Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alkyl-lysophospholipids are unique compounds which have selective anti-cancer activity with relative sparing of normal bone marrow stem cells. Thus, they would appear to be ideal candidates for marrow purging. In contrast to most anti-cancer drugs, these compounds act on the cell membrane resulting in inhibition of phosphatidylcholine biosynthesis. In addition, these compounds inhibit protein kinase C activity and may interfere with signal transmission. In low doses in in vitro systems, they have been shown to induce differentiation in leukemic cell lines. Lethally irradiated Balb/c mice were injected with normal bone marrow cells containing 1-2% leukemic cells (WEHI III-B) to simulate a remission marrow after the cells were incubated in vitro for 24 hours with 0-100 ug/ml of 1-0-octadecyl-2-0-methyl-rac-glycero-3-phosphocholine (ALP). All the mice given cells not treated with ALP succumbed to leukemia, whereas there was a dose-response increase in survival in those given ALP treated cells. Similar results were observed when the cells were cryopreserved and thawed before injection. Very little effect of ALP was noted on stem cells as measured by the spleen colony assay. In vitro studies using human marrow progenitor assays (CFU-GEMM) were undertaken in which marrow was mixed with 0.1% HL60 cells and exposed for 1 or 4 hours to ALP at 0, 25 and 50 ug/ml. The cells were plated and assayed for CFU-GEMM and leukemic colonies. At 50 ug/ml, HL60 colonies were eliminated and there was no significant reduction in normal marrow progenitor cells. Clinical trials were initiated. Eleven patients with acute leukemia in remission who were candidates for autologous bone marrow transplantation had marrow harvested, incubated with 50 ug/ml of ALP and cryopreserved. CFU-GEMM assays before and after purging showed no differences. There was a similar significant reduction after cryopreservation regardless of whether marrows were purged. Two patients were transplanted with purged marrow, one in early relapse and one in a marrow remission, but had evidence of CNS leukemia. In both, ablative therapy consisted of cytosine arabinoside, 3 gm/m2 x 12 doses, followed by fractionated TBI to a total of 12 Gy prior to reinfusion of thawed marrow. The patient in early relapse had progression of leukemia by day 28. The patient in marrow remission is disease-free 9 months after transplantation. These studies indicate that purging marrow with ALP is a promising approach and further clinical studies are indicated.
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PMID:Purging leukemia remission marrows with alkyl-lysophospholipids, preclinical and clinical results. 230 73

Bryostatin 1, a macrocyclic lactone isolated from the marine bryozoan Bugula neritina, has demonstrated both antineoplastic activity against the murine P388 leukemia line in vivo and stimulatory activity against mouse and human hematopoietic progenitors. We studied the effects of bryostatin 1 on the growth of human leukemias in vitro. Bryostatin 1 inhibited 1 to 4 logs of clonogenic leukemia cell growth from three of four leukemia cell lines. Bryostatin 1 also inhibited, by at least 1 log, the proliferation of clonogenic acute nonlymphocytic leukemia (ANLL) cells from 10 to 12 patients with newly diagnosed or relapsed ANLL. Maximal inhibition of leukemic growth occurred at 10(-9) to 10(-7) mol/L bryostatin 1. Interestingly, bryostatin 1 also inhibited the growth of hematopoietic progenitors from eight patients with myelodysplastic syndromes (MDS). Leukemia cells exposed to bryostatin 1 for up to 96 hours and then washed, demonstrated no substantial inhibition of clonogenic growth, indicating that the anti-leukemic effect of bryostatin 1 is cytostatic. The phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA) produced more potent inhibition of clonogenic leukemia growth, and this inhibition was blocked by bryostatin 1. Thus, the anti-leukemic activity of bryostatin 1 may be mediated through activation of protein kinase C. Bryostatin 1 inhibits clonogenic leukemia cells at concentrations that stimulate normal hematopoietic progenitors. The differential effects of bryostatin 1 on normal and abnormal hematopoiesis suggest that bryostatin 1 may have value in the treatment of leukemias and MDS.
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PMID:Bryostatin 1, a unique biologic response modifier: anti-leukemic activity in vitro. 231 Aug 30

