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

The key enzymes in the formation of eicosanoids, including leukocyte 5-lipoxygenase (5LX), platelet 12-lipoxygenase (12LX), reticulocyte 15-lipoxygenase (15LX), prostaglandin G/H synthase cyclooxygenase, and leukotriene A4 (LTA) hydrolase have been studied extensively in recent years. Little is known, however, about the regulation of these enzymes at the gene level. We have developed a quantitative polymerase chain reaction (PCR) assay to quantify the mRNAs for these five enzymes, as well as for cytoplasmic beta-actin (bACT) mRNA. Human erythroleukemia (HEL) cells, which display megakaryocytic/erythroid characteristics, were selected as a source of RNA to characterize the assay. These cells expressed mRNA for bACT, LTA, cyclooxygenase, and 12LX (in decreasing order). mRNA for 5LX and 15LX was undetectable. Bronchoalveolar lavage fluid cells obtained from asthmatic patients, primarily alveolar macrophages, contained mRNA for bACT, LTA, 5LX, cyclooxygenase, and 15LX (in decreasing order). Treatment of HEL cells with phorbol 12-myristate 13-acetate or steroid administration to asthmatic patients apparently selectively regulated certain of these target genes. The utility of this assay in quantifying mRNA for the various target genes in blood cells, including platelets from patients with chronic myelogenous leukemia, has also been demonstrated. Studies on the regulation of genes for enzymes involved in the leukotriene and prostaglandin biosynthetic pathways, especially when only small tissue samples are available, will be facilitated with this approach.
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PMID:Eicosanoid forming enzyme mRNA in human tissues. Analysis by quantitative polymerase chain reaction. 190 25

Basophils were isolated and propagated in large numbers from the blood of patients with chronic myelogenous leukemia. Propagation over 4-6 weeks of culture was dependent upon a growth factor(s) other than interleukin-2 obtained from a lectin-stimulated clone of the Jurkat cell line. Evidence that these basophils were dividing during culture included an increase in both the number of basophils and the histamine content of the cultures over time, as well as ultrastructural studies that demonstrated basophil cell division. The cells also had the capacity to be stimulated in an IgE-dependent manner characteristic of basophils. Cultured basophils passively sensitized with IgE underwent noncytotoxic degranulation after stimulation with specific antigen. Antigen-stimulated basophils released histamine, leukotrienes B4 and C4 and other 5-lipoxygenase products of arachidonic acid metabolism. Culture models such as this may permit the propagation and purification of sufficient numbers of basophils to allow biochemical and immunological analyses of basophil physiology.
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PMID:Propagation and characterization of human blood basophils. 245 92

Eicosanoids regulate a wide spectrum of cellular processes including cell proliferation. We have shown previously that lipoxygenase metabolites of arachidonic acid modulate normal human hematopoiesis by in vitro colony assays. In this study we investigated the role of lipoxygenase metabolites in regulating the proliferation of several malignant hematopoietic cell lines, including K562 and EM-2 (chronic myelogenous leukemia blasts), HL-60 (promyelocytic leukemia cells), and U937 (malignant histiocytes). Piriprost, a specific inhibitor of 5-lipoxygenase, inhibits proliferation of these cell lines up to 95% with 50% cell inhibition at approximately 3 x 10(-5) M. Other less specific lipoxygenase inhibitors such as caffeic acid, nordihydroguaiaretic acid, and BW755C have similar activity in a [3H]-thymidine incorporation assay. In contrast, indomethacin, which is a cyclooxygenase inhibitor, has no suppressive effect in these assays. Inhibition by these drugs is completely reversible. Several nonhematopoietic malignant cell lines do not appear to be affected by these drugs. Two specific lipoxygenase metabolites, leukotriene B4 and leukotriene D4, stimulate leukemia cell line proliferation to 150% of control levels when added directly to cell cultures. These data suggest that certain lipoxygenase products, perhaps leukotrienes, are critical for the proliferation of malignant hematopoietic cells in vitro.
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PMID:Antiproliferative effects of lipoxygenase inhibitors on malignant human hematopoietic cell lines. 290 62

