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)

Myeloma cells have been synchronized by isoleucine starvation. Changes in RNA synthetic rates as a result of starvation have been studied. The ability of isolated nuclei to synthesize RNA declines on starvation and increases subsequently on refeeding isoleucine. There is a coordinate drop in synthetic rate for all three polymerases both in vivo and in vitro. The chain elongation rate in vitro is the same in starved and normal cells, so the difference is in the number of active polymerases in vitro. However, the nuclei do not exactly parallel the state of the cell from which they were isolated, but the in vitro RNA synthesis increases more slowly than the in vivo RNA synthesis. There is no change in relative amounts of synthesis by the different RNA polymerases. The in vitro RNA product is similar in starved and growing cells.
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PMID:RNA synthesis in myeloma cells synchronized by isoleucine starvation. 72 11

Continuous monitoring of fluorescence (CMF) has been used to examine doxorubicin efflux from intact human myeloma cells. The time resolution of these measurements has enabled detailed comparison of the initial rates of efflux for the drug-sensitive myeloma line RPMI 8226 and a series of sequentially derived multidrug-resistant (MDR) lines expressing different amounts of human MDR protein (P-glycoprotein). Cells that are 3-, 10-, 60-, or 120-fold resistant to doxorubicin export approximately 10, 20, 30, or 33% more doxorubicin than the parental sensitive cells, respectively, when all are preloaded to the same level of total intracellular drug. Remarkably, however, when cells are loaded to the same level of exchangeable drug the initial rates of efflux are found to be virtually identical. This agreement between rates is apparently not dependent on the drug concentration. Approximately 50% of the increase in the steady-state level of doxorubicin efflux for the resistant cells is abolished upon glucose starvation. However, surprisingly, the apparent initial rates of efflux from the treated and untreated cells are found to be virtually the same. Pretreatment of the resistant cells with verapamil reduces the steady-state level of efflux but increases the apparent initial rate at some concentrations. Conversely, vincristine does not alter steady state but slows the initial rate of efflux from both sensitive and resistant cells by approximately the same extent. Finally, quite interestingly, a nearly linear relationship between pHi and relative steady state of efflux is found for the series of cell lines. These data are interpreted in terms of existing models for MDR.
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PMID:Analysis of the steady-state and initial rate of doxorubicin efflux from a series of multidrug-resistant cells expressing different levels of P-glycoprotein. 136 58

The uptake of the fluorescent, lysosomotropic weak base acridine orange (AO) by living cells in culture was studied by flow cytofluorometry. A mouse myeloma cell line (SP 2/0), growing in suspension, and an anchorage-dependent human malignant glioma cell line (U-251 MG), brought into suspension by trypsinization, were used. The consequences of trypsinization were also studied using static cytofluorometry. The lysosomal accumulation of AO by myeloma cells growing in suspension was found to be only moderately affected by starvation (i.e. incubation without medium change) for a period of up to five days. Trypsinization of the glioma cells after staining with AO caused pronounced release of the fluorescent dye while trypsinization before staining with AO did not significantly change the average lysosomal concentration of AO. We did, however, notice certain side effects of trypsinization in the form of both increased cellular green fluorescence and greater intercellular variability that reduce the validity of data obtained from cells detached by routine trypsinization. In conclusion, the condition of the lysosomal vacuome of living cultured cells growing in suspension may be studied by flow cytofluorometry after vital staining with the lysosomotropic weak base AO. Anchorage-dependent trypsinized cells, however, yield unsatisfactory results when examined in a flow cytofluorometer system and are better studied while still attached to their substratum, using static cytofluorometry.
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PMID:Flow cytofluorometry of lysosomal acridine orange uptake by living cultured cells. Effect of trypsinization and starvation. 361 27

Treatment of the eukaryotic organism Tetrahymena with various types of DNA-damaging agents has been reported to cause a 35-fold induction of a mitochondrial DNA polymerase. We here report that the enzyme can be induced in large-scale cultures by exposure of the cells to thymine starvation and/or intercalating agents. The induced DNA polymerase has been purified to near homogeneity, with a specific activity of approx. 300,000 units/mg protein. The relative molecular mass of the active form of the enzyme is approx. 100,000, as determined by glycerol gradient sedimentation. The subunit structure has been analysed by SDS polyacrylamide gel electrophoresis of the highly purified preparation and by immunoprecipitation with a monoclonal antibody directed to the DNA polymerase. A polypeptide of Mr 47,000 has been observed to be a subunit of the enzyme. This corresponds to the size of the subunits suggested for mitochondrial DNA polymerase from chicken embryos and mouse myeloma cells.
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PMID:Purification and characterization of an inducible mitochondrial DNA polymerase from Tetrahymena thermophila. 381 2

