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 effects of a combination of melphalan and dexamethasone on cell growth, cell cycle flow, cell loss and DNA cross-links were studied on a myeloma cell line (RPMI 8226). At low concentrations melphalan reduced the cell growth by prolonging the S and G2 stages. Steroid sensitivity of the cell line was characterized by dose-dependent inhibition of cell growth after exposure of up to 1 micron dexamethasone with no cell loss found even at 10-fold saturation concentration. Dexamethasone induced prolongation of all cell cycle phases without any preferences. In combined treatment with melphalan and dexamethasone, inhibition of cell growth was found after 24 h followed by cell loss after 48 h. This cell loss was obtained with concentrations of the drugs which by themselves are only growth inhibitory. Calculation of cell flow showed that cell loss is a delayed process occurring after the cells have left the G1 phase. By alkaline elution it was found that dexamethasone treatment caused an increase in melphalan-induced DNA interstrand crosslinks.
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PMID:Interaction of melphalan and dexamethasone in a human myeloma cell line. 180 33

AL amyloidosis is a serious complication of monoclonal gammopathy. The therapeutic strategy in amyloidosis associated with myeloma is to decrease the amyloidogenic precursor synthetised by the monoclonal plasmocytic proliferation. However, when systemic amyloidosis complicates a so called "benign" monoclonal gammopathy, this therapeutic approach is debatable. We report 10 cases of AL amyloidosis without myeloma treated by chemotherapy. Eight patients were initially given alkylating agents (cyclophosphamide or melphalan) which had no effect on the clinical progression of their systemic amyloidosis or on the plasma concentrations of the precursor. A limited open clinical trial including 4 patients was then undertaken based on the Vincristine, Adriamycine, Dexamethasone combination recently proposed for cases of resistant myeloma. A 50% reduction in the serum monoclonal protein was observed in 2 patients with this treatment. However, the mean survival of the 10 patients (25 months) was not longer than that previously reported for patients receiving more conventional treatment. The results of this limited trial indicate the need for further controlled therapeutic trials with larger numbers of patients in order to assess the effect of polychemotherapy in patients with AL amyloidosis.
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PMID:[Treatment of AL amyloidosis without myeloma]. 320 24

The present AML protocol which only applies one anthracycline associated with arabinosyl-cytosine gives a first remission plateau of 65% and a 75% survival plateau at five years. Contrary to other teams, we do not apply the allogenic bone marrow graft at the first remission but at the second one. The new protocol comprises application of two anthracyclines, adriamycin and aclacinomycin, a possible autologous bone marrow graft at first remission upon reinforcement, a combination of methotrexate and thioguanine as maintenance chemotherapy and immunotherapy with bestatine. The two protocols respectively applied to the ALL good prognosis and reserved prognosis, give 85% global survival. The autologous bone marrow graft is added at first remission to B or T forms or voluminous CALLA + types. The advantage of CNS radiotherapy is compared with its disadvantages. Bestatine is employed in immunotherapy. The immunoprevention protocol applied to CML blastic crisis (vaccination with a pool of CB blasts) from the second year has prolonged survival of patients suffering from this affection and also treated by splenectomy and hydroxyurea. Allogeneic or autologous bone marrow graft is added to the protocol. The same protocol is applied to not very aggressive LLC and LNH (lymphocytic and centrofollicular with small cleaved nucleus cells) and includes maximum remission induced by chemotherapy followed by immunotherapy (by thymuline and then, if immunity disorders are not corrected, by zinc, then bestatine and finally tuftsin). A similar sequence was applied to the myeloma, comprising MLP-PDN-CPM chemotherapy to induce remission, combination of MLP-PDN and CPM and, if there is resistance, CLB, 6-TG, PDN and TNP. Interferon is appropriate with certain cytopenic forms. A protocol comprising VCR, ADM, PDN, CPM and TNP is applied to centrofollicular NHL with small non cleaved nucleus cells or large cells. As Hoerni and Jones have obtained significant benefits with BCG, its terminal application is compared with that of bestatine. Finally a less mutagenic protocol than MOPP and/or ABVD is proposed for Hodgkin's disease. In this protocol, two cycles alternate, and they combine: a) firstly VCR, PDN, THP-ADM and VPS, and b) secondly VLB, DXM, ACM and TNP with alternatively BLM and PPM between the cycles. This chemotherapy is followed by the same immunorestoration protocol as that applied to LLC and myeloma.
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PMID:[Protocols for the treatment of leukemia and lymphoma: toward escalation or toward reduction of degree?]. 638 Jun 5

