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)

We compared the ability of human leukemia cell lines of various origins to grow in glutamine-deficient media. The growth of B lymphoblastoid cell lines, including promyelocytic HL-60, is highly dependent on glutamine, whereas T-cell lines are able to proliferate in glutamine-free media. Such glutamine dependency has a good inverse correlation with the activity of glutamine synthetase. Moreover, glutamine synthetase can be induced in glutamine-deficient media, especially in glutamine-independent cells. In HL-60 cells, glutamine deprivation results in the decrease of both ATP and dATP levels. The addition of adenine to the culture medium abolishes these changes without restoring cell growth, indicating that the effects of glutamine deprivation on cell growth cannot be fully explained by the perturbation of adenine nucleotide pools.
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PMID:Metabolic basis for differential glutamine requirements of human leukemia cell lines. 196 19

A human histiocytic lymphoma cell line, U937, is highly sensitive to L-asparaginase with an ID50 of about 0.0001 U/ml after 72 hr of culture. When U937 cells were made resistant to either L-asparaginase (1 U/ml) or asparagine deprivation, the activity of asparagine synthetase increased to 80- or 7-fold of the wild type, respectively. The phenotype of the resistance to L-asparaginase turned out to be stable under nonselective conditions for over several months. The hybrids between L-asparaginase sensitive (Molt4) and resistant (HL-60) cell lines revealed the latter phenotype in terms of L-asparaginase sensitivity and the activity of asparagine synthetase. Furthermore, U937 cells resistant to L-asparaginase could survive in glutamine-free media with 1.5-fold elevation of glutamine synthetase activity. These results altogether clarify the role of asparagine synthetase in L-asparaginase toxicity and have a good implication for the clinical use of L-asparaginase.
Leukemia 1989 Apr
PMID:Biochemical characterization of U937 cells resistant to L-asparaginase: the role of asparagine synthetase. 256 53

The antifungal drug, ketoconazole, was reported to antagonize the induction of the enzyme tyrosine aminotransferase (TAT) by glucocorticoids in hepatoma tissue culture (HTC) cells, and to compete with glucocorticoids for binding to the glucocorticoid receptor. Since glucocorticoids inhibit the growth of the human leukemia cell line CEM-C7, ketoconazole might be expected to reverse this inhibition. Unexpectedly, ketoconazole inhibited CEM-C7 cell growth without utilizing glucocorticoid receptors. This was confirmed by ketoconazole inhibition of the growth of a receptor-less subline of CEM-C7 cells which are insensitive to glucocorticoids. Ketoconazole competed with triamcinolone acetonide (TA) for binding to the glucocorticoid receptor in cell-free supernatant prepared from CEM-C7 cells, but this was greatly reduced if ketoconazole and TA were incubated with intact cells prior to preparation of the cell-free supernatant. Ketoconazole inhibited induction by TA of the enzyme glutamine synthetase only at concentrations of 45-90 microM. We conclude that ketoconazole antagonism of glucocorticoid activity in CEM-C7 cells is probably not of pharmacologic significance due to the large concentrations required, and its reduced interaction with receptors in intact cells. The growth inhibitory activity of ketoconazole may be of interest in cancer chemotherapy.
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PMID:Ketoconazole inhibition and glucocorticoid action in the human lymphoblastic leukemia cell line CEM-C7. 289 83

