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)

Arsenic trioxide (As2O3) has been approved for the treatment of acute promyelocytic leukemia (APML) and it is a promising candidate for the treatment of patients with lymphoproliferative disorders, such as relapsed or refractory multiple myeloma and myelodysplastic syndromes. The effects of As2O3 on B cells, specifically which do not express Bcl-2, have not been studied. In this study, we have demonstrated that As2O3, at clinically achievable therapeutic concentrations, induces apoptosis in Bcl-2 negative human B cell line Ramos. As2O3-induced apoptosis is associated with reduced mitochondrial transmembrane potential (delta psi), enhanced generation of intracellular reactive oxygen species (ROS), release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria into cytoplasm, activation of caspases, and upregulation of Bax and Bim expression. Exogenous glutathione (GSH) reverses the As2O3-induced apoptosis in a dose-dependent manner. Altogether, these data indicate that As2O3 induces apoptosis in B cells, regardless of Bcl-2 expression, via the mitochondrial pathway by enhancing oxidative stress.
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PMID:Arsenic trioxide induces apoptosis via the mitochondrial pathway by upregulating the expression of Bax and Bim in human B cells. 1720 11

The osteonecrosis of the jaws (ONJ) has been reported occasionally in cancer patients treated with radiotherapy and chemotherapy. However, bisphosphonate (BP)-associated ONJ in patients with cancer such as multiple myeloma, breast cancer and prostate cancer mainly administered with intravenous BPs has been first reported in 2003. Since then, many cases over 2,500 are accumulating worldwide. Since BPs are often used for osteoporosis, cancer-associated hypercalcemia and osteolytic bone metastasis, it is speculated that ONJ cases will increase in Japan where a small number of them were reported until now. Most of ONJ in cancer patients receiving BP administration occur after dental treatments such as tooth extraction, periodontal surgery and dental implants, and do not respond to conventional treatment modalities such as debridement, antibiotic therapy and hyperbaric oxygen therapy. No effective therapy for ONJ is established yet and empirical conservative therapy is recommended in the guidelines for prevention, diagnosis, and treatment of ONJ. Therefore, dentists and oral and maxillofacial surgeons need to recognize ONJ as a serious side effect of BPs and to make informed consent to the patients and a close consultation with medical oncologists for administration of BPs.
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PMID:[Bisphosphonates and osteonecrosis of the jaws]. 1727 82

Although thalidomide has been shown to improve anemia in some patients with myelodysplastic syndromes and stimulates erythropoietin in patients with multiple myeloma, thalidomide's specific effects on gamma-globin gene expression during erythroid differentiation have not been studied. Here, we investigated the effects of thalidomide on gamma-globin gene expression and the involved signaling pathway using an ex vivo culture system of primary human CD34+ cells. We found that thalidomide induced gamma-globin mRNA expression in a dose-dependent manner, but had no effect on beta-globin expression. We also demonstrated that intracellular reactive oxygen species (ROS) levels were increased by treatment with thalidomide for 48 hours (from day 3 to day 5). Western blot analysis demonstrated that thalidomide activated the p38 mitogen-activated protein kinase (MAPK) signaling pathway in a time- and dose-dependent manner and increased histone H4 acetylation. Pretreatment of cells with the antioxidant enzyme catalase and the intracellular hydroxyl scavenger dimethylthiourea (DMTU) abrogated the thalidomide-induced p38 MAPK activation and histone H4 acetylation. Moreover, pretreatment with catalase and DMTU diminished thalidomide-induced gamma-globin gene expression. These data indicate that thalidomide induces increased expression of the gamma-globin gene via ROS-dependent activation of the p38 MAPK signaling pathway and histone H4 acetylation.
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PMID:Thalidomide induces gamma-globin gene expression through increased reactive oxygen species-mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis. 1762 Apr 52