Aggregating agents including phorbol esters which activate protein kinase C induce the rapid phosphorylation of a Mr = 47,000 cytosolic protein in blood platelets (P47 or pleckstrin). This protein is well resolved by analytical 16-BAC----SDS two-dimensional PAGE and was purified from platelets by preparative 16-BAC----SDS PAGE. Polyclonal antibodies were raised to the protein in mice and rabbits. These antisera detected a single protein with the migration of P47 on Western blots of platelet extracts, and the rabbit antisera immunoprecipitated 32P-labelled P47 from platelet cytosol. The presence of P47 in other haematopoietic cells was determined by prelabelling them with 32P and observing increased 32P incorporation into the location of P47 on autoradiographs of 16-BAC----SDS analytical PAGE of cells exposed to phorbol ester. The identity of the phosphoprotein found in this location was further established by probing Western blots of SDS PAGE gels of cultured cell lines with the P47 antisera. P47 was detected in peripheral blood lymphocytes, monocytes and granulocytes (including the granulocytes of two unrelated patients with X-linked chronic granulomatous disease). P47 was also found in HL-60 promyelocytes (especially after differentiation with retinoic acid), U937 histiocytes, HEL leukaemia cells, and Raji 'B' lymphoblasts. It was not detected in normal erythrocytes, K562 leukaemic cells, MOLT-3 'T' lymphoblasts, or in wide range of non-haematopoietic cell lines. We conclude that P47 is a major target for the action of phorbol ester induced phosphorylation in platelets, normal leucocytes and some haematopoietic cell lines. These cells have as their common feature the ability when stimulated to develop adhesive functions on their plasma membranes.
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PMID:P47 phosphoprotein of blood platelets (pleckstrin) is a major target for phorbol ester-induced protein phosphorylation in intact platelets, granulocytes, lymphocytes, monocytes and cultured leukaemic cells: absence of P47 in non-haematopoietic cells. 231 54

Prior studies demonstrated that conversion of sphingomyelin to ceramide via sphingomyelinase action resulted in the generation of free sphingoid bases and inactivation of protein kinase C in human leukemia (HL-60) cells (Kolesnick, R. N. (1989) J. Biol. Chem. 264, 7617-7623). The present studies define the novel phospholipid ceramide 1-phosphate in these cells and present evidence for formation of this compound by preferential utilization of ceramide derived from spingomyelin. A ceramide 1-phosphate standard, prepared enzymatically via diacylglycerol kinase, was utilized for localization. In cells labeled to equilibrium with 32Pi to label the head group of the molecule, the basal ceramide 1-phosphate level was 30 +/- 2 pmol/10(6) cells. Generation of ceramide via the use of exogenous sphingomyelinase resulted in time- and concentration-dependent formation of ceramide 1-phosphate. As little as 3.8 x 10(-5) units/ml was effective and a 3-fold increase was observed with a maximal concentration of 3.8 x 10(-2) units/ml; ED50 approximately 2 x 10(-4) units/ml. This effect was observed by 5 min and maximal at 30 min. Similarly, in cells labeled with [3H]serine to probe the sphingoid base backbone, the basal level of ceramide 1-phosphate was 39 +/- 5 pmol/10(6) and increased 2.5-fold with sphingomyelinase; ED 50 approximately 5 x 10(-5) units/ml. To determine the source of the phosphate moiety, studies were performed with cells short term labeled with 32Pi and resuspended in medium without radiolabel. Under these conditions, sphingomyelin was virtually unlabeled. Nevertheless, sphingomyelin (3.8 x 10(-2) units/ml) induced a 12-fold increase in radiolabel incorporation, suggesting ceramide 1-phosphate formation occurred via ceramide phosphorylation. This event appeared specific for ceramide derived from sphingomyelin since ceramide from glycosphingolipids was not converted to ceramide 1-phosphate. In sum, these studies demonstrate the novel phospholipid ceramide 1-phosphate in HL-60 cells and suggest the possibility that a path exists from sphingomyelin to ceramide 1-phosphate via the phosphorylation of ceramide.
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PMID:Ceramide 1-phosphate, a novel phospholipid in human leukemia (HL-60) cells. Synthesis via ceramide from sphingomyelin. 239 6

