNs) have already demonstrated therapeutic efficacy, including cytogenetic remissions, in patients with chronic myelocytic leukemia (CML). We investigated at the level of ligand-receptor interaction the question whether heterogeneity of receptor number or affinity might contribute to primary or secondary treatment failures in CML. We therefore analyzed IFN-gamma and IFN-alpha receptor expression and regulation during treatment with recombinant IFN-gamma and IFN-alpha in 15 patients with advanced CML. We found no difference in number or affinity of constitutively expressed IFN-gamma receptors (mean 1,100) and, on average, a 30% reduction of IFN-alpha receptors (mean 750) on peripheral blood mononuclear cells (PBMNC) of patients with chronic or accelerated CML as compared to mature granulocytes and/or bone marrow cells of healthy controls, which express on average 1,050 and 1,100 IFN-gamma and IFN-alpha receptors, respectively. While IFN-gamma receptor expression on PBMNC is not influenced upon treatment with rIFN-gamma, there is a substantial downregulation of IFN-alpha receptors in the course of rIFN-alpha therapy. Our data also show a differential pattern of receptor downregulation between patients achieving complete hematologic remission (CHR) (4 out of 12) compared with patients with partial hematologic remission (PHR) and non-responders. We conclude that differences in IFN receptor number cannot explain primary or secondary treatment failures. However, the differential ligand induced downregulation of IFN-alpha receptors in patients achieving CHR compared to those with PHR or non-responders suggest a prospective value of IFN-alpha receptor determination.
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PMID:Sequential therapy with recombinant interferons gamma and alpha in patients with unfavorable prognosis of chronic myelocytic leukemia: clinical responsiveness to recombinant IFN-alpha correlates with the degree of receptor down-regulation. 252 42


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