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 release of slow reacting substance (SRS) from rat basophilic leukemia cells (RBL-1) by the ionophore A23187 (5-10 mug/ml) was stimulated 5-fold by arachidonate and inhibited 78% by 5,8,11,14-eicosatetraynoate (an inhibitor of both fatty acid cyclooxygenase and lipoxygenase). Linoleic acid and linolenic acid both inhibited SRS formation, whereas indomethacin (a cyclooxygenase inhibitor) had no effect. Radiolabel from [14C]- or [3H]arachidonate was incorporated into SRS as indicated by comigration of radioactivity and bioreactivity in several chromatographic systems after purification to apparent radiochemical homogeneity. The radiolabeled SRS was clearly separated chromatographically from other known arachidonate metabolites. Thus, SRS appears to be a previously undescribed product of arachidonic acid metabolism, probably formed through the lipoxygenase pathway. The ability to prepare purified, biosynthetically labeled, SRS should be of considerable help in further studies of its structure, biologic function, and catabolism.
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PMID:Precursor role of arachidonic acid in release of slow reacting substance from rat basophilic leukemia cells. 2 78

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

Gossypol inhibited 5- and 12-lipoxygenases of rat basophilic leukemia (RBL-1) cells with ID50 of 0.3 microM and 0.7 microM, respectively. Nearly two orders of magnitude of higher concentration of gossypol was required to inhibit prostaglandin synthetase. The inhibition was of a non-competitive type with respect to arachidonate.
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PMID:Gossypol, a potent inhibitor of arachidonate 5- and 12-lipoxygenases. 391 71

Various flavonoids were found to be relatively selective inhibitors of arachidonate 5-lipoxygenase which initiates the biosynthesis of leukotrienes with the activity of slow reacting substance of anaphylaxis. Cirsiliol (3',4',5-trihydroxy-6,7-dimethoxyflavone) was most potent, and the enzyme partially purified from rat basophilic leukemia cells was inhibited by 97% at a concentration of 10 microM (IC50, about 0.1 microM). 12-Lipoxygenases from bovine platelets and porcine leukocytes were also inhibited but at higher concentrations (IC50, about 1 microM), and fatty acid cyclooxygenase purified from bovine vesicular gland was scarcely affected. The compound at 10 microM suppressed by 99% the immunological release of slow reacting substance of anaphylaxis from passively sensitized guinea pig lung (IC50, about 0.4 microM).
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PMID:Flavonoids: potent inhibitors of arachidonate 5-lipoxygenase. 641 62

The pharmacological effects of a new anti-inflammatory compound, alpha-(3,5-di-tert-butyl-4-hydroxybenzylidene)-gamma-butyrolactone (KME-4), and its inhibitory effects on arachidonate prostaglandin synthetase and 5-lipoxygenase activities were examined. KME-4 showed anti-inflammatory activity. It was less active than indomethacin, but more active than naproxen and ibuprofen in carrageenin-induced paw edema in rats; and it was less active than indomethacin, equipotent as naproxen, but more active than ibuprofen in granuloma formation in rats. The ulcerogenic activity of KME-4 was weaker than indomethacin and naproxen, but stronger than ibuprofen in starved rats. The ratio of UD50 stomach to ED30 carrageenin edema or to ED25 granuloma for KME-4 showed higher values than those of the reference drugs. KME-4 showed antipyretic activity in yeast-induced fever in rats. It also inhibited platelet aggregation induced by arachidonic acid and protected rabbits from arachidonic acid-induced death. Furthermore, KME-4 was found to be equipotent in inhibiting both prostaglandin synthetase and 5-lipoxygenase activities of rat basophilic leukemia cells, unlike indomethacin, naproxen and ibuprofen. It also inhibited the prostaglandin synthetase activity of bovine seminal vesicle. The present findings indicate that KME-4 may be a new type of anti-inflammatory drug with dual prostaglandin synthetase and 5-lipoxygenase inhibition.
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PMID:Pharmacological properties of a new anti-inflammatory compound, alpha-(3,5-di-tert-butyl-4-hydroxybenzylidene)-gamma-butyrolacto ne (KME-4), and its inhibitory effects on prostaglandin synthetase and 5-lipoxygenase. 643 80

Two adults who had T-cell lymphoma-leukemia and recurrent hypercalcemia in the absence of radiographic evidence of bone disease are described. Bone histopathology showed marked osteoclastic activation. Bone resorbing factors, including both prostaglandin E and a material produced in the presence of a prostaglandin synthetase inhibitor, were detected in the in-vitro culture fluids of malignant cells of one of the patients. Serum levels of parathyroid hormone were not elevated. These findings suggest that hypercalcemia resulted from in-vitro osteoclast activation by tumor cell product(s), one of which may be similar, if not identical, to the lymphocyte product osteoclast-activating factor. Two other patients having T-cell lymphoma-leukemia and hypercalcemia have been identified in the literature: the malignant cells of one of these patients also released a calcium-mobilizing factor in vitro.
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PMID:Hypercalcemia associated with T-cell lymphoma-leukemia. 697 May 19