This case study focuses on the scale-up of a Sp2/0 mouse myeloma cell line based fed-batch bioreactor process, from the initial 3-L bench scale to the 2,500-L scale. A stepwise scale-up strategy that involved several intermediate steps in increasing the bioreactor volume was adopted to minimize the risks associated with scale-up processes. Careful selection of several available mixing models from literature, and appropriately applying the calculated results to our settings, resulted in successful scale-up of agitation speed for the large bioreactors. Consideration was also given to scale-up of the nutrient feeding, inoculation, and the set-points of operational parameters such as temperature, pH, dissolved oxygen, dissolved carbon dioxide, and aeration in an integrated manner. It has been demonstrated through the qualitative and the quantitative side-by-side comparison of bioreactor performance as well as through a panel of biochemical characterization tests that the comparability of the process and the product was well controlled and maintained during the process scale-up. The 2,500-L process is currently in use for the routine clinical production of Epratuzumab in support of two global Phase III clinical trials in patients with lupus. Today, the 2,500 L, fed-batch production process for Epratuzumab has met all scheduled batch releases, and the quality of the antibody is consistent and reproducible, meeting all specifications, thus confirming the robustness of the process.
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PMID:Fed-batch bioreactor process scale-up from 3-L to 2,500-L scale for monoclonal antibody production from cell culture. 1765 76

Clinical trials have shown the high anti-myeloma activity of the proteasome inhibitor bortezomib. The present study examined the activity of bortezomib combined with PXD101, a histone deacetylase inhibitor, against multiple myeloma (MM) and osteoclastogenesis. Treatment of myeloma cell lines with combinations of bortezomib and PXD101 led to synergistic inhibition of proliferation and induction of cell death. The combination significantly decreased the viability of primary human CD138(+) myeloma cells but not of bone marrow mononuclear cells. Further studies showed a dose-dependent activation of caspases-3, -8 and -9 and nuclear fragmentation in myeloma cells. Bortezomib/PXD101 treatment markedly triggered reactive oxygen species (ROS) generation that was accompanied by p53, H2A.X and p38-mitogen-activated protein kinase phosphorylation. ROS generation could be blocked by the free radical scavenger N-acetyl-L-cysteine. The combination of bortezomib and PXD101 also resulted in synergistic inhibition of osteoclast formation. In conclusion, bortezomib and PXD101 have different molecular targets. The combination induces cell death in myeloma cells via ROS-mediated DNA damage and also inhibits osteoclastogenesis. Therefore, this study provides the rationale for the clinical evaluation of bortezomib combined with PXD101 in patients with MM.
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PMID:The histone deacetylase inhibitor, PXD101, potentiates bortezomib-induced anti-multiple myeloma effect by induction of oxidative stress and DNA damage. 1791 Jun 28

The major anionic phospholipid, phosphatidylserine (PS), and the neutral phospholipid, phosphatidylethanolamine (PE), are largely confined to the inner leaflet of the plasma membrane bilayer in mammalian cells under normal conditions. This asymmetry is lost when cells undergo apoptosis, become activated, or are exposed to irradiation, reactive oxygen species or certain drugs. It is not known whether exposure of anionic phospholipids (APLs) and PE occurs simultaneously or in the same region of the plasma membrane. Here we examined the coincidence of exposure of APLs and PE on the surface of bovine aortic endothelial cells and NS0 myeloma cells after irradiation. The cells were irradiated (5 Gy) and stained for APLs and PE using liposomes coated with either an Fab' fragment of a PS-binding antibody (bavituximab) or a PE-binding peptide (duramycin). Using live cell imaging and flow cytometry, we showed that irradiation leads to synchronous externalization of APLs and PE. The time course of appearance of APLs and PE on the cell surface was the same and the two phospholipid types remained colocalized over time. Distinct patches double positive for APLs and PE were visible. Larger areas of APLs and PE appeared to have detached from the cytoskeleton to form membrane blebs which protruded and drifted on the cell surface. We conclude that APLs and PE coincidently appear on the external leaflet of the plasma membrane of cells after irradiation. Probably, this is because PE and the major APL, PS, share common regulatory mechanisms of translocation.
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PMID:Coincident exposure of phosphatidylethanolamine and anionic phospholipids on the surface of irradiated cells. 1857 Aug 87

A new method for real-time monitoring of the oxygen uptake rate (OUR) in bioreactors, based on dissolved oxygen (DO) measurement at two points, has been developed and tested extensively. The method has several distinct advantages over known techniques.It enables the continuous and undisturbed monitoring of OUR, which is conventionally impossible without gas analyzers. The technique does not require knowledge of k(L)a. It provides smooth, robust, and reliable signal. The monitoring scheme is applicable to both microbial and mammalian cell bioprocesses of laboratory or industrial scale. The method was successfully used in the cultivation of NSO-derived murine myeloma cell line producing monoclonal antibody. It was found that while the OUR increased with the cell density, the specific OUR decreased to approximately one-half at cell concentrations of 16 x 10(6) cells/mL, indicating gradual reduction of cell respiration activity. Apart from the laboratory scale cultivation, the method was applied to industrial scale perfusion culture, as well as to processes using other cell lines. (c) 1994 John Wiley & Sons, Inc.
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PMID:Continuous, real-time monitoring of the oxygen uptake rate (OUR) in animal cell bioreactors. 1861 17

