UMLS:C0026764 - FACTA Search

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Query: UMLS:C0026764 (multiple myeloma)
36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple myeloma is a malignant disease with high incidence in middle-aged and old-aged population. Bortezomib is a proteasome inhibitor which target mainly is NF-kappaB. This observation is to study the clinical treatment effect of bortezomib in one relapsed multiple myeloma (MM) patient and one primary refractory MM patient. The first patient diagnosed as IgA IIIA stage, whose state of disease became worse after 8 months of autologous peripheral blood stem cell transplantation. And the disease became further aggressive with 4 courses of chemical therapy regimen including methylprednisolone, Arsenic trioxide, dexamethasone, cyclophosphamide, mitoxantrone, VM-26. Myeloma cells in bone marrow and abnormal monoclonal immunoglobulin in blood plasma both increased. Bone destruction became severe, and there was a plasmacytoma about 5 x 6 cm on the patient's right upper chest wall. Therefore, the patient received therapy of bortezomib combined with doxrubicin, dexamethasone and thalidomide (VADT). After one course of therapy with this VADT regimen, IgA in blood plasma decreased from 54 g/L to 6.6 g/L, and abnormal plasma cells in bone marrow decreased from 40% to 0.6%, and plasmacytoma on the patient's right upper chest wall almost absorbed. But there was no obvious clinical effect after the second course of therapy of VADT, and the disease status became progressive again. The second patient was MM patient with a light chain kappa type, III B stage. There was no any effect after two courses of VAD therapy and one course of MOFP therapy. The patient acquired near complete remission after one course of treatment with VADT. Quantity of kappa protein in urine reduced from 24 - 30 g/24 hours to 1.12 g/24 hours. Blood creatinine reduced from 475.3 micromol/L to 124.2 micromol/L. Beta2-MG reduced from 161g/L to 64 g/L. And this patient got complete remission after three consecutive VADT therapy. The mainly side effects of the bortezomib regimen in the first patient include markedly lassitude, diarrhea, numbness of the end of extremities, marked increase of LDH. All the side effects could be tolerated and became disappeared after contraposing treatment and stopping the bortezomib regimen therapy. The second patient complicated with severe subacute left hemiplegia after the bortezomib dose had been increased to 1.45 mg/m2 at the third time of the first VADT course and the complication became worst at the following day. The upper limb muscle strength was only 1 grade and the lower limb muscle strength was 2 grade. Then the condition improved with the support therapy and gradually recovered after two weeks. Therefore, bortezomib is an effective target drug for therapy in refractory multiple myeloma, and more attentions to the side effects should be paid in order to deal with those side effects in time.
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PMID:[Salvage therapy with proteasome inhibitor bortezomib for relapsed and refractory multiple myeloma]. 1720 82

Mutations in p53 are the most common genetic abnormality in cancers. Arsenic trioxide (ATO) is an effective chemotherapeutic agent for the treatment of acute promyelocytic leukemia (APL) and is being tested in phase II studies in various types of cancers. We have shown that ATO is a potent inducer of apoptosis in multiple myeloma cells, engaging primarily the intrinsic apoptotic pathway in cells expressing w.t. p53 and the extrinsic apoptotic pathway in cells expressing mutant p53. To further establish the differential apoptotic signals of ATO in relation to p53 functional status we studied the activation of the intrinsic and the extrinsic apoptotic pathways in IM9 myeloma cells expressing w.t. p53 following silencing of p53 and p21 with the corresponding SiRNAs-GFP constructs. In untransfected cells or in cells transfected with GFP-empty vector construct we observed weak apoptosis concomitant with mild depolarization of mitochondrial membrane, depletion of reduced glutathione and release of cytochrome c. Following silencing of p53 or p21 we observed extensive apoptosis concomitant with extensive depolarization of mitochondrial membrane and depletion of reduced glutathione. We also observed in these cells activation of the extrinsic apoptotic pathway through upregulation of APO2/TRAIL and APO2/TRAIL-R2, activation of caspase 8, degradation of FLIP-L and release of apoptosis inducing factors from mitochondria, instead of cytochrome c. In addition, we observed marked activation of the MAP kinase pathway and dephosphorylation of Akt in p53 or p21 silenced cells. Hence, silencing of p53 or p21 in IM9 myeloma cells results in diversion of apoptosis to the extrinsic pathway and sensitization of myeloma cells to ATO.
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PMID:Arsenic trioxide induces p53-dependent apoptotic signals in myeloma cells with SiRNA-silenced p53: MAP kinase pathway is preferentially activated in cells expressing inactivated p53. 1733 40

