Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CD38 molecule is well represented on cell surfaces in many cases of a variety of lymphoid tumors, notably multiple myeloma, AIDS-associated lymphomas, and post-transplant lymphoproliferations. As such, this molecule is a promising target for antibody therapy. After early disappointments, improved anti-CD38 antibodies of strong cytolytic potential have been described by 3 groups. First, a human IgG monoclonal anti-CD38 antibody raised in mice transgenic for human Ig has been found to induce potent complement and cellular cytotoxicities against both myeloma cell lines and fresh harvests from myeloma marrow and leukemic blood. This antibody also exhibits the singular property of inhibiting the CD38 cyclase activity. Second, a series of CD38-specific human antibodies, with high affinities and high ADCC activities against cell lines and primary cultures of myeloma, has been selected from a unique phage-display library. Finally, to enhance specificity for myeloma cells, bispecific domain antibodies targeting both CD38 and CD138 have been developed. As they lack any Fc module, these constructs rely on cytotoxicity for delivering a toxin to tumor cells. The list of candidate CD38-bearing neoplasms as targets for these antibody constructs can now be expanded to include acute promyelocytic leukemia, and possibly other myeloid leukemias, in which surface CD38 can be induced by retinoid treatment. One caveat here is that evidence has been produced to suggest that CD38 promotes pulmonary manifestations of the hazardous retinoic acid syndrome.
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PMID:CD38 as a therapeutic target. 1738 Feb 3

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

Recent surveys have indicated that thromboembolic complications are at least as common in hematologic malignancies, if not more frequent, than in solid tumors. The pathogenesis of thrombosis is similar to that in solid tumors, but with additional factors unique in several forms of hematologic malignancies, as seen in acute promyelocytic leukemia, myeloma, and myeloproliferative disorders. Likewise, the factors contributing to bleeding are similar to those seen in solid tumors, with the exception of a higher frequency of thrombocytopenia.
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PMID:Incidence and pathogenesis of thrombosis in hematologic malignancies. 1752 87

Patients with hematologic malignancies have increased risks of thromboembolism or bleeding. The commonest thrombotic complication is venous thromboembolism (VTE). Other thrombotic conditions occur in association with specific disorders, such as thrombotic thrombocytopenic purpura in hematopoietic stem cell transplantation and disseminated intravascular coagulation in acute promyelocytic leukemia. Clinical trials show that unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are efficacious for VTE prophylaxis in cancer patients after major surgery or when hospitalized for acute medical illnesses. These findings in cancer patients are probably applicable to patients with hematologic malignancies, in whom there are very few studies. However, the effectiveness of anticoagulant VTE prophylaxis is not established in ambulatory patients with cancer except for multiple myeloma patients treated with thalidomide and chemotherapy. LMWH is widely used as initial treatment for VTE because it enables home therapy without laboratory monitoring, thereby improving the patient's quality of life. UFH is preferred in patients with high bleeding risks and renal impairment. In cancer patients, vitamin K antagonists for the long-term treatment of VTE are increasingly replaced by LMWH, which show superior efficacy. When prescribing anticoagulant prophylaxis or treatment to patients with hematologic malignancies, clinical benefits must be weighed carefully against the risks of bleeding.
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PMID:Management of thromboembolism in hematologic malignancies. 1752 1

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

Tamibarotene is a new synthetic retinoid drug recently approved for relapsed or refractory acute promyelocytic leukemia (APL) in Japan. It is a specific agonist for retinoic acid receptor alpha/beta. Compared to all-trans retinoic acid (ATRA), a natural retinoid indicated for a first-line treatment of APL, tamibarotene is chemically more stable and several times more potent as an inducer of differentiation in promyelocytic leukemia cells. In contrast to ATRA, whose plasma concentration declines considerably during daily administration, tamibarotene sustains plasma level probably due to a lower affinity for cellular retinoic acid binding protein. Furthermore, adverse side effects were milder than those of ATRA in clinical trials. Clinical trials held in Japan showed that tamibarotene had efficacy in APL patients who had relapsed from ATRA-induced complete remission. Recently, better understanding of the various mechanisms of action of retinoids has stimulated great interest in its potential use for treatment of various diseases. Tamibarotene is being investigated for treatment of multiple myeloma and Crohn's disease in clinical trials. This review focuses on tamibarotene's mechanisms of action, chemical properties, pharmacokinetics and its use in APL as well as its potential use in various disorders.
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PMID:Tamibarotene. 1792 87