Cepharanthine (CEP), a biscoclaurine alkaloid extracted from Stephania Cepharantha Hayata, has been used in Japan for treating patients with radiation-induced leucopenia or thrombocytopenia. We treated a patient with multiple myeloma (MM), who was not responding to preceding chemotherapy, who coincidently received therapy with CEP due to thrombocytopenia. Since the case showed a marked reduction of tumor load, direct anti-tumor effects of CEP to myeloma cells were investigated in vitro. Anti-tumor effects were observed in all myeloma cell lines tested, including a line resistant to melphalan. Exposure to CEP of a myeloma cell line induced the production of reactive oxygen species, activated the caspase-3 pathway and eventually induced apoptosis. Pre-exposure of cells to a pan-caspase inhibitor, Z-VAD-FMK, or a free radical scavenger, Tiron, effectively blocked CEP-induced apoptosis. Interestingly, CEP also inhibited cell growth of myeloma cells by inducing CDK inhibitors. These data show, for the first time, that CEP has anti-myeloma effects by the activation of apoptotic pathways and blocking cell cycle progression via CDK inhibitors. Although analysis of these two pathways should be clarified further, the use of CEP may be considered as a potential therapeutic agent for a subset of MM.
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PMID:Induction of cell cycle arrest and apoptosis in myeloma cells by cepharanthine, a biscoclaurine alkaloid. 1881 95

Angiogenesis, the growth of new capillary blood vessels, is a central regulator of cancer growth, and a validated target for cancer therapy. The antiangiogenic agents in clinical use target one or more cellular pathways involved in the cascade of vascular growth. In haematological malignancies, angiogenesis occurs within a bone marrow ecosystem comprised of closely apposed malignant cells, endothelial cells, pericytes, fibroblasts, endothelial progenitor cells, dendritic cells, and extracellular matrix. Inhibition of angiogenesis therefore blocks not only the delivery of oxygen and micronutrients to cancer cells, but also disrupts the interdependency of these cellular players and the paracrine effects they exert to maintain the malignant phenotype. Agents such as thalidomide, lenalidomide, bortezomib, and bevacizumab, have demonstrated clinical activity in myeloma, myelodysplastic syndrome, and leukaemias. In leukaemia, vascular endothelial growth factor (VEGF) is emerging as a compelling biological target for therapy, as well as a potential predictive marker for disease relapse. Initial clinical studies suggest that the anti-VEGF strategies may advance the primary, sequential or adjunctive treatment for leukaemia, and establish the basis for other potential antiangiogenic strategies in haematological malignancies.
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PMID:Antiangiogenesis in haematological malignancies. 1903 13

Bisphosphonates (BP) have clinically been used as a highly effective drug in the treatment of hypercalcemia of malignancy, multiple myeloma, skeletal events associated with metastatic breast cancer and prostate cancer, and osteoporosis. Despite these benefits, however, the emergence of BP-related osteonecrosis of the jaws (BRONJ) becomes a growing and significant problem in a subset of patients receiving these drugs, especially intravenous preparations. It has also been reported in the patients receiving oral BP, although the incidence is extremely low. Most of BRONJ cases occur after dental treatments such as tooth extraction, periodontal surgery, and dental implants, and are refractory to conventional treatment modalities such as debridement, antibiotics and hyperbaric oxygen therapy. As compared to EU and USA, the number of BRONJ case is still small in Japan, but it is exactly increasing year by year. The ratio of the number of BRONJ in patients receiving oral BP to that in patients receiving intravenous BP is higher in Japan than in EU and USA, speculating due to the difference of time of approval. In this communication, the practical guidelines for prevention, diagnosis and treatment of BRONJ recently released from USA and Canada were introduced. Although no effective therapy for BRONJ is established yet, the importance of oral hygiene, patient education and treatments suitable for clinical stage is emphasized. In addition, it is considered that the survey of incidence of BRONJ in Japan and the preparation of Japanese guideline are urgent need.
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PMID:[New development in bisphosphonate treatment. Bisphosphonate therapy and osteonecrosis of the jaws]. 1912 70


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