Uncontrolled growth of neoplastic cells and unregulated production of immunoglobulin are major components of the morbidity and mortality of multiple myeloma. Suramin, a polysulfonated napthylurea, has antitumor activity in a number of malignancies, but also significant dose-related toxicity. Suramin has been reported to have major antiproliferative effects in a variety of lymphoid cell lines. Glucocorticoids have long been recognized to have activity in lymphoid malignancies and multiple myeloma while IL-6 has been reported to be an autocrine growth factor for multiple myeloma. This study examines growth inhibition and inhibition of IL-6-mediated secretion of immunoglobulin in human lymphoid and myeloma cell lines by dexamethasone and suramin. Dexamethasone and suramin show synergistic inhibition of cell proliferation at their IC10 concentrations. IL-6-mediated immunoglobulin secretion is also inhibited by both dexamethasone and suramin in an additive fashion. Both dexamethasone and suramin induce apoptosis of lymphoid cell lines, and suramin inhibits the binding of IL-6 to its receptor in a multiple myeloma cell line. These findings suggest that the synergistic growth inhibitory activities of dexamethasone and suramin may be related to induction of apoptosis by both agents and inhibition of IL-6-mediated autocrine growth stimulation and immunoglobulin production. These results indicate that the combination of low-dose suramin (in concentrations not associated with significant clinical toxicity) and dexamethasone merit further study in the treatment of myeloma or lymphoid malignancies.
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PMID:Dexamethasone and suramin inhibit cell proliferation and interleukin-6-mediated immunoglobulin secretion in human lymphoid and multiple myeloma cell lines. 754 42

The effects of dexamethasone on the growth of four human multiple myeloma cell lines were studied. In addition, the effects on the expression of interleukin-6 (IL-6) and IL-6 receptor (IL-6R) genes were investigated by the use of reverse-transcriptase polymerase chain reaction. Dexamethasone (Dex) concentrations of 10(-7) to 10(-6) mol/L inhibited IL-6 gene expression in three of four cell lines studied, whereas the higher concentration of the hormone inhibited also IL-6R gene expression. Dex effects were modulated through the glucocorticoid receptor (GR). Dex treatment resulted in killing of sensitive cells associated with DNA fragmentation, which could be reversed by concomitant treatment with IL-6. The reversal of Dex-mediated effects by IL-6 did not result from an inhibition of GR function as measured by receptor nuclear translocation or Dex-regulated reporter gene function. These results indicate that blockage of the IL-6 signaling pathway is essential for effective myeloma cell kill by Dex.
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PMID:Interleukin-6 prevents dexamethasone-induced myeloma cell death. 794 78

Interferon-alpha and the synthetic glucocorticoid dexamethasone are used in the treatment of multiple myeloma. The effect of 48 h exposure to recombinant interferon-alpha 2b (100 to 10,000 U/ml) and dexamethasone (1 microM to 1 mM) was studied in AF10, and IgE-secreting myeloma cell line. Interferon-alpha and dexamethasone at 10,000 U/ml and 1 mM respectively had a synergistic inhibitory effect on IgE concentration. Interferon-alpha and dexamethasone had an additive inhibitory effect on myeloma cell concentration. Interferon-alpha at 10,000 U/ml caused a twofold increase in sialyltransferase activity. Dexamethasone decreased sialytransferase activity and attenuated the stimulatory effect of interferon-alpha. These data suggest that combined interferon-alpha and dexamethasone therapy might have a synergistic effect on monoclonal protein production and a diverse effect on sialytransferase activity.
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PMID:Interferon-alpha and dexamethasone effect on AF10 myeloma cell line sialytransferase activity. 837 39