Different T cell lines, which can be induced to secrete interleukin 2 (IL-2) in vitro, were used to dissect the effect of cyclosporin A (CsA). The T leukemia cell Jurkat requires an increase in cytoplasmic calcium concentration ([Ca++]i) and phorbol myristate acetate (PMA) for the induction of IL-2 production, which is completely blocked by CsA. Another T cell line, HUT 78, also produces IL-2 in response to a rise in [Ca++]i and PMA; however, in HUT 78, PMA alone induces low levels of IL-2 production that is not blocked by CsA. After treatment with 5-azacytidine, HUT 78 cells produced maximal levels of IL-2 in response to PMA alone without requiring [Ca++]i increasing stimuli. In these cells no inhibitory effect of CsA on PMA-induced activation could be demonstrated. In addition, CsA does not inhibit PMA-induced translocation of protein kinase C. These data suggest that CsA does not globally inhibit IL-2 gene expression, but rather interferes with signaling events of T cell activation.
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PMID:Differential effect of cyclosporin A on activation signaling in human T cell lines. 242 8

The thymic leukemia cell line EL4 has been shown to produce the lymphokine Interleukin-2 (IL-2) following stimulation with phorbol ester (PMA). We investigated intracellular enzyme pathways triggered by phorbol stimulation using an EL4 cell line which responds to PMA with IL-2 synthesis (EL4r) and one which does not produce IL-2 following stimulation (EL4nr). By comparing these two cell lines we hoped to establish which enzyme activities were associated with IL-2 synthesis. The enzyme pathways studied included calcium/phospholipid dependent protein kinase (C-kinase) activity, the induction of polyamine synthesis, RNA, DNA and protein synthesis and finally IL-2 production. Our results indicate that both EL4 cell lines have a receptor for PMA, which can activate the C-kinase enzyme. Further, in both cell lines PMA activates the nuclear synthesis of polyamines as demonstrated by ornithine decarboxylase induction. Both RNA and protein synthesis measured by 3H-uridine and 3H-leucine uptake respectively appear comparable between EL4r and EL4nr. The only difference in cellular responsiveness between EL4r and EL4nr was in the 3H-thymidine uptake, and IL-2 production. IL-2 production or lack of production was established by 3H-uridine and 3H-thymidine incorporation as well as viable cell count using the IL-2 dependent cell line CTLL-2. We, therefore, conclude that EL4r and EL4nr cells show similar intracellular responses to phorbol ester except for 3H-thymidine uptake and detectable IL-2 production. Our results suggest that failure of PMA-stimulated EL4nr cells to produce IL-2 is either due to inability of this cell line to synthesize IL-2 or the production of defective IL-2. It is not due to failure of PMA to activate C-kinase or the subsequent nuclear events.
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PMID:The activation of calcium/phospholipid dependent protein kinase and the association with interleukin-2 production. 242 45

IgE-mediated stimulation of rat basophilic leukemia (RBL-2H3) cells results in the secretion of histamine. Myosin immunoprecipitated from these cells shows an increase in the amount of radioactive phosphate incorporated into its heavy (200 kDa) and light (20 kDa) chains. In unstimulated cells two-dimensional mapping of tryptic peptides of the myosin light chain reveals one phosphopeptide containing the serine residue phosphorylated by myosin light chain kinase. Following stimulation a second phosphopeptide appears containing a serine residue phosphorylated by protein kinase C. Tryptic phosphopeptide maps derived from myosin heavy chains show that unstimulated cells contain three major phosphopeptides. Following stimulation a new tryptic phosphopeptide appears containing a serine site phosphorylated by protein kinase C. The stoichiometry of phosphorylation of the myosin light and heavy chains was determined before and after antigenic stimulation. Before stimulation, myosin light chains contained 0.4 mol of phosphate/mol of light chain all confined to a serine not phosphorylated by protein kinase C. Cells that secreted 44% of their total histamine in 10 min exhibited an increase in phosphate content at sites phosphorylated by protein kinase C from 0 mol of phosphate/mol of myosin subunit to 0.7 mol of phosphate/mol of light chain and to 1 mol of phosphate/mol of heavy chain. When RBL-2H3 cells were made permeable with streptolysin O they still showed a qualitatively similar pattern of secretion and phosphorylation. Our results show that the time course of histamine secretion from stimulated RBL-2H3 cells parallels that of myosin heavy and light chain phosphorylation by protein kinase C.
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PMID:Antigen-induced secretion of histamine and the phosphorylation of myosin by protein kinase C in rat basophilic leukemia cells. 247 73

