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

Between January 1980 and March 1983, a study was conducted into the effects of postremission therapy on 20 patients with acute leukemia who had achieved complete remission through induction therapy. Postremission therapy consisted of cyclic administration of six combination therapies given at gradually longer intervals. Postremission therapy used DCMP (D, daunorubicin; C, cytosine arabinoside; M, 6-mercaptopurine; P, prednisolone), DCyMP (Cy, cyclocytidine), DCVP (V, vincristine), BHAC-DMP (BHAC, behenoyl-ara-c), BHAC-AMP (A, aclarubicin) and ACM-MP (ACM, aclacinomycin). Six combinations were given sequentially starting at one month interval, and then at 2, 3, 4, 5 and eventually 6 month intervals until 5 year survival was reached. The median remission duration was 38 months for acute myelogenous leukemia (AML), and 17 months for acute lymphoblastic leukemia (ALL). The median survival was 66 months for AML, and 33 months for ALL. The survival rate at 5 years was 60% for AML., 40% for ALL, and 50% in all 20 patients. Methotrexate and prednisolone were administered intrathecally for prophylaxis of CNS leukemia on Day 4 of each stage of postremission therapy. There was no CNS leukemia. This postremission therapy was shown to be effective in improving the prognosis of adults with acute leukemia.
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PMID:An eight year experience with gradually longer interval postremission therapy for adults with acute leukemia. 278 38

2'-Deoxycoformycin (dCF), a potent adenosine deaminase inhibitor, has been reported to display greater toxicity for T than for B lymphoblasts. Since this compound can block DNA replication and since this effect is mediated by the intracellular ATP/dATP balance, its possible effect on DNA ligase was investigated. dCF at relatively low concentrations (1 microM), in association with dATP (100 microM), is a strong inhibitor of DNA ligase in T blasts, whereas it has no significant effect in B blasts at this concentration. The AMP-ligase complex is the target of the observed inhibition because the combined presence of the inhibitor and dATP results in a more stable dAMP-ligase complex. Because of this observation and of the greater adenosine deaminase activity observed in T cells, the dATP mediated dCF inhibition of ligase might be the crucial replication target of T cell toxicity. These observations are discussed in terms of T immunodeficiencies including Graft Versus Host Disease and related syndromes.
Leukemia 1989 Feb
PMID:dATP-mediated inhibition of DNA ligase by 2'-deoxycoformycin in T and B cell leukemia. 278 73

The mechanism of the depletion of ATP, recorded in the erythrocytes of adenosine deaminase-deficient children and of leukemia patients treated with deoxycoformycin, was investigated in normal human erythrocytes treated with this inhibitor of adenosine deaminase. Deoxyadenosine, which accumulates in both clinical conditions, provoked a dose-dependent accumulation of dATP, depletion of ATP, and increases in the production of inosine plus hypoxanthine. Concomitantly, there was an increase of AMP and IMP, but not of adenosine, indicating that catabolism proceeded by way of AMP deaminase. A series of nucleoside analogues (9-beta-D-arabinofuranosyladenine, N6-methyladenosine, 6-methylmercaptopurine ribonucleoside, tubercidin, ribavirin, and N-1-ribosyl-5-aminoimidazole-4-carboxamide riboside) also stimulated adenine nucleotide catabolism and increased AMP and IMP to various extents. The effects of deoxyadenosine and of the nucleoside analogues were prevented by 5'-iodotubercidin, an inhibitor of adenosine kinase. Strikingly, they were reversed if the inhibitor was added after the accumulation of nucleotide analogues and initiation of adenine nucleotide catabolism. Further analyses revealed linear relationships between the rate of phosphorylation of deoxyadenosine and nucleoside analogues and the increase in AMP and between the elevation of the latter above a threshold concentration of 10 microM and the rate of adenine nucleotide catabolism. Kinetic studies with purified erythrocytic AMP deaminase, at physiological concentrations of its effectors, showed that the enzyme is nearly inactive up to 10 microM AMP and increases in activity above this threshold. We conclude that the main mechanism whereby deoxyadenosine and nucleoside analogues stimulate catabolism of adenine nucleotides by way of AMP deaminase in erythrocytes is elevation of AMP, secondary to the phosphorylation of the nucleosides.
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PMID:Mechanism of adenosine triphosphate catabolism induced by deoxyadenosine and by nucleoside analogues in adenosine deaminase-inhibited human erythrocytes. 278 93

