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)

Fe(III) complexes of EDTA and diethylenetriamine pentaacetic acid (DETAPAC) at low concentrations (between 1 and 100 microM) produced up to a 20-fold increase in anaerobic microsomal NADPH- and NADH-dependent reduction of indicine N-oxide. Under aerobic conditions microsomal indicine N-oxide reduction was stimulated to half the levels seen under anaerobic conditions. EDTA alone was much less effective at stimulating indicine N-oxide reduction, while FeCl3 alone had no effect on reduction. Other complexes of Fe(III) had little or no effect in stimulating microsomal indicine N-oxide reduction. Fe(III)-EDTA stimulated indicine N-oxide reduction by purified NADPH-cytochrome P-450 reductase and NADPH. It is probable that iron serves to transfer electrons between microsomal flavoprotein reductases and indicine N-oxide. The redox potential and the presence of an exchangeable ligand, such as water, in the inner ligand sphere of the iron complex are suggested to be important factors in determining which iron complexes will stimulate indicine N-oxide reduction. EDTA complexes of other transition metal ions do not stimulate indicine N-oxide reduction. Hydroxyl radicals, detected as the spin adduct of 5,5-dimethyl-1-pyroline-N-oxide, appear to be formed during Fe(II)-EDTA-dependent reduction of indicine N-oxide under anaerobic conditions. Fe(III)-EDTA at concentrations between 50 and 250 microM stimulated indicine N-oxide reduction by rat isolated hepatocytes up to 5-fold under anaerobic conditions and to half these values under aerobic conditions. By themselves, EDTA and FeCl3 at similar concentrations produced a small stimulation of indicine N-oxide reduction by hepatocytes under anaerobic conditions. Fe(III)-EDTA stimulated indicine N-oxide reduction by murine leukemia P-388 cells under aerobic conditions and by rat caecal flora under anaerobic but not aerobic conditions. Fe(III)-EDTA, EDTA or FeCl3 administered to rats produced a 3-fold increase in the 24-hr urinary excretion of indicine following an i.p. dose of indicine N-oxide.
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PMID:Iron-EDTA stimulated reduction of indicine N-oxide by the hepatic microsomal fraction, isolated hepatocytes, and the intact rat. 628 Jul 24

5-Fluoro-5'-(2-oxo-1,3,2-oxazaphosphorinan-2-yl)-2'-deoxyuridine (1a) and 5-fluoro-5'-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-2'-deoxyuridine (1b) were prepared by reaction of 5-fluoro-2'-deoxyuridine (7a) and phosphoryl chloride with 3-amino-1-propanol and 1,3-propanediol, respectively. The thymidine analogues, 1c and 1d, were prepared similarly from thymidine. Compound 1b was synthesized in better yield from 13a and trimethylene phosphate with triphenylphosphine/diethyl azodicarboxylate as a condensing agent. Compounds 1a-d were resistant to degradation by 5'-nucleotidase, alkaline phosphatase, venom phosphodiesterase, and crude snake venom. None of these compounds were significantly biotransformed when incubated with mouse hepatic microsomal preparations in the presence of an NADPH-generating system. When administered intraperitoneally (ip) for 5 consecutive days, 1a was nearly as effective as 5-fluorouracil at prolonging the life spans of BDF1 mice implanted intraperitoneally with leukemia P-388. However, much larger dosages of 1a were required for optimal activity. Compound 1b administered similarly was only marginally effective. Neither 1a nor 1b was active against a P-388 mutant resistant to 5-fluorouracil.
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PMID:Synthesis and biological evaluation of neutral derivatives of 5-fluoro-2'-deoxyuridine 5'-phosphate. 630 57

The gp52 glycoprotein of the spleen focus-forming virus found in the Friend and Rauscher complexes of murine leukemia viruses (MuLV) has been previously identified as a recombinant molecule involving substitutions and deletions of the MuLV env gene. Unlike the MuLV structural glycoproteins, gp52 is defective in its transport to the cell surface. We have studied aspects of the intracellular transport and membrane association of gp52 to investigate the possible mechanisms underlying the defective transport process. It was found that a panel of monoclonal antibodies to different epitopes of p 15E, as well as an antiserum to a synthetic peptide corresponding to the carboxy terminus of MuLV envelope precursors, failed to react with gp52. Despite the possible absence of membrane-anchoring regions of MuLV envelope proteins known to reside on p 15E, gp52 was not found to be secreted into the culture fluids. Detergent extraction studies indicated that gp52 is associated with the membranes and not the contents of microsomal vesicles in speen focus-forming virus-infected cells. gp65, the processed form of gp52, could be labeled with [3H]palmitic acid, suggesting a membrane association. To determine whether a spontaneous denaturation occurs leading to aggregation and defective transport of gp52, we studied the surface expression of gp52 in cells grown at different temperatures, as well as the solubility of gp52 in low concentrations of Triton X-100. No evidence of aggregation or of a temperature-dependent difference in transport was obtained. gp52 appears to be a monotopic integral membrane protein, unlike MuLV envelope proteins which are bitopic integral membrane proteins; proteolytic digestion of intact microsomal vesicles did not reveal a detectable cytoplasmic tail under conditions where this could be demonstrated on MuLV envelope precursors. We suggest that a loss of putative signals involved in mediating intracellular transport is a likely cause for the defective transport of the spleen focus-forming virus glycoproteins.
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PMID:Membrane association and defective transport of spleen focus-forming virus glycoproteins. 631 35

