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)

In vivo effects of DL-alpha-difluoromethylornithine (DFMO) on the metabolism of polyamines and nucleotide phosphates were monitored in P388/S leukemia cells grown intraperitoneally in BDF1 inbred male mice. Inhibiting the ornithine decarboxylase (ODC) activity DFMO depleted putrescine and spermidine to 30-50 and 50-60%, respectively, and increased spermine to 25-60% compared with the controls, when given as 2% solution in drinking water of the tumor-bearing animals. DFMO treatment caused a parallel 56% elevation of total nucleotide content in tumor cells with distinct and significant increase of some nucleotide phosphates. The most pronounced alterations were shown in the intracellular UTP (202%), CTP (103%), ADP (92%) and ATP (71%) concentrations. Changes in polyamine and nucleotide phosphate metabolisms were dependent on tumor progression. A possible explanation of the metabolic events induced by DFMO is discussed.
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PMID:In vivo effects of DL-alpha-difluoromethylornithine on the polyamine and nucleotide phosphate metabolism in P388/S leukemia cells. 308 89

A patient is described who presented a thrombocytopenia with thrombocytopathy followed by the development of a leukaemia. The disorder was characterized by decreased aggregation in the presence of ADP, and a lack of aggregation in the presence of arachidonic acid, natural endoperoxide or collagen. In parallel, 14C-serotonin release was severely decreased or nil in response to these inducers. Thrombin induced a slightly decreased aggregation and a normal 14C-serotonin release. Thromboxane B2 (T X B2) synthesis was normal after stimulation by arachidonic acid, natural endoperoxide or thrombin showing a normal arachidonate metabolism. In addition, the mepacrine test showed no significant decrease of the number of dense bodies with an average of 4.6 per platelet (versus 5.4 +/- 0.8 sd in controls). Stimulation by ionophore A 23187 failed to induce aggregation, 14C-serotonin release, or T X B2 synthesis. Furthermore, in the presence of EDTA, A 23187 did not provoke activation as reflected by 14C-serotonin release or T X B2 synthesis. Thus, in this case of thrombocytopathy, the hypothesis of abnormal intracellular Ca++ fluxes responsible for the defective platelet release phenomenon, was suggested.
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PMID:Thrombocytopenia with thrombocytopathy possibly related to abnormalities of intracellular Ca++ fluxes and followed by the development of leukaemia. 308 7

The in vitro differentiation of multipotent stem cells in long-term marrow cultures can be blocked by treatment with agents that modify cholera toxin induced ADP-ribosylation of proteins. The latter agents also inhibit the growth and development of progenitor cells in soft gels in response to interleukin-3 but have little effect upon the development of progenitor cells that respond to the macrophage colony stimulating factor (CSF-1). Cholera toxin, in the same system, inhibits the development of CSF-1 responsive progenitor cells but has little effect on the development of cells that respond to IL-3. Similarly, progenitor cells that respond to IL-3 are relatively more resistant to pertussis toxin than cells that respond to CSF-1. These data indicate that ADP-ribosylation may be an important post-translational modification of regulatory proteins concerned with hemopoietic cell differentiation and growth in response to stromal cells or growth factors.
Leukemia 1988 Jan
PMID:The development of hemopoietic cells in response to stromal cells or growth factors is modified by agents that influence ADP-ribosylation. 312 9

Damages in secondary DNA structure and inactivation or activation of some repair enzymes such as DNA polymerases alpha and beta and poly(ADP-riboso)polymerase induced by 1-methyl-1-nitrosourea (MNU) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) after administration of the drugs at therapeutic single doses to mice bearing parent L1210 leukemia cells (L1210/0) and MNU- and BCNU-resistant L1210 leukemia cells (L1210/MNU and L1210/BCNU) were studied. Damages in DNA structure of all three leukemia strains were investigated using centrifugation on alkaline or neutral sucrose gradients. More MNU-induced single-strand breaks (SSB) and alkali-labile lesions in L1210/0 and L1210/MNU cells were revealed in newly replicated DNA as compared with those in preexisting DNA. BCNU induced fewer SSB in newly replicated DNA of L1210/0 cells than MNU. The fastest repair of the damages in newly replicated DNA was detected in L1210/BCNU and especially in L1210/MNU cells as compared with L1210/0 cells. These results suggest that there are prone errors in the repair of DNA template as many SSB were revealed in the newly replicated DNA synthesized on the repaired DNA. Repair of DNA damages in L1210/BCNU and especially in L1210/MNU cells was accompanied by activation of DNA polymerases alpha and beta and poly(ADP-riboso)polymerase. It was shown that both DNA polymerases alpha and DNA polymerase beta were involved in the repair of damages induced by MNU and only DNA polymerase beta was involved in repair of damages induced by BCNU.
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PMID:In vivo DNA damage and resistance to 1-methyl-1-nitrosourea and 1,3-bis(2-chloroethyl)-1-nitrosourea in L1210 leukemia cells. 312 36

