Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthesis and degradation of poly(A) were examined in wheat germ lysates under conditions used for protein synthesis. The lysate contained both poly(A)-polymerizing and poly(A)-hydrolytic activities. The synthetic activity was dependent on the presence of either poly(A) or polyadenylated mRNA as primer. Concurrent with the synthesis of poly(A), radioactivity was released from labeled poly(A) and from the poly(A) region of mRNA. Both poly(A) synthesis and hydrolysis were independent of Mn2+ and could proceed in the presence of Mg2+, the major divalent metal ion required for protein synthesis. The synthetic activity was favoured at high (1 mM) ATP concentration, whereas the hydrolytic activity was maximal in the absence of ATP or at low (0.1 mM) ATP concentration. These data indicate that the steady-state length of the poly(A) moeity of mRNAs in the cytoplasm may be regulated by the levels of ATP. Translation products of polyadenylated mRNAs isolated from myeloma cells before and after partial deadenylation were separated by dodecylsulfate/polyacrylamide gel electrophoresis. Shortening of the poly(A) moiety did not alter the relative amounts of the peptides synthesized, indicating that this process does not involve a preferential breakdown of certain species of mRNA.
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PMID:Turnover of the poly(A) moiety of mRNA in wheat-germ extract. 743 52

A study was made of the effects of inhibitors of ATP synthesis on the process of rhodamine 123 (R-123) release from sensitive sp2/0-Ag14 cells, multidrug-resistant mouse myeloma spEBR-5 cells and hybridoma IF7, derived from spEBR-5 cells. It has been shown that IF7 cells are cross-resistant to ethidium bromide, colchicine, actinomycin D and adriamycin. However, hybridoma IF7 cells, compared to parental spEBR-5 cells, show a lower resistance index. When studying the dependence of the R-123 efflux rate on glycolysis intensity (effect of 2 mM 2-deoxyglucose) and on the level of oxidative phosphorylation activity (effect of 2 mM KCN and 30 microM dinitrophenol), the following distinctive properties of the R-123 transport system of IF7 cells (compared to spEBR-5 cells) were detected: 1) uptake of R-123 into IF7 cells is similar to that observed for the sensitive sp2/0-Ag14 cells; 2) efflux of R-123 from IF7 cells takes place more intensely; 3) R-123 transport is dependent on the rate of glycolysis and may be inhibited by KCN. It is found that 2,4-dinitrophenol inhibits the R-123 efflux from all the cells. Verapamil reverses the multidrug resistance both in spEBR-5 and IF7 cells. The mechanisms of multidrug resistance of cells are discussed.
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PMID:[The kinetics of rhodamine 123 efflux from cells with multiple drug resistance under the action of energy metabolism inhibitors]. 757 Oct 15

The emergence of drug resistant cells is one of the main obstacles for successful chemotherapeutic treatment of haematological malignancies. Most patients initially respond to chemotherapy at the time of first clinical admission, but often relapse and become refractory to further treatment not only to the drugs used in the first treatment but also to a variety of other drugs. Laboratory investigations have now provided a cellular basis for this clinical observation of multidrug resistance (MDR). Expression of a glycoprotein (referred to as P-glycoprotein) in the membrane of cells made resistant in vitro to naturally occurring anticancer agents like anthracyclines, Vinca alkaloids and epipodophyllotoxins, has been shown to be responsible for the so-called classical MDR phenotype. P-glycoprotein functions as an ATP-dependent, unidirectional drug efflux pump with a broad substrate specificity, that effectively maintains the intracellular cytotoxic drug concentrations under a non-cytotoxic threshold value. Extensive clinical studies have shown that P-glycoprotein is expressed on virtually all types of haematological malignancies, including acute and chronic leukaemias, multiple myelomas and malignant lymphomas. Since in model systems for P-glycoprotein-mediated MDR, drug resistance may be circumvented by the addition of non-cytotoxic agents that can inhibit the outward drug pump, clinical trials have been initiated to determine if such an approach will be feasible in a clinical situation. Preliminary results suggest that some haematological malignancies, among which are acute myelocytic leukaemia, multiple myeloma and non-Hodgkin's lymphoma, might benefit from the simultaneous administration of cytotoxic drugs and P-glycoprotein inhibitors. However, randomised clinical trials are needed to evaluate the use of such resistance modifiers in the clinic.
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PMID:Multidrug resistance (MDR) genes in haematological malignancies. 776 26