Cholera toxin pretreatment has been found to cause a 3-fold increase in the initial rate of antigen-stimulated secretion of serotonin from rat basophilic leukemia (RBL) cells. Under similar conditions, cholera toxin enhances the antigen-stimulated rise in cytoplasmic free ionized calcium levels and causes a 2-3-fold increase in the rate of antigen-stimulated influx of 45Ca. In intact RBL cells cholera toxin pretreatment potentiates the antigen-stimulated production of inositol phosphates, but in permeabilized cells, with strongly buffered free calcium levels, no effect of cholera toxin pretreatment on the antigen-stimulated activation of cellular phospholipase activities is observed. In addition, pretreatment of cells with tetradecanoylphorbol acetate inhibits antigen-stimulated production of inositol phosphates by greater than 95%, while the stimulated influx of 45Ca remains unaffected. These data indicate that the antigen-stimulated influx of calcium into RBL cells can be dissociated from the production of inositol phosphates in these cells. The observed effects of cholera toxin on exocytosis and Ca2+ influx in RBL cells are not due to the elevation of cellular cyclic AMP levels since a variety of agents capable of elevating cellular cyclic AMP levels do not mimic these effects. Together, these data suggest that a cholera toxin-sensitive guanine nucleotide-binding protein is involved in the pathway responsible for the antigen-stimulated influx of calcium into RBL cells.
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PMID:Cholera toxin increases the rate of antigen-stimulated calcium influx in rat basophilic leukemia cells. 284 36

We investigated the intracellular cyclic AMP (cAMP) level and cytotoxic sensitivity to anti-tumor-associated antigen (anti-TAA) antibody in transplantable rat fibrosarcoma cells with regard to each of three days following ip transplantation. The cytotoxic sensitivity of the 3-methylcholanthrene (MCA)-induced transplantable fibrosarcoma KMT-17 cells to anti-TAA antibody decreased daily after ip transplantation in syngeneic WKA/Hok rats. In contrast, the intracellular cAMP level of the tumor cells increased daily after ip transplantation, and the cAMP level of 3-day-old KMT-17 tumor cells (1.31 pmol/10(6) cells) was statistically (p less than 0.01) higher than that of 1-day-old tumor cells (1.01 pmol/10(6) cells). This phenomenon disappeared, however, after artificial infection of the tumor cells with Friend murine leukemia virus (F-MuLV). The cytotoxic sensitivity of F-MuLV-infected KMT-17 (FV-KMT-17) tumor cells to anti-TAA antibody did not decrease and no elevation of the intracellular cAMP level was observed (0.92-0.97 pmol/10(6) cells), regardless of the number of days after ip transplantation. The cytotoxic sensitivity of KMT-17 and FV-KMT-17 tumor cells to anti-TAA antibody was therefore in inverse proportion to the intracellular cAMP levels of the tumor cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Correlation between intracellular cyclic AMP level and cytotoxic sensitivity to anti-tumor-associated antigen antibody in rat fibrosarcoma cells]. 285 17

