Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have used the vitamin D analogue, 1 alpha,25-dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalcifero l (Ro24-5531), for inhibition of mammary carcinogenesis induced by N-nitroso-N-methylurea (NMU) in Sprague-Dawley rats. Rats were first treated with a single dose of either 15 or 50 mg/kg body weight NMU and then fed Ro24-5531 (2.5 or 1.25 nmol/kg of diet) for 5-7 months. Ro24-5531 significantly extended tumor latency and lessened tumor incidence as well as tumor number in rats treated with the lower dose of NMU. In rats treated with the higher dose of NMU, Ro24-5531 was fed in combination with tamoxifen; in these experiments, Ro24-5531 significantly enhanced the ability of tamoxifen to reduce total tumor burden, as well as to increase the probability that an animal would be tumor free at the end of the experiment. In vitro, Ro24-5531 was 10-100 times more potent than 1,25-dihydroxyvitamin D3 for inhibition of proliferation of human breast cancer cell lines as well as primary cultures of cells from 2 patients with acute myelogenous leukemia. When fed chronically, Ro24-5531 did not elevate serum calcium in the present studies. We propose the new term, "deltanoids," for the set of molecules composed of vitamin D and its synthetic analogues, in a manner similar to the naming of "retinoids" for the corresponding set of molecules related to vitamin A.
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PMID:1 alpha,25-Dihydroxy-16-ene-23-yne-26,27-hexafluorocholecalciferol (Ro24-5531), a new deltanoid (vitamin D analogue) for prevention of breast cancer in the rat. 813 76

Annexin VIII is a calcium- and phospholipid-binding protein with anticoagulant activity. Annexin VIII mRNA was found to be specifically expressed in acute promyelocytic leukemia (APL) cells; it was not found in other types of acute myeloid leukemia (AML) nor in lymphoid malignancies. Using Northern blot analysis we investigated annexin VIII expression in 142 continuous human leukemia and lymphoma cell lines at the mRNA level. While the only APL cell line, NB-4, was indeed positive, other cell lines also displayed annexin VIII mRNA: 4/22 myeloid cell lines, 8/23 monocytic cell lines, 2/8 megakaryoblastic cell lines, 5/26 lymphoma-derived cell lines, 2/10 myeloma cell lines and 1/44 lymphoid leukemia cell lines. The strongest expression was seen in NB-4 and in the Hodgkin's disease derived cell line HDLM-2. Treatment of NB-4 cells with all-trans retinoic acid (ATRA) or the phorbol ester TPA induced terminal differentiation and down-regulated annexin VIII mRNA expression rapidly within a few hours; vitamin D3 was ineffective in this regard; the protein kinase C activator Bryostatin 1 up-regulated the expression. A panel of initially negative cell lines could not be induced by any of these biomodulators to transcribe annexin VIII. The half-life (T1/2) of annexin VIII mRNA was about 3-4 h using actinomycin D as transcription inhibitor. Treatment with ATRA or TPA prior to exposure to actinomycin shortened the T1/2 to 2 h while Bryostatin 1 extended it to 6h. As 21/141 non-APL cell lines were positive, annexin VIII cannot be used as a marker gene for APL cells; however, it might be associated with myelomonocytic or erythro-megakaryoblastic precursor cells. Annexin VIII gene expression might play a unique role in the proliferation and/or differentiation of leukemic cells and could be associated with the particular abnormal hemostasis of some leukemias.
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PMID:Expression and modulation of annexin VIII in human leukemia-lymphoma cell lines. 823 Dec 35

Retinoic acid (RA) is an interesting agent which has been shown to induce differentiation and complete remission in patients with acute promyelocytic leukemia. 1,25-(OH)2-delta 16-23-yne-cholecalciferol (16-23-D3) and 1,25-(OH)2-23-yne-cholecalciferol (23-D3) are vitamin D3 analogs capable of inducing differentiation of myeloid leukemic cells with little effect on either calcium absorption or mobilization. Using HL-60 myeloid leukemic cells as in vitro model for human acute myeloid leukemia we observed an additive to synergistic interaction between RA and 16-23-D3 or 23-D3 with respect to the inhibition of cell growth and DNA synthesis, the induction of differentiation and the loss of cell clonogenicity. In addition, we observed that RA and 16-23-D3 interact additively with respect to the reduction of c-myc mRNA expression. These results suggest that Ra used in combination with 16-23-D3 or 23-D3 may be an interesting chemotherapeutic regimen to evaluate in patients with acute myeloid leukemia.
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PMID:Interaction of retinoic acid and vitamin D3 analogs on HL-60 myeloid leukemic cells. 839 95