We have immortalized rat central nervous system (CNS) cells of primary cultures of rat optic nerve with murine leukemia virus psi-2,SV-40-6, which is defective in assembly and contains the SV-40 large T antigen and neomycin resistance genes, to produce a cell line that we named A7. After drug selection, greater than 90% of the growing cells expressed nuclear SV-40 large T cells and a fraction of these contained the astrocyte-specific marker, glial fibrillary acidic protein. The majority of these cells also expressed surface marker A4 (specific for neural tube derivatives), Ran 2, p185 (the 185-kD phosphoprotein product of the neu oncogene), and fibronectin, but did not express the astrocyte enzymes glutamine synthetase and monoamine oxidase B. Surface markers characteristic of glial progenitors (A2B5) and oligodendrocytes (galactocerebroside) were not detected. After two rounds of cell cloning, subclone A7.6-3 expressed Ran 2, fibronectin, and the neural cell adhesion molecule (N-CAM) but not glial fibrillary acidic protein and A4. The A7 cell line and subclones also displayed certain functions of type 1 astrocytes: the conditioned medium of these cells had a potent mitogenic activity for glial progenitor cells which could be neutralized by anti-platelet-derived growth factor antibodies and monolayers of these cells supported the growth of embryonic hypothalamic neurons. We conclude that a retrovirus containing SV-40 large T antigen can immortalize rat CNS cells and that such immortalized glial cells retain at least two important functions of type 1 astrocytes: the ability to secrete platelet-derived growth factor and to support the growth of embryonic CNS neurons. Moreover, such stable immortalized clonal cell lines can be used to study gene regulation in glial cells.
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PMID:Antigenic and functional characterization of a rat central nervous system-derived cell line immortalized by a retroviral vector. 305 37

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

Childhood acute lymphoblastic leukaemia is treated by combination chemotherapy with a number of drugs, almost always including the enzyme L-asparaginase (ASNase). Although the initial remission rate is quite high, relapse and associated drug resistance remain a problem. In vitro studies have demonstrated an adaptive increase in asparagine synthetase (AS) expression in ASNase-resistant cells, which is believed to permit ASNase-resistant human leukaemia cells to survive in vivo. The present results, obtained with ASNase-sensitive and -resistant human MOLT-4 leukaemia cell lines, illustrate that several other adaptive processes occur to provide sufficient amounts of the AS substrates, aspartate and glutamine, required to support this increased enzymic activity. In both cell populations, aspartate is derived almost exclusively from intracellular sources, whereas the necessary glutamine arises from both intracellular and extracellular sources. Transport of glutamine into ASNase-resistant cells is significantly enhanced compared with the parental cells, whereas amino acid efflux (e.g. asparagine) is reduced. Most of the adaptive change for the amino acid transporters, Systems A, ASC and L, is rapidly (12 h) reversed following ASNase removal. The enzymic activity of glutamine synthetase is also enhanced in ASNase-resistant cells by a post-transcriptional mechanism. The results demonstrate that there are several sites of metabolic adaptation in ASNase-treated leukaemia cells that serve to promote the replenishment of both glutamine and asparagine.
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PMID:Multiple adaptive mechanisms affect asparagine synthetase substrate availability in asparaginase-resistant MOLT-4 human leukaemia cells. 1148 52

Adenoviral-mediated transfer of ciliary neurotrophic factor (CNTF) to the retina rescued retinal ganglion cells (RGCs) from axotomy-induced apoptosis, presumably via activation of the high affinity CNTF receptor alpha (CNTFRalpha) expressed on RGCs. CNTF can also activate astrocytes, via its low affinity leukemia inhibitory receptor beta expressed on mature astrocytes, suggesting that CNTF may also protect injured neurons indirectly by modulating glia. Adenoviral-mediated overexpression of CNTF in normal and axotomized rat retinas was examined to determine if it could increase the expression of several glial markers previously demonstrated to have a neuroprotective function in the injured brain and retina. Using Western blotting, the expression of glial fibrillary acid protein (GFAP), glutamate/aspartate transporter-1 (GLAST-1), glutamine synthetase (GS), and connexin 43 (Cx43) was examined 7 days after intravitreal injections of Ad.CNTF or control Ad.LacZ. Compared to controls, intravitreal injection of Ad.CNTF led to significant changes in the expression of CNTFRalpha, pSTAT(3), GFAP, GLAST, GS, and Cx43 in normal and axotomized retinas. Taken together, these results suggest that the neuroprotective effects of CNTF may result from a shift of retinal glia cells to a more neuroprotective phenotype. Moreover, the modulation of astrocytes may buffer high concentrations of glutamate that have been shown to contribute to the death of RGCs after optic nerve transection.
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PMID:Ciliary neurotrophic factor protects retinal ganglion cells from axotomy-induced apoptosis via modulation of retinal glia in vivo. 1571 21