Mono-ADP ribosylation is a post-transcriptional modification of proteins which can alter their biological properties. Particular substrates for this reaction are the GTP-binding proteins involved in the adenylate cyclase and phospholipase C second messenger pathways. Consequently, mono-ADP ribosylation may be an important element in intracellular signaling. Cholera toxin is a potent mono-ADP-ribosyl transferase, while benzylaminododecylguanine hydrochloride (BADGH) is an inhibitor of cholera toxin-induced ADP ribosylation. We have used these compounds to modulate the effects of inducers of differentiation in HL-60 cells. Cholera toxin, although unable to induce differentiation itself, synergized with inducers of both granulocytic and monocytic differentiation. In contrast, BADGH selectively inhibited the growth of undifferentiated cells. These effects imply regulatory roles for substrates for mono-ADP ribosylation both in the proliferation of undifferentiated cells and in the early stages of differentiation.
Leukemia 1988 Aug
PMID:Agents which modify mono-ADP ribosylation can influence the differentiation of hemopoietic cells. 316 78

Meta-iodo-benzylguanidine (MIBG; 3 x 10(-5) M), a novel inhibitor of mono(ADP-ribosylation)-and the general ribosylation inhibitor nicotinamide (NA; 5-20 mM) both stimulated the glucocorticoid-mediated lysis of sensitive L1210 leukemia cells and even induced susceptibility in various human and murine lines refractory or resistant to dexamethasone (DEX). Potentiation and induction of DEX-sensitivity by ADP-ribosylation inhibitors was accompanied by an increase in saturable 3H-DEX binding sites and by a 2-3 fold increase in the affinity of intracellular receptors for hormone binding. Moreover, the ribosylation inhibitors converted the glucocorticoid antagonist RU-486 into a potent agonist for cytolysis of L1210 cells. We conclude that the cytolytic action of glucocorticoid hormones in leukemic cells is negatively controlled by (mono)ADP-ribosylation of receptor proteins.
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PMID:Potentiation of glucocorticoid-induced lysis in refractory and resistant leukemia cells by inhibitors of ADP-ribosylation. 319 12

Using centrifugation of the nucleoid in a neutral sucrose gradient, the damages in the secondary structure of DNA and the activity of repair enzymes, such as DNA-polymerases alpha and beta and poly(ADP-riboso) polymerase, induced by 1-methyl-nitrosourea (MNU) and 1.3-bis (2-chloroethyl)-1-nitrosourea (BCNU) injected at maximal nonlethal single doses to mice bearing parent leukemia cells (L1210/0) and resistant to MNU and BCNU leukemia L1210 cells (L1210/MNU and L1210/BCNU), were studied. The MNU-induced production of single-strand breaks in L1210/0 and L1210/MNU cells was more conspicuous in newly replicated DNA than in those in preexisting DNA. A more fast repair of the damages in newly replicated DNA was detected in L1210/BCNU and especially in L1210/MNU leukemia cells as compared with L1210/0 cells. The data obtained suggest that there are prone errors in the repair of DNA template, since most of the single-strand breaks were revealed in the newly replicated DNA synthesized on the repaired DNA. The repair of DNA damages in L1210/BCNU and especially in L1210/MNU cells was accompanied by the activation of DNA-polymerases alpha and beta and poly(ADP-riboso)polymerase. Both DNA-polymerases--alpha and beta--were shown to be involved in repair of DNA damages induced by MNU and only DNA-polymerase beta was involved in the repair of damages induced by BCNU.
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PMID:[The role of N-nitrosourea-induced changes in the nucleoid structure and activity of repair enzymes in the development of drug resistance in mice with leukemia L1210]. 366 67

In Xenopus oocytes ribosomal protein S6 becomes phosphorylated on serine residues in response to hormones or growth factors and following microinjection of the tyrosine-specific protein kinases associated with Rous sarcoma virus or Abelson murine leukemia virus. To begin characterization of the enzymes responsible for S6 phosphorylation in this system, we have undertaken the purification of S6 protein kinases from unfertilized Xenopus eggs. DEAE-Sephacel chromatography of crude extracts revealed two peaks of S6 kinase activity, and the peak eluting at 160 mM NaCl was chosen for further purification. Successive chromatography on Mono S, Sephacryl S-200, Mono Q, and heparin-Sepharose resulted in purification of the enzyme to a single protein migrating at Mr = 92,000 on polyacrylamide gels. The final preparation was purified about 500-fold from the DEAE-Sephacel peak with a recovery of 10%. Apparent Km values of the enzyme for ATP and 40 S subunits were 28 and 5 microM, respectively, and the specific activity with 330 microM ATP and 5.6 microM 40 S subunits was 300 nmol/min/mg. The enzyme was inhibited by beta-glycerophosphate, sodium fluoride, potassium phosphate, ADP, heparin, quercetin, and spermine. The availability of a purified S6 protein kinase should facilitate elucidation of the molecular mechanism of S6 phosphorylation during growth stimulation.
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PMID:Purification and characterization of a protein kinase from Xenopus eggs highly specific for ribosomal protein S6. 394 Oct 81