Arsenic trioxide (ATO) and proteasome inhibitor bortezomib have been successfully applied to treat acute promyelocytic leukemia (APL) and multiple myeloma (MM), respectively. Their synergistic effects with other anticancer drugs have been widely studied. Here, we investigated the potential synergy of bortezomib and ATO on Bcr-Abl(+) leukemic K562 cells. The results showed that cotreatment of bortezomib at 32 nM, a half concentration for growth arrest, and ATO at 1 microM, a dose with no significant cytotoxic effect, synergistically induced apoptosis in the cell line, followed by enhanced mitochondrial dysfunction, release of cytochrome c and apoptosis-inducing factor, caspase-3 cleavage and degradation of poly-adenosine diphosphate-ribose polymerase together with the decreased Bcr-Abl protein. These two drugs synergistically induced proteolytic activation of protein kinase Cdelta (PKCdelta) with enhanced activation of two mitogen-activated protein kinases phospho-c-Jun NH(2)-terminal kinase and p38. The specific PKCdelta inhibitor rottlerin markedly decreased bortezomib plus ATO-induced apoptosis, suggesting that PKCdelta plays an important role in bortezomib plus ATO-induced apoptosis. Moreover, apoptosis synergy of bortezomib and ATO could also be seen in some kinds of acute leukemic cell lines and primary cells. Totally, our results indicate that combined regimen of bortezomib and ATO might be a potential therapeutic remedy for the treatment of leukemia.
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PMID:Arsenic trioxide and proteasome inhibitor bortezomib synergistically induce apoptosis in leukemic cells: the role of protein kinase Cdelta. 1749 69

Arsenic trioxide (ATO) induces apoptosis of malignant plasma cells through multiple mechanisms, including inhibition of DNA binding by nuclear factor kappa-B, a key player in the development of chemoresistance in multiple myeloma (MM). This activity suggests that ATO may be synergistic when combined with other active antimyeloma drugs. To evaluate this, we examined the antimyeloma effects of ATO alone and in combination with bortezomib, melphalan and ascorbic acid (AA) both in vitro and in vivo using a severe combined immunodeficient (SCID)-hu murine myeloma model. Marked synergistic antimyeloma effects were demonstrated when human MM Los Angeles xenograft IgG lambda light chain (LAGlambda-1) cells were treated in vitro with ATO and any one of these agents. SCID mice bearing human MM LAGlambda-1 tumours were treated with single-agent ATO, bortezomib, melphalan, or AA, or combinations of ATO with either bortezomib or melphalan and AA. Animals treated with any of these drugs alone showed tumour growth and increases in paraprotein levels similar to control mice, whereas animals treated with ATO-containing combinations showed markedly suppressed tumour growth and significantly reduced serum paraprotein levels. These in vitro and in vivo results suggest that addition of ATO to other antimyeloma agents may result in improved outcomes for patients with relapsed or refractory MM.
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PMID:Antimyeloma effects of arsenic trioxide are enhanced by melphalan, bortezomib and ascorbic acid. 1758 38