To date, the FDA has approved 18 monoclonal antibody (MAb) therapeutic drugs with targets ranging from asthma and rheumatoid arthritis to leukemia. Many of these approved products are produced in Chinese hamster ovary cells (CHO) making CHO a significant and relevant host system. We studied the applicability of CHOK1SV cells as a potential host cell line for MAb production in terms of timelines, achievable titers, transfectant stability, and reproducibility. CHOK1SV, developed by Lonza Biologics, is a suspension, protein-free-adapted CHOK1-derivative utilizing the glutamine synthetase (GS) gene expression system. CHOK1SV expresses the GS enzyme endogenously; thus, positive transfectants were obtained under the dual selection of methionine sulfoximine (MSX) and glutamine-free media. We examined outgrowth efficiencies, specific productivities, and achievable batch titers of three different IgG MAbs transfected into CHOK1SV. Reducing the MSX concentration in the initial selection medium resulted in a decreased incubation time required for transfectant colonies to appear. Specific productivities of "high-producers" ranged between 11 and 49 pg/c/d with batch titers ranging from 105 to 519 mg/L. Transfectant stability and the effects of MSX also were investigated, which indicated that the addition of MSX was necessary to maintain stable MAb production. Cell growth was stable regardless of MSX concentration.
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PMID:Development of transfection and high-producer screening protocols for the CHOK1SV cell system. 1717 63

Despite high cure rates 25% of children with acute lymphoblastic leukaemia (ALL) relapse and have dismal outcome. Crucially, many are currently stratified as standard risk (SR) and additional markers to improve patient stratification are required. Here we have used diagnostic bone marrow specimens from 101 children with pre-B ALL to examine the use of gene expression profiles (GEP) as predictors of long-term clinical outcome. Patients were divided into two cohorts for model development and validation based on availability of specimen material. Initially, GEP from 55 patients with sufficient material were analysed using HG-U133A microarrays, identifying an 18-gene classifier (GC) that was more predictive of outcome than conventional prognostic parameters. After feature selection and validation of expression levels by quantitative reverse transcription polymerase chain reaction (qRT-PCR), a three-gene qRT-PCR risk index [glutamine synthetase (GLUL), ornithine decarboxylase antizyme inhibitor (AZIN), immunoglobulin J chain (IGJ)] was developed that predicted outcome with an accuracy of 89% in the array cohort and 87% in the independent validation cohort. The data demonstrate the feasibility of using GEP to improve risk stratification in childhood ALL. This is particularly important for the identification of patients destined to relapse despite their current stratification as SR, as more intensive front-line treatment options for these individuals are already available.
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PMID:Prediction of relapse in paediatric pre-B acute lymphoblastic leukaemia using a three-gene risk index. 1830 14

This is an ambitious effort attempting to present as many aspects as possible in a review article on asparaginases (ASNase), and their use against acute lymphoblastic leukemia (ALL) and T-cell lymphomas. In the process, the modes of drug resistance are described both of the host and in the leukemia cells themselves. These modes of drug resistance, developed by the ALL cells, are an attempt to overcome the toxic insult this class of anti-leukemic drugs causes to them. It is expected that by reading this article one would obtain a better understanding of the initial events in the leukemia development, its microenvironment, and the many issues that a leukemia specialist has to deal with, especially in the treatment of refractory and relapsed patient populations. The specific issues addressed in this review deal with the importance of nutrients in tumor growth and progression of malignancies; the cytogenetics of ALL, as well as its chemotherapy, are also briefly presented. The emphasis will turn to ASNase, their mechanisms of action, the immune responses they cause in a significant percentage of the ALL patients, the significance of the up-regulation of glutamine synthetase and asparagine synthetase and the complexity of the elucidation of the mechanisms of action of ASNase. Additional details on the ASNase epitope mapping of anti-ASNase antibodies, the degradation of the protein, and the unmet needs in producing an optimal ASNase protein, will be also presented. Finally, a brief description of the toxicity, as well as the correlative factor of ALL treatment with ASNase is given.
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PMID:Asparaginases: biochemical pharmacology and modes of drug resistance. 2275 99


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