On the stimulation of rat basophilic leukemia (2H3) cells with an IgE oligomer, the intracellular Ca2+ concentration, which was measured with fura-2 as a fluorescent probe, began to increase after 1 min lag period, reached its maximum at 4 min, and gradually decreased to the original level. The histamine release occurred slightly more slowly than the increase in the intracellular Ca2+. It started 2-3 min after the stimulation, reaching a peak at 6 min and thereafter decreasing slowly. To supplement the released histamine, the activity of histidine decarboxylase, a histamine-forming enzyme, increased 5-fold several hours after the stimulation by an IgE oligomer, and this increase may be mediated by protein kinase C system.
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PMID:Release and synthesis of histamine in rat basophilic leukemia (2H3) cells. 247 45

Rat basophilic leukemia (RBL-2H3) cells were cultured in medium containing [3H]arachidonic acid and labelling of the different lipid fractions was followed with time. After up to 4 h of culture, the label was found mostly in phosphatidylcholine. After 8 h, labelling of phosphatidylethanolamine gradually exceeded that of phosphatidylcholine, until at 24 h, approximate equilibrium labelling of the lipid fractions was attained and 45% of the label was found in phosphatidylethanolamine, 35% in phosphatidylcholine, 18% in the phosphatidylserine/inositide fraction and the remainder in the neutral lipid fraction. Stimulation of cells with A23187 after 30 min of labelling caused release of [3H]arachidonic acid which was accountable by a decrease in radioactivity of phosphatidylcholine, whereas stimulation of cells after 24 h of labelling caused the release of radioactive arachidonic acid, which was accompanied by a decrease of label in both phosphatidylcholine and phosphatidylethanolamine. Incubation of the labelled cells with phorbol 12-myristate 13-acetate prior to ionophore addition enhanced both the release of [3H]arachidonic acid and its metabolites and the decrease in label of the same phospholipids as those affected by ionophore alone. Under our conditions, the enhancement effects of phorbol ester were greatest after 2-5 min of preincubation, prior to ionophore addition. The results suggest that in basophilic leukemia cells, arachidonic acid release proceeds from several pools of phospholipids and that the activity of the phospholipase(s) involved is modulated by protein kinase C.
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PMID:Modulation by phorbol 12-myristate 13-acetate of arachidonic acid release from rat basophilic leukemia cells stimulated with A23187. 249 61

We have tested a panel of recombinant hematopoietic growth factors (HGF) including the interleukins (IL) 1, 2, 3, 4, and 6 and the colony stimulating factors GM-CSF, G-CSF, M-CSF for their ability to induce proliferation of precursor B acute lymphoblastic leukemia cells (ALL) from 19 patients. In Ficoll-Isopaque isolated and T cell-depleted ALL bone marrow samples, IL2 (two cases), IL3 (four cases), and GM-CSF (one case) infrequently stimulated DNA synthesis measured by 3H-thymidine (TdR) uptake, and the other recombinant growth factors completely failed to do so. In repeat experiments with ALL blasts purified by fluorescence activated cell sorting (FACS), IL2, IL3, and GM-CSF responses could not be reproduced, suggesting that nonleukemic contaminant cells, and not the ALL blasts, had been stimulated by these factors. Cocktails containing combinations of IL1-IL4 and IL6 also lacked proliferation inducing potency. Depending on the purity of the incubated ALL cell samples, an impure preparation of B cell growth factors that has been reported to contain a highly effective stimulatory activity for precursor B ALL cells induced proliferation of residual normal cells as well as the ALL cells, as was evident from combined analysis of DNA synthesis and karyotyping. Exposure of the ALL blasts to artificial activators of protein kinase C and Ca2+ mobilization resulted in significant rises in 3H-TdR uptake, suggesting that these intracellular compounds are involved in transducing signals that upregulate proliferation. Although it remains possible that some of the human recombinant growth factors promote the growth of precursor B ALL cells in combination with other stimuli, a dominant role in the regulation of proliferation of these cells cannot be attributed to any of these cytokines at the present time.
Leukemia 1989 May
PMID:Recombinant hematopoietic growth factors fail to induce a proliferative response in precursor B acute lymphoblastic leukemia. 249 81


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