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)

Mice infected with the replication-defective virus (BM5def) in the LP-BM5 murine leukemia virus (MuLV) mixture develop an immune deficiency syndrome and encephalopathy characterized by impaired spatial learning and memory as demonstrated in the Morris water maze. However, the molecular mechanism (or mechanisms) underlying this cognitive deficit remains unknown. Here we report that brain fyn kinase, which has been proposed to be involved in spatial learning and memory, was unresponsive to glutamatergic stimulation in mice with MAIDS. Thus, whereas application of glutamate to hippocampal slices from control mice increased fyn protein tyrosine kinase (PTK) activity more than 2.5-fold, these changes were significantly impaired in LP-BM5 MuLV-infected mice. Moreover, mice with MAIDS exhibited an abnormal histological distribution of fyn PTK in the hippocampus. These findings suggest that virus-associated disruption of fyn kinase-mediated signaling contributes to the cognitive deficits observed in mice with MAIDS and other retrovirus-induced encephalopathies.
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PMID:Altered brain fyn kinase in a murine acquired immunodeficiency syndrome. 864 68

The antimitotic depsipeptide cryptophycin 1 (CP1) was compared to the antimitotic peptide dolastatin 10 (D10) as an antiproliferative agent and in its interactions with purified tubulin. The potent activity of CP1 as an inhibitor of cell growth was confirmed. The agent had an IC50 of 20 pM against L1210 murine leukemia cells versus 0.5 nM for D10. Both drugs were comparable as inhibitors of the glutamate-induced assembly of purified tubulin, with D10 being slightly more potent. CP1, like D10, was a noncompetitive inhibitor of the binding of [3H]vinblastine to tubulin (apparent Ki, 3.9 microM); and the depsipeptide was a competitive inhibitor of the binding of [3H]D10 to tubulin (apparent Ki, 2.1 microM). CP1 was less potent than D10 as an inhibitor of nucleotide exchange on tubulin, but the two drugs were equivalent in stabilizing the colchicine binding activity of tubulin. CP1, like D10, caused the formation of extensive structured aggregates of tubulin when present in stoichiometric amounts relative to the protein. Whereas at lower concentrations the drugs were equivalent in causing formation of small oligomers detected by gel permeation high-performance liquid chromatography, there were notable differences in the aggregation reactions induced by the two drugs. The electron micrographic appearance of the D10-induced aggregate differed substantially from that of the CP1-induced aggregate. With D10, but not CP1, aggregate morphology was greatly altered in the presence of microtubule-associated proteins. Finally, although CP1 caused the formation of massive aggregates, as did D10, there was little turbidity change with the depsipeptide as opposed to the peptide.
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PMID:Characterization of the interaction of cryptophycin 1 with tubulin: binding in the Vinca domain, competitive inhibition of dolastatin 10 binding, and an unusual aggregation reaction. 881 33

Fluoroglutamate-containing analogs of folates and methotrexate (MTX) with altered capacities for poly (gamma-glutamate) metabolism were synthesized to probe the biological roles of polyglutamates. Compared to folic acid, DL-e,t-gamma-fluorofolic acid, a compound that is a poor substrate for polyglutamylation, was approximately 25-fold less potent in promoting growth of folate-depleted H35 rat hepatoma cells. DL-beta,beta-Difluorofolic acid, a compound that forms diglutamates more readily than does folic acid, was at least equivalent to folic acid in potency. Leucovorin (LV), a reduced folate, was 30-fold more potent than folic acid in promoting growth, whereas the analogous form of DL-e,t-gamma-fluorofolate, DL-e,t-gamma-fluoroleucovorin (DL-e,t-gamma-FLV) was only 4-fold more potent than folic acid. Both LV and DL-e,t-gamma-FLV protected or "rescued" cells from the growth inhibitory effects of MTX; however a 37- to 46-fold higher concentration of the fluoro analog was required. Folic acid, DL-e,t-gamma-fluorofolic acid, LV, and DL-e,t-gamma-FLV each potentiated the growth inhibitory effect of 5-fluoro-2'-deoxyuridine on CCRF-CEM human leukemia cells; higher concentrations of fluorinated analogs again were required. Stereochemically pure L-t-gamma-fluoromethotrexate (L-t-gamma-FMTX), a poor substrate for polyglutamylation, was evaluated as a cell growth inhibitor. In continuous exposure, L-t-gamma-FMTX), was 7-fold less potent than MTX as an inhibitor of CCRF-CEM growth. Results with these fluorinated folate and MTX analogs offer insight into the importance of polyglutamate metabolism to these biological and pharmacological effects.
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PMID:Biological properties of fluoroglutamate-containing analogs of folates and methotrexate with altered capacities to form poly (gamma-glutamate) metabolites. 893 38