Several lines of evidence suggest that phospholipases A2, leukotrienes and prostaglandins play a role in the proliferation of haemopoietic cells. The expression of genes involved in the biosynthesis of leukotrienes and prostaglandins was investigated in peripheral B lymphoblasts, isolated from eight patients with acute pre-B-lymphocytic leukaemia (pre B-ALL). RT-PCR analysis demonstrated that four of the investigated pre-B-ALL clones expressed the gene coding for cytosolic phospholipase A2 (cPLA2), but not the gene coding for 5-lipoxygenase. In contrast, the remaining four pre-B-ALL clones expressed 5-lipoxygenase but not cPLA2, suggesting that the transcriptional regulation of these two genes are different and that their cellular functions are not linked to each other. The capacity of pre B-ALL cells to produce LTB4 and to express the 5-lipoxygenase protein, correlated with the expression of 5-lipoxygenase mRNA. All pre-B-ALL clones expressed genes coding for 5-lipoxygenase activating protein (FLAP), leukotriene A4 hydrolase and prostaglandin (PG)H synthase 1. Seven of the eight pre B-ALL clones expressed PGH synthase 2. In comparison, normal tonsillar B cells did not express cPLA2 or PGH synthase 2.
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PMID:Diverse expression of cytosolic phospholipase A2, 5-lipoxygenase and prostaglandin H synthase 2 in acute pre-B-lymphocytic leukaemia cells. 764 98

5-Lipoxygenase has been recognized to be an important enzyme that catalyzes the first step in leukotriene production. In this study we examine whether or not phospholipids containing docosahexaenoic acid (DHA) affect 5-lipoxygenase activity of a rat basophilic leukemia cell line (RBL-1). Among the synthesized phospholipids examined, 1-oleoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (1-oleoyl-2-DHA-PC) was found to be the most potent inhibitor of 5-lipoxygenase. The inhibition was dose-dependent and the ID50 value was 4.0 microM. When the fatty acid at the sn-2-position was replaced by other unsaturated fatty acids, the inhibitory activity decreased with decreasing numbers of both carbon atoms and double bonds in the fatty acids. Substitution at the 1-position of the DHA-containing PC also affected the inhibitory potency. If oleic acid was substituted with palmitic acid, the inhibition activity was completely abolished. Lineweaver-Burk plot analysis showed that the inhibition of 5-lipoxygenase by 1-oleoyl-2-DHA-PC was non-competitive. The inhibition by this synthesized phospholipid was very specific to 5-lipoxygenase; that is, it did not extend to fatty acid cyclooxygenase, 12-lipoxygenase or 15-lipoxygenase. These results suggest that endogenously existing DHA-containing phospholipids may affect 5-lipoxygenase activity and thus control leukotriene biosynthesis in vivo.
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PMID:Inhibitory effect of docosahexaenoic acid-containing phospholipids on 5-lipoxygenase in rat basophilic leukemia cells. 830 21

Phenoxyl radicals are inevitable intermediates in the oxidative enzymatic metabolism of a phenolic antitumour drug, etoposide (VP-16), by peroxidases, cytochrome P-450, prostaglandin synthetase and tyrosinase, as well as in its interactions with oxygen and peroxyl radicals. It has been shown that one-electron reduction of the VP-16 phenoxyl radical by ascorbate and thiols prevents/delays its oxidative metabolism by tyrosinase both in model systems and in cell homogenates. To elucidate the role of endogenous thiols in the reduction of VP-16 phenoxyl radicals, K562 human leukaemia cells grown in Dulbecco's modified Eagle's medium which does not contain vitamin C (ascorbate) were used, thus excluding the ascorbate-dependent reduction of VP-16 phenoxyl radicals. VP-16 phenoxyl radicals were reduced by endogenous reductants in K562 cell homogenates, intracellular thiols mainly being responsible. Depletion of endogenous thiols by mersalyl acid resulted in almost complete inhibition of the ability of cell homogenates to reduce VP-16 phenoxyl radicals. Three systems were used to evaluate the contribution of thiol-dependent reduction of VP-16 phenoxyl radicals: (1) K562 cell homogenates depleted or supplemented with glutathione (GSH) in vitro; (2) homogenates derived from K562 cells with a decreased level of endogenous thiols and GSH (using a specific inhibitor of gamma-glutamyl cysteine synthetase, buthionine-S,R-sulfoximine; BSO) and (3) homogenates derived from K562 cells with increased content of endogenous thiols as a result of treatment with cadmium chloride. Depletion of thiols in K562 cells or cell homogenates proportionally decreased the ability of homogenates to reduce VP-16 phenoxyl radicals. Similarly, depletion or supplementation of K562 cells or cell homogenates with GSH proportionally decreased or increased the ability to reduce VP-16 phenoxyl radicals. Reduction of VP-16 phenoxyl radicals by K562 cell homogenates was similar to that obtained from cell homogenates isolated from K/VP.5 cells, a VP-16 resistant cell line derived from K562 cells. Elevation of endogenous thiols by cadmium chloride increased the ability of homogenates to reduce VP-16 phenoxyl radicals but did not reveal any significant difference in the ability of the two types of cells to interact with VP-16 radicals. Finally, BSO treatment of K562 cells led to potentiation of VP-16-induced DNA damage and to an increase in VP-16-induced growth inhibition, suggesting that, in the absence of ascorbate, modulation of endogenous thiols may be an important factor determining the oxidative metabolism and cytotoxic activity of VP-16 in tumour cells.
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PMID:Reduction of phenoxyl radicals of the antitumour agent etoposide (VP-16) by glutathione and protein sulfhydryls in human leukaemia cells: Implications for cytotoxicity. 2065 Jan 83