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)

The generation of slow reacting substance (SRS) from ionophore A23187-stimulated rat peritoneal mast cells was enhanced by arachidonic acid (AA). This SRS generation was inhibited by 5,8,11,14-eicosatetraynoic acid (ETYA), an acetylenic analogue of AA and an inhibitor of both fatty acid cyclooxygenase and lipoxygenase. Indomethacin, a fatty acid cyclooxgenase inhibitor, had an enhancing effect upon SRS generation. This suggests SRS generation occurred through an ETYA sensitive step--perhaps a lipoxygenase. Radiolabel from [14C]-AA was incorporated into SRS with comigration of radioactivity and bioreactivity in silicic acid and thin layer chromatographies. Upon silicic acid chromatography, the active principle was eluted in the methanol fraction. Two-dimensional thin layer chromatography revealed chromatographic separation from other known spasmogenic substances and phospholipids. Mast cell SRS was found to display physiochemical properties similar to those of rat basophilic leukemia cell SRS, namely: that mast cell SRS generation was 1) enhanced by arachidonic acid; 2) inhibited by ETYA but not by indomethacin; 3) incorporation of [14C]-AA into the active principle; and 4) similar behavior during purification in silicic acid and thin layer chromatographies.
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PMID:Slow reacting substance (SRS) from ionophore A23187-stimulated peritoneal mast cells of the normal rat. II. Evidence for a precursor role of arachidonic acid and further purification. 37 31

The treatment of human U-937 leukemia cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) is associated with induction of monocytic differentiation. However, the signaling pathways responsible for induction of the differentiated monocytic phenotype remain unclear. The present studies demonstrate that dexamethasone blocks TPA-induced U-937 cell growth inhibition, adherence, and alpha-naphthyl acetate esterase staining. The results also demonstrate that dexamethasone inhibits the appearance of c-fms transcripts associated with TPA treatment. Run-on transcription assays demonstrated that the c-fms gene is transcriptionally active in uninduced U-937 cells and that the rate of transcription is unchanged after dexamethasone and/or TPA treatment. These findings indicated that TPA increases c-fms expression by a dexamethasone-sensitive posttranscriptional mechanism. Treatment of U-937 cells with TPA was also associated with stimulation of arachidonic acid metabolism. Furthermore, dexamethasone, an inhibitor of phospholipase A2 activity, blocked TPA-induced increases in arachidonic acid release. These findings suggested that TPA may regulate certain features of monocytic differentiation, such as c-fms gene expression, through the formation of arachidonic acid metabolites. Indomethacin, an inhibitor of cyclooxygenase, had no detectable effect on c-fms gene expression. However, the cyclooxygenase metabolite, prostaglandin E2, inhibited the TPA-induced increases in c-fms mRNA levels. Taken together, the results indicate that TPA regulates c-fms gene expression by a dexamethasone-sensitive mechanism and that c-fms mRNA levels are controlled by metabolites of the arachidonic acid pathway.
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PMID:Inhibition of phorbol ester-induced monocytic differentiation and c-fms gene expression by dexamethasone: potential involvement of arachidonic acid metabolites. 214 78

We conducted a phase II trial of deoxycoformycin (pentostatin [DCF]) in chronic lymphocytic leukemia (CLL). Eligibility criteria included age greater than 18 years, Cancer and Leukemia Group B (CALGB) performance status 0 to 2, lymphocyte count greater than or equal to 15,000 cells/microL, international stage B or C disease (multiple lymph nodes involved and/or hemoglobin [Hgb] less than 11 g and/or platelets less than 100,000/microL) and no more than one prior treatment regimen. DCF dose was 4 mg/m2 intravenously (IV) weekly for 3 weeks and then every 2 weeks. There were 39 eligible patients (35 men and four women; median age, 63 years; median time from diagnosis to study entry, 3 years). Of these 39 patients, 31% were stage B and 33% had no prior treatment. Median laboratory values at entry were Hgb 10.5 g, WBC 96,100/microL, and platelets 93,500/microL. Nodal involvement was present in 90%, splenomegaly in 81%, and hepatomegaly in 47%. Patients received a median of nine DCF injections, with a range of four to 26. Three patients were not evaluable for response. Overall, 3% achieved a complete response (CR), 23% a partial response (PR), 28% showed clinical improvement (CI), and 38% had stable disease (SD). Associated toxicities (grade 2 or worse) observed were infections (52%), worsening of thrombocytopenia (26%) or anemia (33%), nausea and vomiting (31%), rash or pruritus (20%), and stomatitis (8%). We conclude that DCF is an active agent in CLL with acceptable toxicity.
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PMID:Pentostatin in chronic lymphocytic leukemia: a phase II trial of Cancer and Leukemia group B. 278 91