The effects of the glucose supply on growth and metabolism of an SP2/0 derived recombinant myeloma cell line were studied in chemostat culture during growth on IMDM medium at a fixed dilution rate of 0.032 h-1. Lowering of the feed medium glucose concentration from 25.0 to 1.4 mmol/L resulted in a decrease of steady-state viable cell concentration from 1.9 x 10(9) to 1.0 x 10(9) L-1, whereas viability remained above 90%. Mass balances indicated that only a minor amount of glucose was utilized via the TCA cycle irrespective of the glucose concentration in the feed medium. The apparent biosynthetic yield of cells from ATP was independent of the ratio between the specific glucose and glutamine consumption rate. It is concluded that the primary role of glucose is the provision of intermediates for anabolic reactions. In addition, glucose may play an indirect catabolic role in the process of glutaminolysis by providing the pyruvate for the transamination of glutamate to alanine and alpha-ketoglutarate. At low glucose concentrations in the feed medium, glutamine is probably the sole energy source for this myeloma in chemostat culture.
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PMID:Effects of glucose supply on myeloma growth and metabolism in chemostat culture. 782 30

The phenomenon of cell resistance to prolonged energy deprivation after mild thermal stress was studied in vitro. Murine P3O1 myeloma and Ehrlich ascites carcinoma cells were treated with rotenone (an inhibitor of respiration) in glucose-free medium to block ATP generation. ATP rapidly decreased in these cells to 3-6% of the initial level that resulted in powerful aggregation of cytoskeletal proteins, blebbing, and necrotic death of 60-70% cells within 2 h. Prior heat shock (43 degrees C for 10 min) with a subsequent 3-h recovery in a rich medium considerably suppressed the rotenone-induced actin aggregation and rate of necrosis in the energy-deprived cells without effecting the ATP drop in them. Using [14C]leucine labeling, gel electrophoresis, and fluorography, stimulation of the heat-shock protein (HSP) synthesis and total suppression of any other translation were revealed in the cells during recovery after the heat pretreatment. Significantly elevated levels of HSP70 but not HSP90 and HSP27 were found by means of immunoblotting in both cell cultures rendered resistant to necrosis under ATP-depleting conditions. Inhibition of the thermo-induced HSP synthesis by cycloheximide fully prevented development of the tolerance to energy deprivation. A novel function of HSP70 consisting of protection of ATP-deprived cells from "lethal" aggregation of cytoskeletal proteins is suggested.
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PMID:Heat shock-induced accumulation of 70-kDa stress protein (HSP70) can protect ATP-depleted tumor cells from necrosis. 786 13

The immunoglobulin kappa light chain produced by the CH12 lymphoma is unusual because it is not secreted when expressed in the absence of a heavy chain. Instead, it undergoes rapid intracellular degradation. This degradation is selective, as another light chain expressed in the same cell is not degraded. It is also a property of the CH12 kappa chain itself, since it is degraded rapidly when expressed either in another myeloma cell or in COS-1 fibroblasts. When provided a heavy chain, this kappa chain assembles into IgM and is then protected from proteolysis. The degradation of kappa requires ATP, is sensitive to reduced temperature and to the thiol reagent diamide. Of all the proteolytic inhibitors tested, 3,4-dichloroisocoumarin, L-1-tosylamido-2-phenylethyl chloromethyl ketone, and to a lesser extent 1-chloro-3-tosylamido-7-amino-2-heptanone, inhibit kappa degradation, suggesting the involvement of a serine protease. The degradation of kappa does not require transport to the Golgi complex, nor is it sensitive to a variety of lysosomotropic agents. Both immunofluorescence and the observed association with the endoplasmic reticulum (ER) stress proteins GRP78/BiP and GRP94 indicate that the kappa chain is localized mostly in the ER. When a point mutation which blocks transport to the Golgi complex is introduced into this kappa chain, the association with the stress proteins is enhanced but the rate of degradation is not significantly decreased. We conclude that the CH12 kappa chain is a particularly good substrate for an ER degradation machinery, and that its sensitivity to the protease(s) is governed by its state of assembly. This ER degradation provides a possible quality control mechanism during the differentiation of B lymphocytes.
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PMID:Rapid degradation of an unassembled immunoglobulin light chain is mediated by a serine protease and occurs in a pre-Golgi compartment. 824 27