An anion-exchange high-performance liquid chromatography method has been used to quantitate the intracellular purine and pyrimidine nucleotides in extracts of pure lymphocytes, monocytes, neutrophils, eosinophils, erythrocytes, and platelets isolated from the blood of healthy human donors. For accurate and reproducible measurements of the nucleotide profiles in different types of pure leukocytes, the cell suspensions have to be free of platelets and erythrocytes. Incubation of the purified leukocytes for 1 h at 0 degrees C did not alter the nucleotide concentrations but reduced the interdonor variation to 10%. Incubation of purified lymphocytes for 1 h at 37 degrees C caused considerable changes in the relative concentrations of the adenine, guanine, uracil, and cytosine nucleotides. During this incubation the cell viability, the cell number, and the ATP:ADP ratio decreased. Incubation of monocytes and granulocytes for 1 h at 37 degrees C caused considerable loss of cells and/or cell death. For erythrocytes and platelets reproducible nucleotide concentrations were obtained after extraction of freshly isolated cells. During storage of erythrocytes, both at 0 degrees C and at 37 degrees C, a decrease in the ATP:ADP ratio was detected. In all cell types the predominant nucleotides were purine nucleotides, especially adenosine triphosphate. The relative concentrations of the adenine, guanine, uracil, and cytosine nucleotides were very reproducible per cell type and appeared to be characteristic for each cell type. The total nucleotide content was nearly the same for all cell types except erythrocytes, when expressed per microgram of protein. The described methods for purification and storage of blood cells will be useful for comparison of blood cells from healthy donors with those of patients, for example, leukemia patients, in which deviations of the purine and pyrimidine metabolic enzymes have already been described.
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PMID:Nucleotide profiles of normal human blood cells determined by high-performance liquid chromatography. 402 17

Following the parenteral administration of tiazofurin, 2-beta D-ribofuranosylthiazole-4-carboxamide (thiazole nucleoside, TR), a potent but reversible inhibitor of IMP dehydrogenase is generated in subcutaneous nodules of the P388 leukemia. The compound responsible for this effect has been isolated from homogenates of the tumor by ion-exchange HPLC, and its presence monitored by enzyme-inhibition assay. The inhibitor has also been prepared by incubation of tiazofurin with P388 cells in culture. Chromatographically, the inhibitory principle exhibits a moderately strong set negative charge at pH 3, and elutes in the general vicinity of the nucleoside-5'-diphosphates; its absorption maximum in aqueous solution (pH 7) lies at 252 nm. Exposure of the molecule to snake-venom phosphodiesterase or to nucleotide pyrophosphatase destroys its inhibitory potency, whereas other phosphodiesterases are either less effective or inert. Since these results suggested that the anabolite might be a dinucleotide with a phosphodiester linkage of the kind found in NAD, attempts were made to synthesize such an analogue from the 5'-monophosphate of thiazole nucleoside and ATP-Mg2+, using a purified preparation of NAD pyrophosphorylase; modest yields were obtained of a compound with chromatographic, spectral and enzyme-inhibitory properties identical to those of the material isolated from P388 tumor nodules. This enzyme-synthesized material was radioactive when [3H]ATP was used as cosubstrate, and yielded both AMP and thiazole nucleoside-5'-monophosphate on treatment with phosphodiesterase. It resisted attack by NAD glycohydrolase. An apparently identical dinucleotide was also synthesized chemically by means of the Khorana condensation. Mass spectral analysis and nuclear magnetic resonance studies with homogeneous preparations of both the enzymically and chemically synthesized compound were compatible with its being a dinucleotide in which the nicotinamide of NAD has been replaced by thiazole-4-carboxamide. Versus IMP dehydrogenase, the dinucleotide exhibited a K1 of approximately 2 X 10(-7) M and was non-competitive with NAD as the variable substrate. Other NAD utilizing enzymes, including representative dehydrogenases and poly ADP ribose polymerase, were, by comparison to mammalian IMPD, resistant to inhibition by TAD. The properties of this novel dinucleotide are compared and contrasted with those of analogs of NAD containing modifications in the pyridine, adenine or ribofuranose rings, as well as in the pyrophosphate bridge.
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PMID:Studies on the mechanism of action of tiazofurin metabolism to an analog of NAD with potent IMP dehydrogenase-inhibitory activity. 615 29


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