Interferon-alpha (IFN-a) or 2'-deoxycoformycin (pentostatin; DCF) have each been shown to be highly active in hairy-cell leukemia (HCL). In this phase II study of the Leukemia Cooperative Group of the European Organization for Research and Treatment of Cancer (EORTC), the efficacy and toxicity of DCF were investigated in patients who were resistant to IFN-a treatment. Resistance was defined as: (1) progressive disease (PD) under IFN-a therapy for more than 2 months; (2) stable disease (SD) after more than 6 months of IFN-a treatment; (3) relapse within 3 months of discontinuing IFN-a; and (4) intolerance to IFN-a because of World Health Organization (WHO) grade 3 or 4 toxicity. DCF was applied at a dosage of 4 mg/m2 weekly x 3, then 4 mg/m2 every other week x 3. Responders were given a maintenance therapy once per month for a maximum of 6 months. At the time of report, 33 patients with resistant disease were evaluable for response and toxicity. Median duration of IFN-a therapy before DCF administration was 14.7 months (range, 1 to 41 months). Complete remissions (CRs) were achieved in 11 patients and partial remissions (PRs) in 15, resulting in a total response rate of 78.8%. Median interval between beginning of DCF therapy to best response was 3.9 months with a range from 2.0 to 7.0 months. Two patients who achieved PR have relapsed 7 and 14 months after cessation of DCF therapy. The median duration of response was over 11.5 months (range, over 3.0 to over 24.0 months). Three patients died within the first 6 weeks of DCF treatment: one of drug-unrelated cardiomyopathy and two of fungal pneumonia. The patients with early death (n = 3) and nonresponsive disease (n = 4) received IFN-a treatment for a longer period (median, 18.0 months) than did the 26 responsive patients (median, 10.0 months). Major side effects included nausea, skin rash, and infections and were otherwise mild. Thus, DCF is highly active in patients with HCL resistant to IFN-a.
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PMID:Response to pentostatin in hairy-cell leukemia refractory to interferon-alpha. The European Organization for Research and Treatment of Cancer Leukemia Cooperative Group. 278 73

Serum thiobarbituric acid (TBA) reactivity for lipoperoxidation products was assessed at diagnosis in children with T-cell and common acute lymphocytic leukemia (ALL) and T-lymphoblastic lymphoma. Comparisons were made among these groups and with healthy controls. Mean TBA reactivity (mumol malondialdehyde/L serum) was increased (P less than 0.01) in the T-cell leukemia group versus common ALL and T-lymphoblastic lymphoma patients and controls, respectively. The increase in lipoperoxidation products in T-cell ALL appeared to bear a positive relation to peripheral leukocyte counts, and was accompanied by increased serum prostaglandin E2 (PGE2) levels in most representative cases. Indomethacin added to a childhood T-cell ALL line (SUP-T3), at a concentration known to inhibit prostaglandin synthesis in vitro (i.e., 3 micrograms/mL), effected significant increases in the numbers of natural killer (NK; Leu-11+ and Leu-19+) cells (P less than 0.01) and B-lymphocytes (P less than 0.05), and significant decreases in cell viability (P less than 0.01). Indomethacin may be a useful agent for enhancing the antileukemic immune response in T-cell ALL.
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PMID:Lipoperoxidation and T-cell leukemia of childhood. Effects of indomethacin. 280 98