Rat basophil leukemia cell homogenates effectively catalyze the conversion of leukotriene A4 to a mixture of leukotrienes C4 and D4 in the presence of glutathione. These homogenates also catalyze the formation of adducts of halogenated nitrobenzene with glutathione, as determined spectrophotometrically. While all the classical glutathione S-transferase activity resides in the soluble fraction of the homogenates, the thiol ether leukotriene-generating activity is found in the particulate fraction. This "leukotriene C synthetase" activity has been solubilized from a crude high-speed particulate fraction by means of the nonionic detergent, Triton X-100. The solubilized enzyme is incapable of converting 2,4-dinitrochlorobenzene to a colored product in the presence of glutathione. Nor will it react with 3,4-dichloronitrobenzene. On the other hand, under optimal conditions, this enzyme preparation is capable of generating about 0.1 nmol leukotriene C mg protein-1 min-1 in a reaction which continues in linear fashion for at least 10 min. This dissociation in substrate specificity, as well as differences in the inhibition profile, distinguish the enzyme activity in the particulate fraction from rat basophil leukemia cell homogenates from the microsomal glutathione S-transferase which has been described in rat liver homogenates, suggesting that this "leukotriene C synthetase" is a new and unique enzyme.
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PMID:Solubilization and characterization of the leukotriene C4 synthetase of rat basophil leukemia cells: a novel, particulate glutathione S-transferase. 632 87

The cytosolic glutathione S-transferases of rat liver have been fractionated by chromatofocusing into 10 distinct fractions based on their reactivity with 2,4-dinitrochlorobenzene. All these fractions were capable of generating leukotriene C4 (LTC4) from leukotriene A4 (LTA4) to some extent. An inhibitor of leukotriene synthesis, U-60,257, inhibited the activity of these enzymes. The cytosolic glutathione S-transferases of rat basophil leukemia (RBL) cells have been similarly fractionated. U-60,257 inhibited the activity of some of these fractions but not that of others. None of the fractions of the enzyme from RBL cells formed LTC4 from LTA4. The microsomal glutathione S-transferase from rat liver also produced LTC4 from LTA4. It differs from the microsomal LTC synthetase of RBL cells in at least two respects: (1) The enzyme from RBL cells did not react with chromophoric substrates like dinitrochlorobenzene while the enzyme from liver did react. (2) Triton X-100 potentiated the activity of the enzyme from basophil leukemia cells and solubilized it, while it inhibited the activity of the leukotriene-synthesizing enzyme in the rat liver preparation. These results, along with a distinctly different inhibitor profile, indicate that LTC synthetase is a new and distinct glutathione S-transferase.
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PMID:Leukotriene C synthetase, a special glutathione S-transferase: properties of the enzyme and inhibitor studies with special reference to the mode of action of U-60,257, a selective inhibitor of leukotriene synthesis. 638 74

Health conditions were evaluated in 80 electrical workers exposed for many years to polychlorinated biphenyl (PCB) mixtures with a 42% mean chlorine content, who had blood PCB concentrations from 41 to 1319 micrograms/kg. The clinical study was based on personal history data, physical examination, and laboratory tests (red cell and leukocyte count; determination of haemoglobin, packed cell volume, bilirubin, serum protein electrophoretic fractions, pseudocholinesterase, AST, ALT, GGT, and OCT). Fifteen workers were found to have skin diseases--chloracne (4), folliculitis (4), oil dermatitis (1), juvenile acne (1), and dermatitis due to irritative or allergic agents (5). Sixteen workers showed more or less pronounced hepatic involvement, consisting most often of hepatomegaly with an increase in serum GGT, AST, ALT, and OCT values. In two workers bleeding cavernous haemangiomas were discovered, in one case associated with chronic myelocytic leukaemia. All the workers with chloracne were employed on electric capacitor impregnation with PCBs, and no definite association was found between chloracne and blood PCB concentrations. Conversely, a significant positive association was found between the abnormal liver findings and blood PCB concentrations, particularly trichlorobiphenyl blood concentrations. The abnormal hepatic findings observed are similar to those reported in experimental animals given PCBs, and in some workers such findings should probably be considered as clinical signs of hepatic microsomal enzyme induction.
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PMID:Occupational exposure to polychlorinated biphenyls in electrical workers. II. Health effects. 645 Dec 37