Interleukin-6 (IL-6)/IL-6 receptor (IL-6R) plays a major role in autocrine/paracrine growth regulation of myeloma cells. We investigated the effect of dexamethasone and all-trans retinoic acid, previously shown to modulate IL-6/IL-6R, on the in vitro growth of a human myeloma cell line, OPM-2. Both agents inhibited the clonogenic growth and 3H-thymidine incorporation in a concentration-dependent fashion. Isobologram and median effect analysis showed a strong synergy between these two agents with a combination index in the range of 0.2 to 0.6. Both agents decreased the labeling index and the cell fraction in S and G2/M phases, suggesting a block in G1-S phase transition. The clonogenic growth was stimulated by exogenous IL-6 and was inhibited by monoclonal antibody to IL-6, suggesting an autocrine function of IL-6. The effect of dexamethasone but not all-trans retinoic acid was completely reversed by exogenous IL-6. Dexamethasone increased, while all-trans retinoic acid reduced, IL-6R but not gp130 mRNA expression. Their combination caused a net reduction in IL-6R mRNA. Cellular IL-6R density was altered correspondingly without changes in the binding affinity. IL-6 mRNA expression was reduced by dexamethasone and the combination, but was not affected by retinoic acid alone. However, IL-6 secretion into culture supernatant was abolished by both agents. A survey of 4 additional human myeloma cells showed that 1 was sensitive to both, 1 was sensitive to one agent only, and 2 were resistant to both. The study demonstrates the possibility of regulating myeloma cell growth through modulation of IL-6/IL-6R autocrine/paracrine loop and the principle of achieving a synergistic effect by blocking this loop at multiple sites.
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PMID:Inhibition of myeloma cell growth by dexamethasone and all-trans retinoic acid: synergy through modulation of interleukin-6 autocrine loop at multiple sites. 854 58

The cytokine IL-6 has been proposed as an autocrine growth factor in multiple myeloma, and is also required for stimulation of immunoglobulin production and secretion in normal plasma cells and myeloma cells. In this study, we showed that secreted IL-6 is detectable by Western blot analysis in a panel of lymphoid and myeloma cell lines. Previous studies in our laboratory have shown that dexamethasone and suramin inhibit cell proliferation and IL-6-mediated immunoglobulin secretion in various lymphoblastoid and myeloma cell lines. In the present study, we present study, we present data to examine mechanisms by which dexamethasone and suramin inhibit IL-6-mediated immunoglobulin secretion in the lymphoid cell line SKW 6.4. Cells treated with rIL-6 or the IC10 concentration of dexamethasone respectively undergo a doubling of intracellular IgM. Moreover, rIL-6 and dexamethasone additively stimulate cells to accumulate intracellular IgM. In contrast, cells treated with the IC10 concentration of suramin undergo no significant alteration of total cellular IgM, and do not respond to IL-6 with an increase in intracellular IgM. Northern blot analysis demonstrates that cells treated with exogenous rIL-6 and/or dexamethasone respectively undergo a coordinate one to three fold increase of kappa and mu chain mRNA expression, while there is a 30-40% decrease of kappa and mu chain mRNA when cells are treated with suramin and suramin plus rIL-6. Western blot analysis shows that levels of intracellular IL-6 modestly increase when cells are treated with exogenous rIL-6, whereas treatment with dexamethasone plus rIL-6 causes a 70% decrease of immunoreactive IL-6 protein in comparison with untreated cells. An rtPCR analysis of IL-6 mRNA expression shows an abolished signal in response to dexamethasone or rIL-6 and/or dexamethasone. Using a flow cytometric assay, it is demonstrated that suramin inhibits IL-6 binding to its receptor. Taken together, these results indicate that SKW 6.4 cells treated with rIL-6 and/or dexamethasone undergo increased expression of IgM mRNA leading to increased intracellular IgM levels. Treatment with suramin or suramin plus rIL-6 does not alter the IL-6 protein level or the mRNA levels for IL-6 and IL-6 receptor. Suramin treatment causes a moderate decrease in IgM mRNA, and this is associated with a decreased intracellular level of IgM in SKW 6.4 cells. Overall these findings support the concept that IL-6 is an autocrine factor for immunoglobulin production and secretion in myeloma cells. Suramin interferes with IL-6 binding to its receptor and/or decreases IL-6 receptor expression. Dexamethasone has neither of these effects on IL-6 receptor expression or IL-6 binding to its receptor, and we postulate that it acts through a block in secretion or in degradation of intracellular immunoglobulin by decreasing IL-6 mRNA expression and IL-6 protein content. These studies suggest that the combination of suramin and dexamethasone not only synergistically growth inhibit myeloma cells but also act in concert to inhibit immunoglobulin secretion and represent a therapeutic approach worthy of further investigation.
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PMID:Mechanisms of inhibition of IL-6-mediated immunoglobulin secretion by dexamethasone and suramin in human lymphoid and myeloma cell lines. 872 10