Flupirtine is a triaminopyridine analogue which has been successfully applied in clinics as a non-opiate analgesic drug. Previously we described that flupirtine acts like an N-methyl-D-aspartate (NMDA) receptor antagonist in neuronal cells both in vitro and in vivo. Here we show that flupirtine displays its anti-apoptotic effect also in hNT (human Ntera/D1) neurons. hNT neurons were induced to apoptosis applying glutamate (Glu; at concentrations > or = 1 mM) or NMDA (> or = 1 mM). During Glu/NMDA-mediated apoptosis the levels of the intracellular anti-apoptotic agents Bc1-2 and glutathione dropped by more than 50%. Flupirtine completely abolished this reduction of Bc1-2 and glutathione level at a concentration of 10 microM. In the presence of 3 microM flupirtine a > 6-fold increase of the Bc1-2 (B-cell leukemia/lymphoma-2) level was observed in hNT neurons. At the same concentration, the intracellular level of glutathione increased to 200%. We conclude that the Glu/NMDA-mediated neuronal cell death in vitro is controlled at least partially by Bc1-2 and glutathione. Neuronal cell death by Glu or NMDA in vitro can be overcome applying the drug flupirtine which is in clinical use.
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PMID:Flupirtine increases the levels of glutathione and Bc1-2 in hNT (human Ntera/D1) neurons: mode of action of the drug-mediated anti-apoptotic effect. 898 32

Analysis of rat, pre-T cell 'Nb2 lymphoma' sublines, manifesting different degrees of malignant progression, can indicate phenotypic changes potentially useful as therapeutic targets. In this study, the prolactin (cytokine)-dependent Nb2-11 and autonomous Nb2-SFJCD1 sublines were compared for in vitro thiol growth requirements. Whereas Nb2-11 culture growth depended on 2-mercaptoethanol (2-ME; 33-100 microM), Nb2-SFJCD1 cells were 2-ME-independent. This difference stemmed from differential uptake of exogenous L-cystine, critically required for proliferation. Uptake of 35S-L-cystine (10 microCi/ml; 40 microM) showed Nb2-11 cells had low cystine uptake capability; 2-ME enhanced cystine uptake to growth-sustaining levels. Nb2-SFJCD1 cells did not require 2-ME due to intrinsic, 11-fold higher cystine uptake via the x(c)- cystine/glutamate transport system. In absence of 2-ME, monosodium glutamate abrogated Nb2-SFJCD1 proliferation by specifically inhibiting cystine uptake (85% at 10 mM). Elevated glutathione (GSH) levels were not essential for growth of either line as shown with L-buthionine-(S,R)-sulfoximine (0.1-4 mM) treatment. The cyst(e)ine requirement therefore did not primarily involve maintenance of normal GSH levels, reported critical for T lymphocyte replication. These and other results suggest increased cystine uptake capability constitutes another potential step in progression of T cell cancers which is not coupled to cytokine autonomy or metastatic ability development. The x(c)- transport system apparently provides a novel target for T cell cancer therapy. Its inhibition would suppress cystine uptake by certain progressed cells, and also interfere with cystine uptake, and subsequent cysteine release, by eg macrophages, thought to have a role in cysteine delivery to lymphoid cells.
Leukemia 1997 Aug
PMID:Increased cystine uptake capability associated with malignant progression of Nb2 lymphoma cells. 926 89

Decreased methotrexate (MTX) long-chain polyglutamate formation is associated with MTX resistance whereas high levels of MTX polyglutamate accumulation are found in the blasts of leukemia patients who respond to therapy and have improved outcome. The steady-state level of long-chain MTX polyglutamates depends on the balance of activities of two enzymes: folylpolyglutamate synthetase (FPGS), which adds glutamates to MTX in a gamma-carboxyl linkage, and gamma-glutamyl hydrolase (GGH) or conjugase, which sequentially removes the terminal glutamate residue of MTX polyglutamates. FPGS and GGH activities as well as the formation of total and long-chain MTX polyglutamates were measured after incubation with [3H]MTX in 15 blast samples from patients with acute leukemias (myeloid and lymphoid). The ratio between GGH and FPGS activities was better at predicting the amount of polyglutamate accumulated in the 24-h [3H]MTX assay compared to the determination of either activity alone. The linear regression curve relating the relative levels of long-chain polyglutamates/total polyglutamates with the ratio of GGH/FPGS showed an r value of 0.81 (P < 0.001). These data suggest that the evaluation of both these enzymes at diagnosis may be used as a predictor of MTX polyglutamylation and therefore for response to MTX therapy and outcome.
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PMID:gamma-Glutamyl hydrolase and folylpolyglutamate synthetase activities predict polyglutamylation of methotrexate in acute leukemias. 930 33