Carbon tetrachloride is an hepatotoxin that depresses hepatic microsomal cytochrome P-450 and other enzyme activities. Cyclophosphamide is an anticancer drug that is activated by hepatic microsomal cytochrome P-450, while the products of cyclophosphamide metabolism by cytochrome P-450 can be metabolized by other hepatic enzymes. Carbon tetrachloride pretreatment has been found to increase the in vivo antitumor activity of cyclophosphamide against murine leukemia P-388. Carbon tetrachloride did not, however, affect the direct cytotoxicity of cyclophosphamide or 4-hydroxycyclophosphamide to cells in culture. Pharmacokinetic studies in mice revealed a delayed plasma disappearance of cyclophosphamide after carbon-tetrachloride pretreatment with an apparent initial half-time of 20.4 min compared to 9.0 min in non carbon-tetrachloride-pretreated mice. Plasma levels of total alkylating activity and plasma 4-hydroxycyclophosphamide increased more slowly and reached a lower peak, but were maintained for a longer time period in mice pretreated with carbon-tetrachloride than in untreated mice. The half-life for plasma elimination of 4-hydroxycyclophosphamide in untreated mice was 12 min and in carbon-tetrachloride-pretreated mice 27 min. There was, however, no difference in the area under the curve for either plasma total alkylating activity or plasma 4-hydroxycyclophosphamide between the two groups. It is suggested that prolonged exposure of tumor cells to 4-hydroxycyclophosphamide might be responsible for the increased antitumor activity of cyclophosphamide following carbon-tetrachloride pretreatment.
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PMID:Carbon tetrachloride-induced increase in the antitumor activity of cyclophosphamide in mice: a pharmacokinetic study. 670 34

The metabolism, antitumor activity, and acute toxicity of 5-fluoro-1,3-bis-(tetrahydro-2-furanyl)-2,4-pyrimidinedione (FD-1) were investigated in animals, compared with 5-fluoro-1-(tetrahydro-2-furanyl)-2,4-pyrimidinedione (FT). It was found that after oral administration of FD-1, the level of 5-fluorouracil (5-FU) was maintained higher and longer than after administration of FT, and that a large amount of 5-FU was released from FD-1 by liver microsomal drug-metabolizing enzymes or spontaneous hydrolysis via 5-fluoro-3-(tetrahydro-2-furanyl)-2,4-pyrimidinedione (3-FT) and FT. FD-1 had a significant activity against the solid form of Ehrlich carcinoma, sarcoma-180, hepatoma AH130, Yoshida sarcoma, Walker carcinosarcoma-256, and leukemia L1210 and P388, but not the ascitic forms, and it produced greater inhibition of tumor growth than FT. The acute toxicity of FD-1 was less than that of FT.
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PMID:Metabolism, antitumor activity, and acute toxicity of 5-fluoro-1,3-bis(tetrahydro-2-furanyl)-2,4-pyrimidinedione by oral administration to animals. 676 37

The inducers of microsomal drug-metabolizing enzymes phenobarbital (PB) and 20-methylcholanthrene (MC) inhibited the lethargic effect of high doses of ftorafur in C57BL/6j mice, but stimulated the animal mortality at days 4-8 after the drug administration. The opposite effect has been obtained by the combination of ftorafur with the inhibitor of the microsomal enzymes SKF 525A. Animal pretreatment with PB or with PB + MC markedly enhanced the antineoplastic activity of ftorafur in Rauscher leukemia-, leukemia La-, or hemangiopericytoma-bearing mice but seemed unlikely to afford any therapeutic advantage over this drug because the lethal toxicity of ftorafur was increased.
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PMID:Changes in toxic and antitumor properties of ftorafur by induction or inhibition of the microsomal enzymes activity. 679 84

The effects of some inducers of microsomal cytochrome P450-dependent monooxygenases on the metabolic bioactivation and the cytotoxicity of the antitumoral drug ellipticine (ELPT) were studied. Rate of growth of leukemia L1210 cells was measured in vitro in the absence and presence of ELPT or measured when the ELPT was metabolically transformed by noninbred Sprague-Dawley rat liver microsomes. The animals used were either untreated or pretreated by various inducers such as phenobarbital, 3-methylcholanthrene, beta-naphthoflavone, 2,3,7,8-tetrachlorodibenzo-p-dioxin, Aroclor 1254, or ELPT. The transformation of ELPT into its two main metabolites, 9-hydroxyellipticine (9-OHE) and 7-hydroxyellipticine, was studied and measured by high-pressure liquid chromatography in conjunction with the determination of cytotoxic activity. A large variability was observed in the bioactivation and cytotoxic efficiency of ELPT mediated by the different microsomal preparations: The more P448 and/or P1-450 forms of cytochrome were induced, the more the 9-OHE was produced and the more the cytotoxicity toward L1210 cells was enhanced. These features were compared with those elicited by the activation of cyclophosphamide, which was transformed into cytotoxic metabolites by the cytochrome P450 form specifically induced by phenobarbital-type inducers.
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PMID:Influence of inducers of monooxygenases on cytotoxic efficiency of ellipticine on leukemia L1210 cells. 694 54


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