Histone mRNA was partially purified from mouse myeloma cells synchronized in S phase by isoleucine starvation. A cDNA was prepared that contained sequences complementary to all five mouse histone genes. This cDNA was used to screen a library of mouse DNA in lambda phage. The positive clones were screened by hybridization with sea urchin histone gene-specific probes to identify those clones that contained histone genes. Confirmation of this identification was obtained by hybridization with Drosophila histone genes. Two independent clusters of histone genes were isolated. One, MM531, contains regions hybridizing specifically to H3, H4, and H1 and the other, MM221, contains two regions hybridizing specifically to H3 and single regions complementary to H4, H2b, and H2a. They are not part of a simple repeating structure. The nucleotide sequence of the coding region of the H3 gene in MM531 has been determined. This gene could code for a variant H3 protein that has several amino acid substitutions not reported in other H3 proteins.
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PMID:Isolation of two clusters of mouse histone genes. 645 99

It has been known for several years that DNA replication and histone synthesis occur concomitantly in cultured mammalian cells. Normally all five classes of histones are synthesized coordinately. However, mouse myeloma cells, synchronized by starvation for isoleucine, synthesize increased amounts of histone H1 relative to the four nucleosomal core histones. This unscheduled synthesis of histone H1 is reduced within 1 h after refeeding isoleucine, and is not a normal component of G1. The synthesis of H1 increases coordinately again with other histones during the S phase. The DNA synthesis inhibitors, cytosine arabinoside and hydroxyurea, block all histone synthesis in S-phase cells. The levels of histone H1 mRNA, relative to the other histone mRNAs, is increased in isoleucine-starved cells and decreases rapidly after refeeding isoleucine. The increased incorporation of histone H1 is at least partially due to the low isoleucine content of histone H1. Starvation of cells for lysine resulted in a decrease in H1 synthesis relative to core histones. Again the ratio was altered on refeeding the amino acid. 3T3 cells starved for serum also incorporated only H1 histones into chromatin. The ratio of different H1 proteins also changed. The synthesis of the H1(0) protein was predominant in G0 cells, and reduced in S-phase cells. These data indicate the metabolism of H1 is independent of the other histones when cell growth is arrested.
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PMID:Uncoordinate synthesis of histone H1 in cells arrested in the G1 phase. 715 89

Multiple myeloma (MM) is a slow-growing malignancy whose plasma cells express the BCL-2 antiapoptosis gene. It is also associated with high levels of interleukin-6 (IL-6), a cytokine that prevents programmed cell death (PCD) in other target cell types. We thus investigated the ability of MM cells to undergo PCD and the possible regulatory effects of IL-6. Four MM cell lines underwent PCD when exposed to serum starvation, doxorubicin (dox), etoposide (VP-16), or dexamethasone (dex). Apoptosis was confirmed by morphologic criteria and/or detection of endonucleosomal DNA fragmentation. The concentrations of dox, VP-16, and dex required for PCD were at least 10-fold greater than that required to inhibit proliferation. Addition of IL-6 (but not IL-1 beta, IL-4, IL-7, or IL-10) inhibited PCD of 8226 targets induced by serum starvation or dexamethasone in a concentration-dependent fashion. In contrast, it had no effect on PCD induced by dox or VP-16. Exposure of targets to IL-6 did not increase BCL-2 expression (it actually consistently decreased expression), suggesting IL-6's protection against apoptosis was not mediated by direct effects on BCL-2. Targets protected from PCD by IL-6 were still sensitive to serum starvation and dex-induced cytostasis, but, after reculturing in drug-free complete media, they reinitiated normal proliferation. These data suggest that high levels of IL-6 may contribute to expansion of myeloma clones by inhibiting apoptotic death.
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PMID:Interleukin-6 inhibits apoptosis of malignant plasma cells. 774 52