The arachidonate metabolism by leukocytes and platelets was studied in 14 patients with myeloproliferative disorders including 7 patients with chronic myeloid leukemia (CML), 5 with polycythemia vera (PV) and 2 with essential thrombocythemia (ET). When the leukocytes were incubated with arachidonate and A23187, leukotriene B4 and hydroxyeicosatetraenoic acids (HETEs) were constantly detected using reversed-phase high-performance liquid chromatography in normal subjects, while selective deficiency of 5-lipoxygenase products (leukotriene B4 and 5-HETE) was found in 4 patients with CML. this novel abnormality of the leukocytes seemed to be derived from the possible deficiency of 5-lipoxygenase in these patients' polymorphonuclear neutrophils (PMNNs). The formation of 15-HETE appeared to be almost normal in all the patients. Platelet 12-lipoxygenase deficiency was detected in 2 patients with PV and 2 with CML in whom one was associated with the deficiency of 5-lipoxygenase products. These bicellular abnormalities of the arachidonate metabolism might contribute to understand dysfunctions of PMNNs and platelets in some patients with myeloproliferative disorders.
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PMID:Altered arachidonate metabolism by leukocytes and platelets in myeloproliferative disorders. 631 27

Several inhibitors of the arachidonic acid-metabolizing enzyme, 5-lipoxygenase reduce proliferation of hematopoietic and non-hematopoietic cells and cell lines and some cells undergo limited differentiation. Cells were cultured from patients with chronic myelogenous leukemia in "blast" crisis with the selective inhibitor of 5-lipoxygenase, SC41661A[3-(3,5-bis(1,1-dimethyl)-4-hydroxyphenyl)hiol]-N-me thyl-N-[2-(2- phridinyl-propanamide)]. Cells cultured for 3 to 5 days with 40 microM SC41661A exhibited reduced cellular numbers along with ultrastructural changes and DNA laddering characteristic of apoptosis. Similar culture conditions reduced proliferation of U937 monoblastoid cells. In U937 cells, the ultrastructural features of apoptosis were not observed at 72 hours, when DNA laddering was present and cell numbers were reduced, but was present after 144 hours of culture. Dissociation between certain morphologic and biochemical sequelae of apoptosis has been described in other systems. These observations are of interest since the induction of apoptosis in dividing chronic myelogenous leukemia (CML) cells by a non-cytotoxic agent suggests paradigmatically new sites for therapeutic intervention.
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PMID:Morphologic changes of apoptosis induced in human chronic myelogenous leukemia "blast" cells by SC41661A (Searle), a selective inhibitor of 5-lipoxygenase. 774 66

Participation of leukotriene products in normal ex vivo hematopoiesis is well established. With increasingly specific inhibitors of lipoxygenases, it becomes possible to more closely define any participation of their biosynthetic products in these events. We cultured chronic myelogenous leukemia cells from the peripheral blood of several patients in blast crisis with three inhibitors of lipoxygenases: ETYA, and the more selective A63162 (Abbott) or SC41661A (Searle). All three agents reduced labelling of DNA with H3 thymidine measured at 4 h and reduced cell numbers by 72 h. An antisense deoxyoligonucleotide to the 5-lipoxygenase mRNA 'start' codon inhibited DNA synthesis at 24 h, as did two control oligonucleotides. Marked nuclear ultrastructural changes characteristic of apoptosis were induced by SC41661A in a subset of cells with the ultrastructure of promyelocytes. Whether this response characterizes a common pattern of this subset of leukemic cells to SC41661A, if damage to mitochondria with reduced function of bcl-2 protooncogene product located at that site might have contributed or some other mechanism was responsible, and if inhibition of 5-lipoxygenase activity was involved, are questions to be decided in the future.
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PMID:Induction of apoptosis in blood cells from a patient with acute myelogenous leukemia by SC41661A, a selective inhibitor of 5-lipoxygenase. 849 93

Inhibitors of the arachidonic acid metabolizing enzyme, 5-lipoxygenase, reduce the rate of proliferation of chronic myelogenous leukemia blast cells. The inhibitory agents studied were ETYA, A63162 and SC41661A. These reagents induced differentiation of cultured chronic myelogenous leukemia cells from blast to promyelocytic morphology. Promyelocytic cells then underwent apoptosis, which was identified by nuclear and cytoplasmic morphological features and by DNA laddering. Proliferation of monoblastoid U937 and myelomonocytic HL60 cell lines, known to contain 5-lipoxygenase and synthesize leukotrienes, was reduced by these inhibitors. U937 cells cultured with ETYA, A63162 or SC41661A for 48 h exhibited apoptosis as assessed by DNA laddering and morphology. Characteristic ultrastructural changes of apoptosis were seen at 120 h. MK886, an inhibitor of 5-lipoxygenase with a mechanism of action distinct from oxidation/reduction reagents, at 20-40 microM also inhibited CML and U937 cell proliferation and induced apoptosis, as shown by DNA laddering and ultrastructure.
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PMID:Selective inhibitors of 5-lipoxygenase reduce CML blast cell proliferation and induce limited differentiation and apoptosis. 855 95