Arsenic trioxide (As2O3, Trisenox) is used to treat patients with refractory or relapsed acute promyelocytic leukemia (APL). Its ability to induce apoptosis in various malignant cell lines has made it a potential treatment agent for other malignancies and many clinical trials are currently in progress to evaluate its clinical usefulness for multiple myeloma and glioblastoma cancer. In the present study, we investigated the metabolism of As2O3 regarding its cellular biotransformation and interaction with metallothionein (MT) as a possible protective responses of cells to arsenic-induced cytotoxicity. The study was performed on two types of cell treated with As2O3: (1) human astrocytoma (glioblastoma) cell line U87MG treated with 0.6 microM arsenic for 0, 3, 12, 24, and 48 h or 12 microM arsenic for 3, 6, 12, 24, and 48 h and (2) bone marrow cells (BM) from two patients with multiple myeloma (MM) treated with 7 microM arsenic for 0, 43, and 67 h. Cotreatment with vitamin C (1 mg/mL) was tested in longer exposure of MM BM cells. Traces of methylation products (mainly monomethylarsenic acid) were detected in cell lysates of both cell types and in pellets of U87 MG cells, although we found problems with column-sample interactions in cases where methanol pretreatment of the sample was not used. Pentavalent inorganic arsenic (AsV) was identified in both cell types, and up to 80% of total As in MM bone marrow cell lysates was present as AsV. Such an occurrence (generation) of pentavalent arsenic after As2O3 treatment demonstrates the presence of biological oxidation of trivalent arsenic, which could represent an additional protective mechanism of the cell. Vitamin C decreased As cell content and increased the percentage of pentavalent inorganic arsenic (in the growth medium and cells). The presence of metallothionein (MT) and its response to arsenic treatment was checked in all U87 MG cells, in the control, and in one exposed sample of MM BM cells. During 48 h exposure to 0.6 or 12 muM arsenic MTI/II levels increased in U87 MG cells, but with variable Zn levels, increased Cu levels, and As binding observed in traces only. Involvement of the MT-III isoform was negligible. In contrast, 43 h exposure to 7 microMarsenic did not increase MT content in multiple myeloma cells, and the levels even decreased with respect to the control. To evaluate the importance of the observed processes, MTs in U87 and AsIII-AsV conversion in MM BM cells, which could represent a resistance response of cancer cells treated by As2O3, longer-term observation with different arsenic concentrations should be performed.
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PMID:Arsenic metabolism in multiple myeloma and astrocytoma cells. 1763 24

Arsenic trioxide (As2O3) is an effective therapy in acute promyelocytic leukemia (APL), but its use in other malignancies is limited by the higher concentrations required to induce apoptosis. We have reported that trolox, an analogue of alpha-tocopherol, increases As2O3-mediated apoptosis in a variety of APL, myeloma and breast cancer cell lines, while non-malignant cells may be protected. In the present study, we extended previous results to show that trolox increases As2O3-mediated apoptosis in the P388 lymphoma cell line in vitro, as evidenced by decrease of mitochondrial membrane potential and release of cytochrome c. We then sought to determine whether this combination can enhance antitumor effects while protecting normal cells in vivo. In BDF1 mice, trolox treatment decreased As2O3-induced hepatomegaly, markers of oxidative stress and hepatocellular damage. In P388 tumor-bearing mice, As2O3 treatment prolonged survival, and the addition of trolox provided a further significant increase in lifespan. In addition, the combination of As2O3 and trolox inhibited metastatic spread, and protected the tumor-bearing mice from As2O3 liver toxicity. Our results suggest, for the first time, that trolox might prevent some of the clinical manifestations of As2O3-related toxicity while increasing its pro-apoptotic capacity and clinical efficacy in hematological malignancies.
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PMID:Trolox enhances the anti-lymphoma effects of arsenic trioxide, while protecting against liver toxicity. 1769 Jun 99

