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)

Glucocorticoid receptors and glucocorticoid receptor RNA (GR RNA) were measured in doxorubicin resistant myeloma cell lines to investigate the relationship between multi-drug resistance and glucocorticoid sensitivity. Glucocorticoid binding sites and GR RNA were found to be lowered in all the tested doxorubicin resistant cell lines: R10, R40 and R60 compared to the untreated wild type RPMI 8226 cells (Dalton, et al., 1984). The least resistant cell line, R10, maintained a down regulation of GR RNA after 48 hours of dexamethasone (10(-6) M) treatment of the cells. Interestingly, the R10 cell line has been reported to be very sensitive to dexamethasone treatment. However, the GR RNA levels increased in presence of dexamethasone in the most resistant cell line, R40, R60 by comparison to the wild type. Thus, the reduction of GR RNA by doxorubicin treatment appears to be overcome by dexamethasone in the most resistant cell lines. Steroids may be helpful in reversing resistance and maintaining drug sensitive human tumor populations that will continue to respond to cancer chemotherapeutic agents.
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PMID:Dexamethasone reverses glucocorticoid receptor RNA depression in multi-drug resistant (MDR) myeloma cell lines. 134 65

One class of genes coding for the acute-phase proteins (acute-phase genes) is induced by interleukin 6 (IL-6) through the human transcription factor NF-IL-6 and its rat homolog IL-6-DBP/LAP. A second class, represented by the rat alpha 2 macroglobulin gene, utilizes a different IL-6 response element (IL-6-RE) and different DNA-binding proteins interacting with this element, the so-called IL-6-RE binding proteins (IL-6 RE-BPs). Human Hep3B and HepG2 hepatoma, U266 myeloma, and CESS lymphoblastoid cells contain IL-6 RE-BPs that form complexes, with the IL-6-RE, with gel mobilities indistinguishable from those of the corresponding complexes of rat liver cells. The ability to form these complexes was induced by IL-6 in human hepatoma cells with a maximum reached after 4 h and required ongoing protein synthesis. Multiple copies of an 18-bp element containing the IL-6-RE core were sufficient to confer both induction by IL-6 and a synergistic induction by IL-6 plus glucocorticoids to minimal promoters. The synergism was blocked by the receptor antagonist RU486 and thus was dependent on the glucocorticoid receptor (GR). However, the 18-bp element contained no consensus GR-binding site, and recombinant GR did not bind at this sequence. Therefore, the synergism was probably achieved by an indirect effect of a glucocorticoid-activated intermediate gene on the IL-6 RE-BPs. The rat IL-6 RE-BP had a molecular weight of 102 +/- 10 kDa and was thus distinct from NF-IL-6 and IL-6-DBP/LAP. Therefore, IL-6 must activate two different classes of liver acute-phase genes through at least two different nuclear DNA-binding proteins: NF-IL-6/IL-6-DBP/LAP and the IL-6 RE-BP.
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PMID:Synergistic action of interleukin-6 and glucocorticoids is mediated by the interleukin-6 response element of the rat alpha 2 macroglobulin gene. 137 12

Glucocorticoids are widely used for the treatment of multiple myeloma. To investigate the direct actions of glucocorticoids on myeloma cells, we have used three cell lines of human multiple myeloma, OPM-1, OPM-2, and RPMI 8226. When growth curves of these cells were examined, OPM-1 cells were resistant, while OPM-2 were sensitive to dexamethasone (DEX). In cultures of OPM-2 cells, addition of DEX led to virtual cessation of growth, with only 16% of the residual cells viable after 4 days. RPMI 8226 appeared to be slightly sensitive, showing some slowing of growth for several days in DEX, with later recovery. Viabilities of OPM-1 and RPMI 8226 cells were not affected. Secretion of immunoglobulin (Ig-lambda) was also partially suppressed, by 30% in OPM-2 and 14% in OPM-1. No significant suppression was observed in RPMI 8226. To explore the mechanism of these differential responses to the steroid, glucocorticoid receptor (GR) was examined. Binding assays showed high affinity binding sites in all three cell lines: 64 +/- 11 fmol/10(6) cells in OPM-1, 78 +/- 14 in OPM-2, and 62 +/- 16 in RPMI 8226. Nuclear transfer of GR and DNA-cellulose binding after heat activation appeared similar in all three cell lines. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of cytosol proteins labeled with [3H]dexamethasone mesylate showed a GR of Mr 95,000 in all three. When GR mRNA was studied in these cells, all of them had GR mRNA of approximately 7 kilobases, but OPM-2 and RPMI 8226 had 3 times more GR mRNA than OPM-1. OPM-2 GR mRNA was induced 2-fold by DEX treatment at 5 x 10(-9) M or greater. OPM-1 GR mRNA was much less sensitive, with no response at less than 10(-6) M DEX and only 1.5-fold induction at that concentration. These results demonstrate that some myeloma cells can be killed by a direct action of glucocorticoids. The quantity and affinity of GR in the cells were not predictive of this response. Therefore, we propose that the resistance of OPM-1 and the relative resistance of RPMI 8226 to glucocorticoid inhibition of cell growth is by post-receptor mechanisms. The high sensitivity of induction of GR mRNA in OPM-2 may correlate with glucocorticoid-evoked cell kill.
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PMID:Glucocorticoid effects on myeloma cells in culture: correlation of growth inhibition with induction of glucocorticoid receptor messenger RNA. 210 90