MK886 (Merck Frosst) is a selective in vivo inhibitor of 5-lipoxygenase, active at nanomolar concentrations. At micromolar concentrations, it inhibited the proliferation of U937 monoblastoid cells and of cultured malignant cells from patients with chronic myelogenous leukemia. These cells became morphologically apoptotic, a form of physiologic cell death. U937 cell apoptosis was assessed by flow cytometry, ultrastructure, DNA laddering and immuno-histology for free 3'OH-DNA. MK886-induced apoptosis developed over time as cells were recruited in concert with reduction in their numbers. Some CML cells exhibited cytoplasmic changes of apoptosis without typical nuclear changes. Under conditions used for measuring Ca2+ with Fura 2, 10 micromolar MK886 increased U937 intracellular Ca2+ 4-fold or more over the 8 minute period of measurement. Since MK886 inhibits the association of arachidonic acid with the 5-lipoxygenase activating protein, altered arachidonic acid metabolism may have contributed to these results.
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PMID:An in vivo inhibitor of 5-lipoxygenase, MK886, at micromolar concentration induces apoptosis in U937 and CML cells. 891 56

Micromolar MK886, a selective inhibitor of 5-lipoxygenase at nanomolar concentration, induces physiologic cell death in U937 and chronic myelogenous leukemia blast cells. When U937 cells were challenged with 10 microM MK886, an acute, biphasic and sustained rise in intracellular Ca2+ occurred, as determined with Fura-2. The initial increase was followed by a transient decline and a larger rise due to an influx of external Ca2+. The first increase and part of the subsequent rise also developed in Ca(2+)-free medium, identifying their origin from intracellular stores. The intracellular Ca2+ concentration of U937 cells that remained after culture for 24 or 48 h with 5 or 10 microM MK886 was not reliably altered from the control values of 130 +/- 8.3 nM. Under similar conditions MK886 did not increase cytosol Ca2+ of a human prostate (PC3) cell line examined in suspension. The increase in intracellular Ca2+ in response to MK886 in calcium-containing medium was confirmed with an ACAS laser spectrometer. U937 cytosol pH was measured with the fluorescent probe BCECF, but not persistent acute or chronic change was induced by MK886. The rapid and sustained rise in Ca2+ induced by MK886 is an early event in U937 cells which subsequently undergo physiologic cell death characterized in many by apoptosis.
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PMID:A 5-lipoxygenase inhibitor at micromolar concentration raises intracellular calcium in U937 cells prior to their physiologic cell death. 904 39

The effect of Granulocyte-Macrophage, Colony Stimulating Factor (GM-CSF) and Interleukin-6 (IL-6) on leukotriene production by CML white blood cells induced by calcium ionophore (A23187) was investigated and the leukotrienes formed were identified and quantified using high performance liquid chromatography (HPLC). The in vivo levels of IL-6 and LTB4 were determined by enzyme immunoassay reagents, while GM-CSF was measured by enzyme amplified sensitivity immunoassay. Although GM-CSF or IL-6 alone did not stimulate the synthesis of 5-lipoxygenase product, preincubation of the white blood cells of CML with GM-CSF or IL-6 for 30 minutes at 37 degrees C enhanced the ionophore A23187 induced leukotrienes synthesis, thus the CML white blood cell suspension primed with GM-CSF or IL-6 produced 26.6 +/- 2.8 and 18.9 +/- 1.3 pmol LTC4/10(6) cells respectively, and 30.2 +/- 3.6 and 25.5 +/- 2.5 Pmol LTB4/10(6) cells. In contrast minute amount of leukotrienes were produced by the control cells. In vivo levels of GM-CSF, IL-6 and LTB4 were investigated in CML and normal healthy donors, elevated chemotactic B4 was found in plasma from CML (267 +/- 70.4) while the mean value in normal healthy donors was (127 +/- 13.6) pg/ml. The plasma level of GM-CSF was 32.4 +/- 15.7 pg/ml and 10.5 +/- 3.1 pg/ml respectively in CML and normal healthy donors, while the mean value of GM-CSF and IL-6 in normal healthy donors were 6.7 +/- 2.2 and 4.9 +/- 2.4 pg/ml respectively. No significant correlation was observed between the level of LTB4 and the level of GM-CSF or IL-6 in CML.
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PMID:Granulocyte-macrophage colony stimulating factor and interleukin-6 enhanced white blood cell synthesis of leukotrienes in chronic myelogenous leukemia. 932 31


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