Interleukin-8 (IL-8), a member of the family of small inducible cytokines, is mainly known for its striking neutrophil-activating properties. Constitutive IL-8 production is negligible in normal leukocytes. We examined expression of IL-8 and its receptor in purified leukemic cells from patients with untreated acute myeloblastic leukemia (AML) and lymphoid leukemias. In the majority of cases (18 of 26 AML, 8 of 15 lymphoid leukemias), the cells constitutively expressed IL-8 mRNA transcripts. In all but 3 of these cases, IL-8 mRNA-expressing cells secreted biologically active IL-8 protein. Immunocytochemical analysis showed intracellular IL-8 (5% to 90% of total cells), demonstrating that the leukemic cells themselves rather than contaminants (monocytes or lymphocytes) were the source of IL-8. Ten of 25 AML samples expressed IL-8 receptor mRNA and, with 1 exception, the IL-8 receptor expressing cells also produced its ligand. In contrast, all lymphoid leukemias were negative. Furthermore, frequent coexpression of IL-8 and IL-1 beta transcripts was seen in both AML and lymphoid leukemia samples, whereas fewer cases coexpressed IL-8 and either macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor. In leukemic cells expressing the IL-8 receptor, IL-8 induced cytosolic free calcium changes, indicating activation of the classical signaling pathway. These results suggest that IL-8 may have biologic activities in hematopoiesis.
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PMID:Constitutive expression of interleukin-8 and its receptor in human myeloid and lymphoid leukemia. 840 Feb 99

Serious cardiac arrhythmias and QT interval prolongation have been reported following Amsacrine chemotherapy. The underlying mechanism is unknown. In this study, electrolyte and electrocardiographic parameters were prospectively studied in patients with acute myeloid leukemia (AML) treated with an Amsacrine containing combination chemotherapy regime. Data were collected immediately before and at 20 (+20) and 90 (+90) min after commencement of Amsacrine administration. Sixteen episodes were studied in six consecutive patients over a continuous 9 month period. One patient developed asymptomatic ventricular tachycardia during administration. Results from +20 and +90 min were compared with baseline by Wilcoxon matched pairs test. There was no significant change in potassium, albumin, or ionized calcium concentration at +20 or +90 min. The magnesium concentration at +20 min was significantly reduced (mean -0.04 mmol/liter; P < 0.05) but not so at +90 min. Sodium concentration at +20 min was significantly reduced (mean - 1.9 mmol/liter; P < 0.01). Electrocardiographic analysis showed no significant alteration in PR interval or QRS duration. Heart rate fell significantly from baseline, mean change -10 and -8 min-1 at +20 and +90 min, respectively (P < 0.01 for both). Corrected QT interval (QTc) was significantly prolonged at +20 min (+0.05) and +90 min (+0.05) (P = 0.0001 and P < 0.0001, respectively). This study confirms the high incidence of QTc prolongation with Amsacrine administration and suggests that transient hypomagnesemia may contribute to the risk of cardiac arrhythmia in this setting.
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PMID:Induction of hypomagnesemia during Amsacrine treatment. 843 99

The endogenous endonucleases capable of producing nucleosomal-size DNA fragmentation are considered candidates of the key enzyme of apoptosis. We examined these activities in the nuclear fraction of non-adherent marrow mononuclear cells (NonAd-MNCs) from patients with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) using a nuclear autodigestion method. We detected Ca2+/Mg(2+)-dependent endonuclease activity in all samples examined. In contrast, Ca(2+)-independent activity with the ability to produce nucleosomal-size DNA fragmentation was found only in samples from a proportion of patients with MDS (12 of 26 consecutive cases) and all the patients with AML (n = 6), but not in the samples from control group patients (n = 10). This activity was correlated with the percentage of bone marrow (BM) blast cells to some extent. Although the levels of these endogenous endonuclease activities seem not to be correlated directly with the susceptibility of the cells to apoptosis, we postulate that the Ca(2+)-independent endonuclease activity may be associated with apoptosis and/or cell proliferation. Further follow-up study of these patients may be meaningful to clarify the prognostic significance of the Ca(2+)-independent endonuclease activity in patients with MDS.
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PMID:High levels of Ca(2+)-independent endonuclease activity capable of producing nucleosomal-size DNA fragmentation in non-adherent marrow mononuclear cells from patients with myelodysplastic syndromes and acute myelogenous leukemia. 855 41