Replication-defective Moloney murine leukemia virus expressing the GAD67 gene under the control of the GFAP promoter was produced using selected clones of a fibroblast-packaging cell line. A spontaneously immortalized astrocyte cell line was infected with this virus and cellular clones expressing GAD67 selected. Astrocyte and fibroblast clones expressed functional GAD (detected by glutamic acid decarboxylation), but only fibroblasts were able to also produce GABA in the extracellular medium. When exposed to 200 microM glutamate, despite an observed difference in the rates of glutamate accumulation in control and GAD67-expressing astrocytes, similar proportions of glutamate taken up were detected. In GAD67-expressing astrocytes, the glutamate was mainly converted into GABA, suggesting GAD transgene activity to be dominant over other glutamate metabolic pathways, such as glutamine synthetase and glutamate dehydrogenase. Moreover, rapid GABA release into the cell medium was also observed, suggesting the involvement of reverse GABA transporters. The use of the GFAP promoter might be able to take advantage of its activation in response to factors inducing reactive gliosis observed in pathological insults. GAD67-expressing astrocytes might therefore be used for future grafting in pathological situations in which an excess of glutamate results in neuronal dysfunction or cell death.
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PMID:Glutamate-modulated production of GABA in immortalized astrocytes transduced by a glutamic acid decarboxylase-expressing retrovirus. 943 90

To gain insight into the neurochemical pathologies contributing to AIDS dementia complex, neurotransmitter levels were measured in the brains of mice infected with the LP-BM5 leukemia retrovirus. These mice develop immunologic and cognitive deficits analogous to human HIV-1 infection. Met-enkephalin and substance-P levels declined approximately 50% in the striatum and hypothalamus beginning as early as 4 weeks after infection. Hippocampal met-enkephalin levels were reduced to 50% only at 12 weeks after inoculation. Significant decreases (60-70%) in acetylcholine concentrations were observed in the striatum, cerebral cortex and hippocampus by 12 weeks after virus inoculation, while striatal GABA concentrations decreased to 50-60% at 8-12 weeks after infection. Striatal somatostatin levels were unchanged. Administration of the NMDA receptor antagonists MK-801 or LY 274614 ameliorated the decline in striatal met-enkephalin levels observed in mice after 8 weeks of infection. This pattern of neurotransmitter depletion and the ability of NMDA receptor antagonists to attenuate the loss of striatal met-enkephalin are consistent with an excitotoxic lesion. Thus, the elevation of glutamate levels secondary to glial activation may contribute to the contemporaneous development of cognitive deficits observed in mice infected with the LP-BM5 virus.
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PMID:The pattern of neurotransmitter alterations in LP-BM5 infected mice is consistent with glutamatergic hyperactivation. 963 May 62

A model of spinal trauma was developed where spinal neurones of adult mice were exposed to the excitotoxic glutamate analogue beta-N-oxylamino-L-alanine (L-BOAA). After 24 h, the injured neurones received a single dose of [125I]-LIF at the same site of the spinal cord, and 2 h later, tissues were removed to assess the distribution of leukaemia inhibitory factor (LIF). There was a significant increase in LIF binding to the injured region of the spinal cord over saline controls, and this corresponded with a significant increase in LIF mRNA expression in the same region of the cord. There was a change in the expression of ciliary neurotrophic factor, but the expression of cardiotrophin-1 (CT-1) and the common receptor subunit LIF receptor beta (LIFRbeta) did not change after neurotoxin treatment. The results add to the evidence that LIF plays a significant role in the response of adult neuronal tissue to injury.
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PMID:Leukaemia inhibitory factor (LIF) production in a mouse model of spinal trauma. 967 74

A temperature-sensitive mutant of Moloney murine leukemia virus (MoMuLV-ts1) induces polioencephalomyelopathy and hind limb paralysis in highly susceptible FVB/N strains of neonatal mice. This disease is characterized by progressive motor neurons loss and severe gliosis within specific target areas of the central nervous system (CNS). The mechanism(s) of this neurodegeneration is unknown. In the neonatal infection of the CNS, the MoMuLV-ts1 virus was reported to replicate within the endothelial, ependymal, astrocytes and microglial cells. Since no virus or viral products were recognized in the degenerating neurons, it is postulated that an indirect mechanism(s) caused the loss of neurons in the neonatally infected mice. This study was undertaken to investigate the possible pathogenic role of excitatory amino acids (EAAs) such as glutamate and other nonneurotransmitters amino acids (NAAs) in this animal model. The free amino acids concentration was analysed by a fluorometric HPLC method. The temporal measurements of the free amino acids concentration, glutamate, glutamine and arginine from the brain stem and spinal cord of MoMuLV-ts1-infected mice was significantly decreased when compared with the control non-infected mice. The concentration of EAAs during the course of this infection indicated a sharp decline in glutamate and its precursor, glutamine with early infection (10 days post infection-dpi). This deficiency persisted (20 and 30 dpi) in the spinal cord, where the neuronal loss was most severe, but not in the brain stem. A similar pattern occurs with the amino acid arginine. These observations suggest that an astrocyte-induced metabolic disturbance of glutamate and arginine in the CNS of developing mice, could be, in part responsible for the loss of motor neurons observed in this model.
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PMID:Quantitative variation of free amino acids in the central nervous system of MoMuLV-ts1-infected mice. 970 91


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