The immunosuppressive effect of feline leukemia virus (FeLV) and its 15,000 dalton envelope protein (p15E) were studied to determine if the mechanism of action was due to an increase in prostaglandin production. We examined the effects of exogenous PGE1 and PGE2 on the normal Con A response of feline peripheral blood lymphocytes (PBL) and found them to be inhibitory. The addition of the cyclooxygenase inhibitor indomethacin to cells incubated with FeLV or FeLV p15E and Con A completely abrogated the viral suppressive effects. This reversal was titratable and time-dependent. Other non-steroidal anti-inflammatory (NSAI) drugs were found to have similar actions. Indomethacin was also able to increase the suppressed Con A response of PBL from FeLV-infected cats. Upon measurement of PGE2 levels from PBL cultured with FeLV, we found a decrease in PGE2 accumulation associated with FeLV presence during the first 24 h of culture. These findings indicate that FeLV does not cause its immunosuppressive effects by increasing PG production and suggests that indomethacin and the other tested NSAI drugs do not produce their effect by PG inhibition.
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PMID:Reversal of feline retroviral suppression by indomethacin. 300 36

Treatment of BALB/c, C57Bl/6 or C3H/HeJ mice with non-toxic concentrations of indomethacin (75-100 micrograms/day) led to a depression of plasma neutral proteinase activity as determined with an (125I)-caseinolytic assay. Lower concentrations of indomethacin (50 micrograms/day), aspirin (1 mg/day), LiCl (3 meq/kg/day), Sulindac (100 micrograms/day), indomethacin analogs (MK-410, MK-555) or lipopolysaccharide (100 micrograms) did not induce depression in proteinase activity. Indomethacin did not directly inhibit the proteinase activity of normal plasma in vitro. The in vivo effects of indomethacin were reversible and plasma proteinase activity returned to normal values within 8 days of cessation of treatment. These results indicate that indomethacin can uniquely alter plasma proteinase homeostasis in normal mice. While effective in depressing the plasma proteinase activity of normal mice, treatment of mice bearing either the BCL1 leukemia or the B16-F10 melanoma with indomethacin did not depress the elevated plasma proteinase levels detected in tumor-bearing animals. Thus the elevation in proteinases detected in tumor-bearing animals may not be the result of increased prostaglandin synthesis and plasma proteinase activity in such disease states may be regulated differently than in normal mice. However, the ability of this potent anti-inflammatory agent to alter proteinase metabolism may contribute to its therapeutic efficacy in the management of inflammatory disease.
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PMID:Indomethacin induces the suppression of plasma neutral proteinase activity in mice: possible relationship to efficacy as an anti-inflammatory drug and induction of alterations in the immune system. 302 Feb 55

The biological actions of pure slow-reacting substance of anaphylaxis (SRS-A) from guinea-pig lung, pure slow-reacting substance (SRS) from rat basophilic leukaemia cells (RBL-1) and synthetic leukotrienes C4 (LTC4) and D4 (LTD4) have been investigated on lung tissue from guinea pig, rabbit and rat. In the guinea pig, the leukotrienes released cyclo-oxygenase products from the perfused lung and contracted strips of parenchyma. The effects of SRS-A, SRS and LTD4 were indistinguishable. LTC4 and LTD4 had similar actions although LTD4 was more potent than LTC4. Indomethacin (1 microgram/ml) inhibited the release of cyclo-oxygenase products from perfused guinea-pig lung and caused a marked reduction in contractions of guinea-pig parenchymal strips (GPP) due to LTC4 and LTD4. The residual contraction of the GPP was abolished by FPL 55712 (0.5 - 1.0 microgram/ml). It appears, therefore, that a major part of the constrictor actions of LTC4 and LTD4 in guinea-pig lung are mediated by myotropic cyclo-oxygenase products, i.e. thromboxane A2 (TxA2) and prostaglandins (PGs). In rabbit and rat lung, however, SRS-A, SRS and the leukotrienes were much less potent in contracting parenchymal strips and there was little evidence of the release of cyclo-oxygenase products. FPL 55712 at a concentration of 1 microgram/ml failed to antagonise leukotriene-induced contractions.
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PMID:The mechanism of action of leukotrienes C4 and D4 in guinea-pig isolated perfused lung and parenchymal strips of guinea pig, rabbit and rat. 612 36