The rate of venous thromboembolism (VTE) in patients with acute leukemia or lymphomas is comparable with that of other "high-risk" cancer types. Chemotherapy and anti-angiogenic drugs increase the thrombotic risk in patients with lymphomas, acute leukemias and multiple myeloma (MM). Patients with hematologic malignancies often present with a hypercoagulable state or chronic disseminated intravascular coagulation (DIC) in the absence of active thrombosis and/or bleeding. Malignant cell procoagulant properties, cytotoxic therapies, and concomitant infections are major determinants for clotting activation in hematologic malignancies. In acute leukemia, clinical manifestations range from localized venous or arterial thrombosis to a diffuse, life-threatening thrombohemorrhagic syndrome (THS). All-trans retinoic acid (ATRA) has greatly improved the management of acute promyelocytic leukemia (APL), but has not significantly changed the rate of early hemorrhagic deaths and may actually promote thrombosis. Randomized, controlled trials (RCTs) of different prophylactic regimens to prevent VTE or THS in hematologic malignancies are urgently needed, particularly in patients with lymphoma or MM during chemotherapy and in patients with APL. Anticoagulant therapy is a particular challenge in patients with hematologic malignancies, since these patients are at very high risk for hemorrhage. No guidelines are available for the prophylaxis or treatment of VTE; extrapolations can be made from existing guidelines for management of patients with other malignancies; prolonged periods of treatment-induced thrombocytopenia in patients with hematologic malignancies, however, require a more judicious application of standard anticoagulant approaches. Use of the newer anticoagulants will require careful assessment of hemorrhagic risk in this group of high-risk patients but may be justified under special circumstances.
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PMID:Management of Thrombohemorrhagic Syndromes (THS) in hematologic malignancies. 1802 25

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

Onconase (Onc), a ribonuclease from oocytes or early embryos of Northern Leopard frog (Rana pipiens), is cytostatic and cytotoxic to a variety of tumor lines in vitro, inhibits growth of tumors in animal in vivo models and is currently in Phase IIIb clinical trials for malignant mesothelioma where it displays antitumor activity with minor overall toxicity to the patient. One of the characteristic features of Onc is a synergism with a variety of other antitumor modalities. Cepharanthine (Cep), a biscoclaurine alkaloid from Stephania cepharantha Hayata, is widely used in Japan to treat variety of ailments. It also shows low toxicity to patients. The aim of the present study was to assess the interaction of these two drugs on different tumor cell lines. When human promyelocytic leukemia HL-60, histiomonocytic lymphoma U937, multiple myeloma RPMI-8228, prostate carcinoma DU 145 and prostate adenocarcinoma LNCaP cells were exposed to relatively low concentrations of Onc or Cep their growth rates were somewhat suppressed but the cells were still able to proliferate. Cell growth, however, was totally abolished in each of these cell lines when treated with Onc and Cep combined. The frequency of apoptosis was also many-fold higher in cultures treated with a combination of Onc and Cep than in respective cultures treated with Onc or Cep alone. The mechanism of the observed synergism is unclear but it may be associated with the Onc activity in targeting microRNAs and/or NFkappaB and Cep activity also targeting NFkappaB. The data suggest that the combination of these two drugs, that individually express a low toxic profile, may have strong antitumor potential.
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PMID:Remarkable enhancement of cytotoxicity of onconase and cepharanthine when used in combination on various tumor cell lines. 1844 30


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