Glucocorticoid receptor levels of myeloma cells were quantitated in 7 patients with multiple myeloma. In 4 patients, glucocorticoid receptor levels were less than 10 fmol/10(6) cells. In 3 patients, receptor levels were from 17.6 to 21.4 fmol/10(6) cells. We further examined the correlation between glucocorticoid receptor levels and effect of dexamethasone on 14C-thymidine incorporation and cell viability using 2 myeloma cell lines, OPM-1 and OPM-2, established from a patient with multiple myeloma. Glucocorticoid receptor levels of OPM-1 and OPM-2 were 8.5 fmol/10(6) cells and 63.2 fmol/10(6) cells, respectively. The sensitivity of OPM-1 to dexamethasone in these studies was lower than that of OPM-2. These results suggest the possibility that the low level of glucocorticoid receptor in myeloma cells may be important for predicting a poor response to glucocorticoid therapy.
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PMID:Glucocorticoid receptor in multiple myeloma. 365 72

Splenic cells from one BALB/c mouse and one C57/BL mouse, immunized with purified rat liver glucocorticoid receptor (GR), were fused with the mouse myeloma cell line Sp 2/0-Ag 14. Screening for production of anti-GR-antibodies by the hybridomas was carried out with an enzyme-linked immunosorbent assay, using partially purified rat liver GR as antigen. Further screening was by a second-antibody immunoprecipitation assay using [3H]triamcinolone acetonide-GR complex from rat liver cytosol as tracer. Hybridomas from 10 different microplate wells, positive in both assays, were successfully cloned by the limiting dilution method to monoclonality. The different origins of the monoclonal antibodies were confirmed by their various isoelectric points when analyzed by isoelectric focusing. Four of the monoclonal hybridoma cell lines secreted IgM antibodies; two, IgG1; three, IgG2a; and one, IgG2b. The GR-antibody complex was identified in glycerol density gradients by a shift of the 4S GR to an 8.5S or 19S GR-antibody complex when incubated with monoclonal IgG or IgM antibody, respectively. The 10 monoclonal antibodies recognized different determinants on the GR, all situated on that domain of the receptor that is separate from the ligand and DNA-binding domains. Also, the cross-reactivity to the mouse liver GR varied among the monoclonal antibodies. No cross-reactivity was observed to the human lymphocytic GR. NaDodSO4 electrophoresis of a 0.5% pure GR preparation followed by immunoblotting using one of the monoclonal antibodies identified a single peptide with a molecular weight of 94,000, identical to the purified rat liver GR.
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PMID:Monoclonal antibodies against the rat liver glucocorticoid receptor. 620 Aug 80