Five cell lines selected for resistance to the cytotoxicity of inhibitors of DNA topoisomerase II have point mutations in the gene that codes for the M(r) 170,000 form of this enzyme. In each case, the mutation results in an amino acid change in or near an ATP binding sequence of the M(r) 170,000 isozyme of topoisomerase II. We used single-strand conformational polymorphism analysis to screen for similar mutations in other drug-resistant cell lines or in leukemic cells from patients previously treated with etoposide or teniposide. We also analyzed the region of the gene that codes for amino acids adjacent to the tyrosine at position 804 of topoisomerase II which binds covalently to DNA. CEM/VM-1, CEM/VM-1-5, and HL-60/AMSA human leukemic cell lines were used as controls; 3 of 3 known mutations were detected by migration differences of polymerase chain reaction products from the RNA extracted from these three lines. A previously unknown mutation was found in the tyrosine 804 region of the M(r) 170,000 topoisomerase II expressed by CEM/VM-1 and CEM/VM-1-5 cells. Sequence analysis showed that substitution of a T for a C at nucleotide 2404 resulted in an amino acid change of a serine for a proline at amino acid 802. No mutations in any of the ATP binding sequences or in the tyrosine 804 region were detected in polymerase chain reaction products from RNA extracted from human leukemia HL-60/MX2 or CEM/MX1 cells (both cell lines selected for resistance to mitoxantrone) or in human myeloma 8226/Dox1V cells (selected for resistance by simultaneous exposure to doxorubicin and verapamil). No mutations were detected in polymerase chain reaction products from RNA extracted from blasts of 15 patients with relapsed acute lymphocytic leukemia, previously treated with etoposide or teniposide. We conclude that: (a) single-strand conformational polymorphism analysis is useful for screening for mutations in topoisomerase II; (b) resistance to the cytotoxicity of inhibitors of DNA topoisomerase II is not always associated with mutations in ATP binding sequences or the active site tyrosine region of M(r) 170,000 topoisomerase II; and (c) mutations similar to those detected in drug resistant cells selected in culture have not been identified in blast cells from patients with relapsed acute lymphocytic leukemia, previously treated with etoposide or teniposide.
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PMID:Single-strand conformational polymorphism analysis of the M(r) 170,000 isozyme of DNA topoisomerase II in human tumor cells. 838 9

In clinical trials with interferon alpha 2b (IFN-alpha 2b) as maintenance therapy for multiple myeloma, the therapeutic benefit is inconclusive. Although the mechanism(s) by which IFN-alpha 2b prolongs remission in some patients is unknown, 2',5'-oligoadenylate synthetase (2,5-A synthetase) has been used as an objective indicator that IFN-alpha 2b is active in vivo. The enzyme was assayed in cytosol preparations of peripheral blood mononuclear cells (MNCs) from 111 patients who were receiving IFN-alpha 2b and 54 patients who were not, using an assay which measures the conversion of [alpha-32P]ATP to triphospho(adenylyl 2',5')adenosine. 2,5-A synthetase activity was compared with response to intensive therapy and with duration of maintenance therapy. Seventy-three per cent of patients had measurable amounts of 2,5-A synthetase during the first 6 months of maintenance therapy. This percentage decreased with longer follow-up but not significantly. There was no difference between the magnitude of enzyme induction amongst patients who were in complete remission, partial response or who had no change in disease status following intensive therapy. Peripheral blood T cells were a major source of 2,5-A synthetase activity in patients receiving the cytokine. However, both T and B cells produced the enzyme following exposure to IFN-alpha in vitro. The data show that the level of 2,5-A synthetase in patients with multiple myeloma is not indicative of clinical response to IFN-alpha 2b.
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PMID:2',5'-Oligoadenylate synthetase levels in patients with multiple myeloma receiving maintenance therapy with interferon alpha 2b do not correlate with clinical response. 851 71