Rat basophil leukemia cells (RBL-1), when grown in monolayer, synthesize from endogenous substrates the prostaglandins (PG) E2, F2 alpha, and I2 (measured as 6-keto-PGF1 alpha) and 6-sulfidopeptide-containing leukotrienes (SRS), as well as materials that react serologically with anti-12-hydroxyeicosatetraenoic acid (HETE). The non-steroidal anti-inflammatory drugs indomethacin and aspirin inhibited PGE2 synthesis by RBL-1 cells, which had been stimulated with the calcium ionophore A-23187, in a dose-dependent manner with an IC50 of 0.7 and 7.8 microM respectively. Indomethacin, when used at higher concentrations, also inhibited iSRS synthesis with an IC50 of 230 microM. Benoxaprofen, also a non-steroidal anti-inflammatory drug, inhibited both PGE2 and iSRS production in a dose-dependent manner, but inhibition of the iSRS biosynthesis was three times more effective than inhibition of PGE2 production. The anti-oxidants gossypol, butylated hydroxyanisole (BHA), nordihydroguariatic acid (NDGA), and 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW755c) also inhibited iSRS synthesis more effectively than PGE2 biosynthesis. The IC50 values for inhibition of iSRS production were 0.2 microM (gossypol), 0.5 microM (BW755c), 0.6 microM (BHA), and 0.6 microM (NDGA) compared to 2.8 microM (gossypol), 2.0 microM (BW755c), 4.8 microM (BHA) and 2.6 microM (NDGA) for inhibition of PGE2 synthesis. Gossypol, BW755C, BHA, and NDGA, as well as benoxaprofen, inhibited i12-HETE-biosynthesis (IC50 for gossypol, 0.32 microM; and for benoxaprofen, 0.5 microM). Two calcium channel blockers, verapamil and nifedipine, inhibited PGE2, iSRS and i12-HETE synthesis in a dose-dependent manner. The calcium channel blockers inhibited iSRS synthesis ten times more effectively than PGE2 production.
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PMID:Inhibition of the A-23187-stimulated leukotriene and prostaglandin biosynthesis of rat basophil leukemia (RBL-1) cells by nonsteroidal anti-inflammatory drugs, antioxidants, and calcium channel blockers. 631 14

Indomethacin is a non-steroidal anti-inflammatory agent that inhibits prostaglandin synthesis. Administration of indomethacin, in doses which were non-toxic to normal BALB/c mice, to mice bearing the BCL1 leukemia resulted in increased mortality of these animals. This effect was only observed if the indomethacin was administered to animals with advanced disease (splenomegaly, hepatomegaly and leukemia). If indomethacin treatment was initiated prior to transplantation of the tumor or 2 weeks post-transplantation, and continued throughout the disease process, there was no effect on either the course of the disease or mortality. Injection of similar doses of indomethacin into mice bearing advanced B16 melanoma tumors did not result in increased mortality. Therefore, metabolic changes which occur in the leukemic animals may uniquely alter host sensitivity to this non-steroidal anti-inflammatory agent. The BCL1 leukemia may be a useful animal model to provide insights into the biochemical basis for the adverse reactions experienced by some Hodgkin's disease patients when they are treated with anti-inflammatory agents such as indomethacin.
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PMID:Increased sensitivity to indomethacin of mice bearing the BCL1-leukemia. 674 40


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