Multidrug resistance (MDR) is a phenomenon by which tumor cells exposed to a single anti-proliferative agent acquire resistance to other structurally and functionally unrelated drugs. The classical form of MDR is caused by a plasma-membrane protein currently named P-glycoprotein or P-170 encoded by the human mdr-1 gene in its functional isoform. In vitro cell lines expressing P-170 usually also present phenotypic and functional alterations. In the present study we report that the cytotoxicity mediated by tumor necrosis factor alpha (TNF alpha) in MDR variants of the human T-lymphoblastoid CEM cell line is associated with apoptosis (programmed cell death). Susceptibility of MDR cells to apoptosis was increased upon cycloheximide + TNF alpha sequential treatment, whereby the impairment of protein synthesis due to the former agent was followed by the effect of cytokine exposure. Massive apoptosis of P-170-positive cells, but not of controls, was also obtained by depletion of nutrients (i.e., serum starvation). In contrast, TNF-alpha exerted a similar apoptotic effect in epithelial (MCF-7) or myeloma (S8226) drug-sensitive/ -resistant cell pairs. However, the MDR variant of myeloma S8226 was more sensitive to the cytostatic effect of TNF alpha than the parental drug-sensitive cell line. These results suggest that the presence of the MDR phenotype may be associated with increased histotype-dependent cell susceptibility to specific, protein-synthesis-independent, apoptotic pathways.
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PMID:Tumor necrosis factor alpha is a powerful apoptotic inducer in lymphoid leukemic cells expressing the P-170 glycoprotein. 876 May 94

Enhanced expression of the antiapoptotic gene BCL-2 may participate in chemoresistance. To ascertain if multiple myeloma cells surviving exposure to chemotherapy alter their BCL-2 expression, we treated the myeloma cell lines 8226, IM-9, and U266 as well as a primary myeloma cell culture with various injurious agents. Doxorubicin, etoposide, and hydrogen peroxide consistently induced a concentration- and time-dependent upregulation of BCL-2 expression in all myeloma target cell types assayed by flow cytometry and Western blot analysis. In contrast, serum starvation, dexamethasone, and anti-fas antibodies had no effect on expression. Enhanced expression of BCL-2 was relatively selective as treatments had no effect on expression of Ig light chains, BCL-X, or actin. An reverse transcriptase-polymerase chain reaction assay showed increased levels of BCL-2 RNA in 8226 cells as early as 4 hours after treatment with doxorubicin at a time when cell recoveries were not decreased. Thus, doxorubicin stimulates BCL-2 expression in individual 8226 cells rather than simply allowing a selected survival of high BCL-2-expressing cells in culture. Doxorubicin-treated 8226 cells with upregulated BCL-2 expression were relatively resistant to a second exposure of doxorubicin. In addition, BCL-2-transfected IM-9 cells, with enhanced expression of BCL-2 which was comparable to that achieved by initial exposure to doxorubicin, were resistant to doxorubicin and etoposide cytotoxicity. These data suggest that exposure to chemotherapeutic agents may enhance BCL-2 expression in surviving myeloma cells and contribute to acquired chemoresistance.
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PMID:Upregulated expression of BCL-2 in multiple myeloma cells induced by exposure to doxorubicin, etoposide, and hydrogen peroxide. 878 38

Fas belongs to the family of type-1 membrane proteins that transduce apoptotic signals. In the present studies, we characterized signaling during Fas-induced apoptosis in RPMI-8226 and IM-9 multiple myeloma (MM) derived cell lines as well as patient plasma cell leukemia cells. Treatment with anti-Fas (7C11) monoclonal antibody (MoAb) induced apoptosis, evidenced by internucleosomal DNA fragmentation and propidium iodide staining, and was associated with increased expression of c-jun early response gene. We also show that anti-Fas MoAb treatment is associated with activation of stress-activated protein kinase (SAPK) and p38 mitogen-activated protein kinase (MAPK); however, no detectable increase in extracellular signal-regulated kinases (ERK1 and ERK2) activity was observed. Because interleukin-6 (IL-6) is a growth factor for MM cells and inhibits apoptosis induced by dexamethasone and serum starvation, we examined whether IL-6 affects anti-Fas MoAb-induced apoptosis and activation of SAPK or p38 MAPK in MM cells. Culture of MM cells with IL-6 before treatment with anti-Fas MoAb significantly reduced both DNA fragmentation and activation of SAPK, without altering induction of p38 MAPK activity. These results therefore suggest that anti-Fas MoAb-induced apoptosis in MM cells is associated with activation of SAPK, and that IL-6 may both inhibit apoptosis and modulate SAPK activity.
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PMID:Interleukin-6 inhibits Fas-induced apoptosis and stress-activated protein kinase activation in multiple myeloma cells. 897 96


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