The divalent cation selective ionophores A23187 and ionomycin were compared for their effects on the Ca2+ contents, nucleotide contents, and protein synthetic rates of several types of cultured cells. Both ionophores reduced amino acid incorporation by approximately 85% at low concentrations (50-300 nmol/L) in cultured mammalian cells without reducing ATP or GTP contents. At these concentrations A23187 and ionomycin each promoted substantial Ca2+ efflux, whereas at higher concentrations a large influx of the cation was observed. Ca2+ influx occurred at lower ionophore concentrations and to greater extents in C6 glioma and P3X63Ag8 myeloma than in GH3 pituitary cells. The ATP and GTP contents of the cells and their ability to adhere to growth surfaces declined sharply at ionophore concentrations producing increased Ca2+ influx. Prominent reductions of nucleotide contents occurred in EGTA-containing media that were further accentuated by extracellular Ca2+. Ionomycin produced more Ca2+ influx and nucleotide decline than comparable concentrations of A23187. The inhibition of amino acid incorporation and mobilization of cell-associated Ca2+ by ionomycin were readily reversed in GH3 cells by fatty acid-free bovine serum albumin, whereas the effects of A23187 were only partially reversed. Amino acid incorporation was further suppressed by ionophore concentrations depleting nucleotide contents. Mitochondrial uncouplers potentiated Ca2+ accumulation in response to both ionophores. At cytotoxic concentrations Lubrol PX abolished protein synthesis but did not cause Ca2+ influx. Nucleotide depletion at high ionophore concentrations is proposed to result from increased plasmalemmal Ca2+-ATPase activity and dissipation of mitochondrial proton gradients and to cause intracellular Ca2+ accumulation. Increased Ca2+ contents in response to Ca2+ ionophores are proposed as an indicator of ionophore-induced cytotoxicity.
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PMID:Translational suppression by Ca2+ ionophores: reversibility and roles of Ca2+ mobilization, Ca2+ influx, and nucleotide depletion. 873 79

EctoATPases are extracellular membrane-bound enzymes that catalyze the hydrolysis of the gamma phosphate from ATP. EctoATPase is expressed by activated and immortalized Epstein-Barr virus-transformed human peripheral blood B lymphocytes and murine B cell hybridomas. By contrast, ectoATPase activity is not expressed on nontransformed human peripheral blood B lymphocytes, murine spleen cells, or murine myeloma cells. The K(m) for ATP for the B cell ectoATPases ranged from 5 to 77 microM; the Vmax ranged from 48 to 129 pmol/ min/10(4) cells. The enzyme required Mg2+ for maximal activity with little dependence on Ca2+. ADP and purine and pyrimidine nucleoside triphosphates were competitive inhibitors of the catalytic reaction. A putative ectoATPase protein has been identified by Western blot analysis of membrane proteins from the immortalized B cells. Under reducing conditions, antiectoATPase antibodies cross-reacted with a 66-kDa protein from murine B cell hybridoma membranes. By contrast a 200-kDa protein from the B cell hybridoma membranes cross-reacted with the antibodies under nonreducing conditions, suggesting a disulfide-linked trimer. The antibodies also cross-reacted with a 66-kDa protein from human B cell membranes under reducing conditions, but did not cross-react with membrane proteins under nonreducing conditions. This suggests that the antibody epitope(s) recognized on the reduced human protein is masked under nonreducing conditions. Thus, this work demonstrates: (1) that ectoATPase may serve as a marker for B cell activation; and (2) mammalian and avian ectoATPases have conserved interspecies immunological epitopes and kinetic properties.
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PMID:Identification and partial characterization of ectoATPase expressed by immortalized B lymphocytes. 912 71


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