Arsenic and its derivatives have been used for medicinal purposes for thousands of years. Arsenic trioxide has demonstrated remarkable activity in the treatment of acute promyelocytic leukemia (APL), for which it can bring about complete remissions (CR) in > 80% of patients with relapsed disease, and molecular remission in 90% of those who enter a CR. Clinical trials have explored its use in the first-line setting and as part of consolidation therapy for de novo APL, for which it appears to provide an event-free and overall survival advantage. Two multicenter trials have examined its use in the treatment of the myelodysplastic syndromes; as a single agent, it yields responses in 20% of patients, and smaller trials have provided evidence for its use in non-APL acute myeloid leukemia populations in combination with other drugs such as gemtuzumab ozogamicin, ascorbic acid, and cytarabine.
Clin Lymphoma Myeloma 2007 Dec
PMID:New data with arsenic trioxide in leukemias and myelodysplastic syndromes. 1828 65

Arsenic has been used for more than 2,000 years in the treatment of a variety of medical conditions, including plague, hysteria, syphilis, and cancer. Numerous potential mechanisms of action have been identified. Arsenic trioxide has remarkable efficacy in acute promyelocytic leukemia and is approved by the US Food and Drug Administration for this indication. It has also been studied in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma and has limited single-agent efficacy in these diseases. We have completed a phase I/II trial of arsenic trioxide combined with low-dose ara-C (LDAC) in 49 patients with Int-2/high-risk MDS and 64 patients age 60 years and older with untreated AML. The regimen was generally well tolerated and complete remissions were observed in both MDS and AML patients, including in patients with poor baseline performance status and unfavorable cytogenetics. Manuscript has been accepted for publication.
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PMID:Arsenic and old lace: novel approaches in elderly patients with acute myeloid leukemia. 1876 Jul 7

Arsenic trioxide (ATO) is synergistic with ascorbic acid (AA) and melphalan against myeloma both in vitro and in vivo. The aim of this randomized phase II trial was to determine the safety and efficacy of a combination of ATO, melphalan, and AA as preparative regimen in 48 patients undergoing autologous hematopoietic stem cell transplantation (ASCT) for multiple myeloma (MM). Forty-eight patients received melphalan 200 mg/m2 i.v. over 2 days and AA 1000 mg i.v. over 7 days in 3 treatment arms: no ATO (arm 1), ATO 0.15 mg/kg i.v. x 7 days (arm 2), and ATO 0.25 mg/kg i.v. x 7 days (arm 3). No dose-limiting toxicity, engraftment failure, or nonrelapse mortality (NRM) was seen in the first 100 days post-ASCT. Complete responses (CR) were seen in 12 of 48 patients (25%), with an overall response rate (ORR = CR + PR) of 85%. Median progression-free survival (PFS) was 25 months; median overall survival (OS) has not yet been reached. There was no significant difference in CR, PFS, or OS among the 3 treatment arms, and no adverse effect of ATO on melphalan pharmacokinetics. Addition of ATO + AA to high-dose melphalan is safe and well tolerated as a preparative regimen for MM.
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PMID:Arsenic trioxide with ascorbic acid and high-dose melphalan: results of a phase II randomized trial. 1904 Oct 63

Arsenic trioxide (As(2)O(3); ATO) is considered to be one of the most potent drugs in cancer chemotherapy and is highly effective in the treatment of acute promyelocytic leukemia (APL). It is well established that treatment of APL patients with ATO is associated with the disappearance of the PML-RARalpha fusion transcript, the characteristic APL gene product of the chromosomal translocation t(15;17). Although its mode of action is still not fully understood, ATO is known to induce cell apoptosis via generation of reactive oxygen species and activation of caspases. Several reports have indicated that ATO acts principally by inducing cell apoptosis not only in APL, but in a variety of non-APL cells including myeloma cells, chronic myeloid leukemia cells and cells of immune origin, including B or T lymphocytes, macrophages and, more recently, neutrophils. There is an increasing amount of data, including some from our laboratory, concerning the interaction between ATO and human primary cells. The focus of this review will be to cover the role of ATO in human immune primary cells with special emphasis on cells of myeloid origin.
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PMID:Interaction between arsenic trioxide and human primary cells: emphasis on human cells of myeloid origin. 1927 90

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