The progesterone receptor of the hen oviduct is composed of two non-identical hormone-binding polypeptide subunits, A (Mr = 79,000) and B (Mr = 108,000). We used a highly purified preparation of B to immunize mouse spleen cells in vitro. After 5 days in culture, the cells were fused with SP2/0-Ag 14 myeloma cells. The resultant hybridomas were screened using an enzyme linked immunosorbent solid phase assay, and those hybridomas producing antibodies binding to the immunogen were cloned by limiting dilution. One such clone, 9B3-12, secreted an antibody of immunoglobulin class IgM, which binds to B. This was indicated by the ability of the antibody to increase the rate of sedimentation coefficient of the B subunit. Further, when the proteins in the B preparation were separated by electrophoresis and blotted onto nitrocellulose filters the antibody bound to a protein of 108,000 daltons. The antibody produced by 9B3-12 also reacted with subunit A and with the human progesterone receptor but failed to bind to the chick liver glucocorticoid receptor or to progesterone in the absence of its receptor.
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PMID:Monoclonal antibody to the hen oviduct progesterone receptor produced following in vitro immunization. 653 13

A mouse was immunized with purified rabbit uterine cytosolic progesterone receptor (specific activity: 3 nmol of steroid bound per mg of protein). After fusion of its spleen cells with Sp2-OAg myeloma cells, supernatants of 11 hybrid cultures were found to react in both an immunoenzymatic test and a double-immunoprecipitation test with the progesterone receptor. Clones were obtained from the five hybrid cells that gave the strongest response in both tests. Antibodies from cell culture supernatants and ascitic fluids were characterized. Three are of the IgG1 and two of the IgG2a isotype. Their apparent affinity for the progesterone receptor was measured by immunoprecipitation in physiological salt conditions. The equilibrium dissociation constants were between 0.1 and 4 nM. All five monoclonal antibodies crossreacted with the rabbit nuclear receptor, the human cytosolic receptor, and other mammalian (rat, guinea pig) but not avian (chicken) cytosolic progesterone receptors. There was no interaction with the glucocorticoid receptor and corticosteroid binding globulin.
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PMID:Monoclonal antibodies to rabbit progesterone receptor: crossreaction with other mammalian progesterone receptors. 657 31

The rat liver glucocorticoid receptor was partially purified and used to immunize a BALB/c mouse whose splenic lymphocytes were fused with the nonsecreting myeloma cell line P3-AgX-653. The fusion products were selected in HAT (hypoxanthine, aminopterine, and thymidine) medium and a stable antibody-producing clone designated BuGR1 obtained from 1 of 81 positive wells. Immunological specificity for the receptor was confirmed by sucrose density gradient analysis when the sedimentation constant of the specifically labeled receptor was altered by reaction with the antibody and by Western blot analysis, which showed that the BuGR1 antibody detected a single band with a mobility (mol wt, approximately 95,000) identical to that of the [3H]dexamethasone 21-mesylate-labeled rat glucocorticoid receptor. Similar sucrose gradient and Western blot experiments showed that the BuGR1 antibody reacted with the mouse glucocorticoid receptor. BuGR1 is a stable hybridoma producing an antibody which detects loci common to both rat and mouse glucocorticoid receptors.
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PMID:Characterization of a monoclonal antibody to the rat liver glucocorticoid receptor. 669 Feb 72

One thousand-fold purified unactivated rat liver glucocorticoid receptor was obtained by affinity chromatography followed by gel filtration. Splenic lymphocytes of immunized mice were fused with a nonproducer SP2 myeloma cell line to obtain hybridomas secreting antibodies against receptor. Hybridoma lines, injected into mice, developed ascites tumors which provide substantial amounts of monoclonal antibodies. A monoclonal antibody was purified from ascites fluids by chromatography on an anti-mouse IgG column. The antibody was shown to react physically with the glucocorticoid receptor.
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PMID:Monoclonal antibodies to the glucocorticoid receptor. 712 34

In multiple myeloma cells resistant to glucocorticoids, we have previously identified a variant glucocorticoid receptor (GR) transcript (P. A. Moalli et al., Cancer Res., 53: 3877-3879, 1993). Here, we report a reverse transcription-PCR assay to assess whether this aberrant GR transcript is present in myeloma patients. We detected both the wild-type and variant GR transcripts in the patient isolate that was the source of our myeloma cell lines, in patients refractory to steroid treatment, and in healthy control subjects. Simultaneous amplification of wild-type and variant GR mRNAs indicates that the variant GR is more highly expressed in cells that are resistant to glucocorticoids. We hypothesize that the variant GR is a normal mRNA transcript that acts to modulate glucocorticoid responsiveness, and increased expression contributes to a resistant phenotype.
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PMID:A variant glucocorticoid receptor messenger RNA is expressed in multiple myeloma patients. 779 94


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