Ehrlich carcinoma and P388 leukemia cells were rendered resistant to 4-carbamoylimidazolium 5-olate (SM-108), and assessments were made of biochemical and pharmacological determinants for the sensitivity to SM-108 using both sensitive and resistant sublines. We observed that the treatment of cells with SM-108 in vitro caused a remarkable decrease in the intracellular guanosine 5'-triphosphate pool level in sensitive but not in resistant sublines. There was no difference in the ability to take up SM-108 between sensitive and resistant sublines, but the cellular conversion of SM-108 to its nucleotide, which is the putative active anabolite of SM-108, proceeded only in sensitive sublines. Enzymological studies revealed that the activity of adenine phosphoribosyltransferase (EC 2.4.2.7), which is believed to conjugate SM-108 with 5-phospho-alpha-D-ribose 1-diphosphate, was very low in the resistant sublines. These results strongly support our previous hypothesis that SM-108 is activated by adenine phosphoribosyltransferase to SM-108-nucleotide which then inhibits hypoxanthine-5'-monophosphate dehydrogenase (EC 1.2.1.14), a key enzyme for the de novo synthesis of guanosine 5'-monophosphate.
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PMID:Selective reduction of intracellular guanosine 5'-triphosphate pool by 4-carbamoylimidazolium 5-olate in murine tumor cells. 286 32

The aggregation of IgE bound to rat basophilic leukaemia (RBL) cells leads to the exocytosis of mediators, the endocytosis of the antigen-aggregated mouse IgE anti-DNP, as well as the coendocytosis of some unaggregated monomeric rat IgE (IR162) and/or unbound receptors. We describe here the relative effect on endocytosis and coendocytosis of various pharmacological agents that block or enhance exocytosis. We have previously shown that, unlike exocytosis, endocytosis by RBL and normal rat mast cells was independent of extracellular calcium. We show here that the presence of calcium chelators or antagonists also had no effect on endocytosis of cross-linked IgE. However, coendocytosis of non-cross-linked IgE was partially inhibited by the elimination of extracellular calcium and the addition of calcium chelators such as EDTA or EGTA-Mg2+. Moreover, the addition of calcium antagonists such as Ni2+ and Co2+ (5 mM) to an incubation mixture containing Ca2+ (1 mM) resulted in the complete inhibition of coendocytosis without affecting endocytosis. Other inhibitors of exocytosis such as sodium azide (10-2M), quercetin (10-4M) and dibutyryl cyclic AMP (10-2 M) blocked coendocytosis completely but had no effect on endocytosis. Sodium azide (10 mM) in combination with 2-deoxyglucose (10 mM) effectively inhibited (90%) endocytosis. Cytochalasin B (10-4 M), which was shown to enhance serotonin release, had no effect on the extent of endocytosis or coendocytosis observed 20 min after the initiation of aggregation. Thus, in RBL cells, endocytosis, coendocytosis and exocytosis exhibit distinguishable sensitivities to some pharmacological drugs.
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PMID:Comparative evaluation of the effect of pharmacological agents on endocytosis and coendocytosis of IgE by rat basophilic leukaemia cells. 301 52

A promyelocytic cell line known as HL-60 can be induced to mature to granulocytes or monocytes after exposure to a variety of physiologic agents including 1-alpha 25 dihydroxy Vitamin D3 (Vit D), retinoic acid, cyclic AMP cell permeant compounds, and stimulators of adenylate cyclase. These compounds were used in primary culture of blast cells from 12 patients with acute nonlymphocytic leukemia. Maturation was assessed by morphology, superoxide production, development of esterase activity and chemotactic peptide receptor expression. Morphologic maturation and superoxide production correlated with chemotactic peptide receptor expression. The majority of blast cells treated with inducer showed no significant change in morphologic or functional markers compared to the blast cells cultured in fresh media alone. Chemotactic peptide receptor expression increased 3 to 30-fold in 13 of 14 cases studied. In 4 patients, the highest receptor expression was without inducer and in 4 patients the highest increase was with dibutyryl cyclic AMP treatment. Our study suggests that physiologic inducers of HL-60 differentiation do not consistently have the same effect on primary suspension culture of freshly isolated human leukemia cells.
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PMID:Study of differentiation of fresh myeloid leukemic cells by physiologic agents that induce a human promyelocytic leukemic line (HL-60) to differentiate. 301 13