To improve the outcome for patients with relapsed or refractory multiple myeloma (MM), we combined idarubicin (Ida), dexamethasone and interferon (IFN) in a new regimen, 'I-Dexa'. Here we report our results of a phase I/II study using the I-Dexa protocol in an outpatient setting. A total of 31 patients were enrolled. Most patients were heavily pretreated with a median of two different chemotherapy regimen (range, 1-4). All but four patients had advanced disease (stage III). The dose of Ida was escalated to define the maximal tolerated dose (MTD) in this regimen. Four patients were treated with 5 mg/m2 and 27 patients with 7.5 mg/m2 Ida (day 1, i.v.). Dexamethasone was given at a fixed dose of 20 mg per os daily on days 2-5 and 11-14. Treatment was repeated at day 21 and consisted of up to six cycles. Patients who achieved a response or stable disease received IFN maintenance. IFN was administered three times weekly at a dose of 3 x 10(6) U/day s.c. until relapse. At the time of evaluation, 125 courses of I-Dexa were analyzed. The MTD of Ida in this regimen was 7.5 mg/m2. Hematological toxicity was mild including 5% leukocytopenia, 3% thrombocytopenia and 1% anemia (WHO grade III) at dose level 2. The MTD was defined by nonhematological toxicities including two WHO grade IV infections and one renal failure. The overall response rate including stable disease was 62.5% (PR: nine patients, 37.5%). So far, nine patients have been treated with IFN maintenance therapy with a median duration of 7 months (range, 1-16). In conclusion, I-Dexa can be given safely in an outpatient setting and is effective for the treatment of relapsed and refractory MM.
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PMID:A phase I/II study of idarubicin, dexamethasone and interferon-alpha (I-Dexa) in patients with relapsed or refractory multiple myeloma. 943 39

Syndecan-1 is a cell membrane proteoglycan that binds extracellular matrix components and various growth factors. It is expressed only on malignant plasma cells in bone marrow samples from patients with multiple myeloma (MM). Several reports have suggested that syndecan-1 was present only on a part of the myeloma cells. By using either IL-6-dependent myeloma cell lines or primary myeloma cells stained by annexin V, we report here that syndecan-1 was rapidly lost by myeloma cells undergoing apoptosis. In the same experimental conditions, expression of other cell membrane antigens such as CD38, HLA class-I or CD49d on apoptotic myeloma cells was not affected. In addition, we show that syndecan-1 loss was independent of activation of the gp130 IL-6 transducer. Dexamethasone induced a strong apoptosis of myeloma cells associated with the loss of syndecan-1. Finally, by using freshly-explanted tumoural samples, we show that syndecan-1 rapidly disappeared from myeloma cells in association with induction of apoptosis. In conclusion we showed that syndecan-1 is a marker for viable myeloma cells which is rapidly lost by apoptotic cells. These results emphasize the usefulness of anti-syndecan-1 antibodies to purge tumoural cells from haemopoietic grafts or to purify these cells for further manipulations for immuno or gene therapies.
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PMID:The myeloma cell antigen syndecan-1 is lost by apoptotic myeloma cells. 953 28


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