Cytosine arabinoside is usually considered to be lethal by incorporation into DNA followed by chain termination. Recently, we have reported that the radical scavenger N-acetyl-cysteine (NAC) protects cultured clonogenic AML blast cells from the lethal affects of Ara-C if given before the drug. This observation provides indirect evidence that toxic reactive oxygen intermediates (ROI) are generated in AML blast cells following Ara-C-induced damage to DNA. In the present paper we present evidence in support of this hypothesis. Using flow cytometry and multiple fluorescent probes for live cell function, we have mapped a sequence of discrete stages that occur during Ara-C cytotoxicity. An early event was the increased generation of ROI. Initially this oxidative stress was countered by an increase in the cellular content of reduced glutathione (GSH), but cells then underwent an abrupt transition to a state characterized by low GSH and very high ROI generation indicative of collapse of cellular redox balance. Next, the capacity to maintain low intracellular ionized calcium was lost, probably due to lipid peroxidation at membrane sites of calcium regulation. Finally, surface membrane integrity was lost. Concurrent measurements of clonogenic cell survival insured the relevance of these flow cytometry measurements to the stem cell population. We used OCI/AML-2 cells transfected with bcl-2 to look for the place in this sequence where bcl-2 protein protects cells against apoptosis; bcl-2 transfectants showed an increase in ROI generation similar to controls, but were able to maintain GSH levels in the face of this oxidative stress. We conclude that oxidative stress plays a major role in Ara-C toxicity, and that bcl-2 protein protects cells by maintaining cellular redox balance in a reducing state. These studies complement previous work showing how regulators of AML growth affect the sensitivity of blast cells to Ara-C by changing the concentration or stability of bcl-2 protein.
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PMID:Generation of reactive oxygen intermediates after treatment of blasts of acute myeloblastic leukemia with cytosine arabinoside: role of bcl-2. 868 94

Recent reports indicate an increased risk of acute myeloid leukaemia in children exposed to extremely low frequency magnetic fields (ELFMFs) emitted by high voltage power lines, suggesting that ELFMFs may act as weak tumour promoters. We have investigated possible interactions of weak ELFMFs with primitive haemopoietic cells in vitro using the multipotential progenitor cell line FDCP-mix(A4). We have determined the proliferative activity and clonogenic potential of cells under both optimal and sub-optimal growth conditions and exposed to either ambient laboratory ELFMFs or three other ELFMF regimes representative of those produced by high voltage power lines: nulled fields, Ca2+-ion cyclotron resonance conditions at 50 Hz, and vertical 50 Hz fields of 6 muT(RMS). Using exposures of 1, 4, 7 and 21 days, we found no significant alteration of growth rate, cell-cycle state or clonogenic efficiency indicating that neither the proliferation nor self-renewal of multipotential FDCP-mix(A4) cells was perturbed.
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PMID:Exposure to extremely low frequency magnetic fields has no effect on growth rate or clonogenic potential of multipotential haemopoietic progenitor cells. 891 28

The inhibition of Na(+)-H+ exchange (NHE) with amiloride analogues in vitro has been shown to prevent reperfusion arrhythmias and additional cell necrosis. Inhibition of intracellular Ca2+ overload via NHE inhibition has been suggested as a mechanism of these protective effects. The aim of this study was to examine whether treatment with amiloride analogues reduces the incidence of reperfusion arrhythmias and limits infarct size in vivo. Open-chest swine were exposed to a 30-minute left anterior descending artery (LAD) occlusion and 180 minutes of reperfusion during atrial pacing at 150 ppm. Intravenous 5-(N,N-dimethyl)-amiloride (AML, 5 micrograms/kg per min) was administered in the treatment group (n = 7) and intravenous saline in the control group (n = 7), starting 10 minutes before coronary occlusion. The infusion was continued during ischemia and reperfusion. The area at risk was defined by monastral blue dye and infarct size by triphenyltetrazolium chloride staining. Limb leads ECG and monophasic action potentials (MAPs) from the epicardium in the ischemic area were recorded. There was no significant difference in the size of the area at risk and hemodynamic parameters between the groups. However, the infarcted area was 0.4% +/- 1.0% of the area at risk in the treatment group, whereas it was 62% +/- 29% in the control group (P < 0.05). Pathological examination (Hematoxylin-eosin and Mallory's phosphotungstic acid-hematoxylin staining) revealed that all of the infarcted area consisted of contraction band necrosis. MAP duration in both groups was significantly shortened during ischemia. After reperfusion, MAP duration in the treatment group recovered earlier than that of control group. However, there was no significant difference in the incidence of ventricular tachyarrhythmia between the groups. Inhibition of NHE with AML prevented reperfusion related cell necrosis in the in vivo swine model, but did not reduce the incidence of ventricular tachyarrhythmia.
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PMID:Role of Na(+)-H+ exchange on reperfusion related myocardial injury and arrhythmias in an open-chest swine model. 894 91

We studied the effects of a novel vitamin D analog CB1093, EB1089 (one of the most antileukemic analogs yet) and 1 alpha,25(OH)2D3 both on HL-60 cells and cells from 13 AML patients. Differentiation was measured both by induction of superoxide production and non-specific esterase. Cell proliferation was assessed by colony assay and 3H-thymidine incorporation. The effect on serum calcium was measured in rats. The CB1093 proved to be the most efficient of the analogs tested so far, both in inducing differentiation and in inhibiting proliferation. This, combined with its low hypercalcemic effect shown here, makes it a promising candidate for preclinical animal studies.
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PMID:CB1093, a novel vitamin D analog; effects on differentiation and clonal growth on HL-60 and de novo leukemia cells. 915 Mar 49


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