The role of 5'-nucleotidase in the uptake of adenosine from AMP was investigated in lymphocytes from normal subjects and patients with common variable hypogammaglobulinaemia (CVH) and chronic lymphatic leukaemia (CLL). At physiological pH, the Km values for the uptake of adenosine and of adenosine from AMP by intact cells were one order of magnitude higher than the Km values for 5'-nucleotidase. The Vmax values for the hydrolysis of AMP by 5'-nucleotidase were two orders of magnitude greater than for the uptake of adenosine itself or the uptake of adenosine from AMP by normal lymphocytes. 5'-Nucleotidase activity is clearly not rate-limiting in normal lymphocytes for uptake of adenosine from AMP in steady state conditions. Patients with common variable hypogammaglobulinaemia showed a low Vmax for 5'-nucleotidase assayed at pH 7.4 in intact cells as compared to values from control subjects. Michaelis constants (Km) for the uptake of free adenosine and adenosine from AMP as well as 5'-nucleotidase were similar compared to those obtained for controls. The uptake of adenosine moiety from AMP in CLL lymphocytes with a low Vmax for 5'-nucleotidase was also reduced, although not to the same extent as the reduction in 5'-nucleotidase activity. One CLL patient with supranormal levels of 5'-nucleotidase activity showed elevated uptake of adenosine moiety from AMP and of free adenosine. These results suggest that 5'-nucleotidase can influence the salvage of purine by lymphocytes from extracellular nucleotides but only when the enzyme activity is greatly reduced.
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PMID:Uptake of free adenosine and adenosine from adenosine monophosphate by human peripheral blood lymphocytes: possible kinetic role for ecto-5'-nucleotidase in the regulation of intracellular adenosine. 302 95

5'-Deoxy-5'-methylthioadenosine phosphorylase (MTAPase) phosphorolyzes 5'-deoxy-5'-methylthioadenosine (MTA) generated during polyamine biosynthesis to adenine and 5-methylthioribose-1-phosphate. Two doubly-substituted, 2-fluoroadenine-containing analogs of MTA, 5'-deoxy-2-fluoroadenosine (5'-dFAdo) and 5'-deoxy-5'-iodo-2-fluoroadenosine (5'-IFAdo), were synthesized and studied as substrates of MTAPase: their reaction with this enzyme resulted in the liberation of the cytotoxic base, 2-fluoroadenine, as well as potentially cytotoxic analogs of 5-methylribose-1-phosphate. The activities of these MTA analogs were compared to that of the singly-substituted analog, 5'-deoxy-5'-methylthio-2-fluoroadenosine (5'-MTFAdo). The cytotoxic action of these MTA analogs depended primarily on their conversion to 2-fluoroadenine-containing nucleotides, as a cell line that contains both MTAPase and adenine phosphoribosyltransferase (APRT) activity (HL-60 human promyelocytic leukemia) readily converted these MTA analogs to 2-fluoroadenine-containing nucleotides (especially 2-fluoroadenosine triphosphate) and was highly sensitive to the growth-inhibitory effects of all three compounds (IC50 values in the 10(-8) M range), whereas cell lines lacking MTAPase (CCRF-CEM human T-cell leukemia) or APRT (HL-60/aprt1 cells) did not form analog nucleotides and were relatively insensitive to these compounds (IC50 values in the 10(-5) M range). The doubly-substituted analogs were not more growth inhibitory than 5'-MTFAdo in wild type HL-60 cells as the potent effects of 2-fluoroadenine may mask the activity of the 5-methylthioribose-1-phosphate analogs generated in the reaction of these compounds with MTAPase. 5'-dFAdo and 5'-IFAdo also were irreversible inhibitors of S-adenosylhomocysteine hydrolase, which may explain in part the weak but observable growth inhibitory action of these compounds against MTAPase-deficient cell lines.
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PMID:5'-deoxy-5'-methylthioadenosine phosphorylase--IV. Biological activity of 2-fluoroadenine-substituted 5'-deoxy-5'-methylthioadenosine analogs. 310 31


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