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)

Patients with multiple myeloma (MM) have increased bone marrow angiogenesis, but the angiogenic properties of myeloma cells and the mechanism of MM-induced angiogenesis have not been completely clarified. The brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, TrkB, have been identified as critical factors in the regulation of vessel formation. In this study, we demonstrate that patients with MM had increased BDNF and vascular endothelial growth factor (VEGF) in their peripheral blood. We also found in particular that a decreased BDNF level was correlated with the remission of MM. BDNF was expressed by the human myeloma cell line RPMI8226 and primary myeloma cells, and TrkB was expressed by human umbilical vein endothelial cells (HUVEC) at the protein levels. In a coculture system, we observed that both RPMI8226 cells and primary myeloma cells induced the migration and formation of a net-like structure in HUVEC. The anti-BDNF monoclonal antibody significantly but partially restrained the angiogenesis effect of MM cells. Moreover, in an experimental model of angiogenesis in vivo, BDNF and VEGF significantly promoted vessel formation in Matrigel plug compared to the control. These effects were also blocked by anti-BDNF monoclonal antibody. Finally, our in vitro results were supported by the in vivo finding in human myeloma xenograft NOD/SCID models. Anti-BDNF mAb treatment resulted in inhibition of tumor growth, decreased vessel density, and tumor necrosis. Our study suggested that the BDNF/TrkB signaling pathway could be involved, at least in part, in MM-induced angiogenesis.
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PMID:Identification of brain-derived neurotrophic factor as a novel angiogenic protein in multiple myeloma. 1788 2

Previous studies have demonstrated the effects of brain-derived neurotrophic factor (BDNF) on promoting proliferation of multiple myeloma (MM) cells and inducing angiogenesis in MM in vitro. This study was aimed to further explore whether BDNF/TrkB pathway is a potential therapeutic target in MM, and to elucidate the advantages and disadvantages of two ways developed for human myeloma xenograft in animal models. The models of xenograft tumors were established in the non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice by subcutaneous or intravenous injection of human myeloma cell line RPMI8226. Mice were monitored daily for life state, and the volume of subcutaneous tumors were measured after inoculation. 3 weeks after inoculation, red blood cell counts, BDNF level in plasma, human lambda light chain and calcium level in serum of NOD/SCID were detected every two weeks. The histological and cytological examinations were performed to observe pathological features of tumors. Using flow cytometry to observe the expression of human CD38+ cell in murine blood and bone marrow. The changes of bone density and skeletal lesions were detected by computer radiography. The results showed that the subcutaneously injected animal model showed a high growth efficiency of RPMI8226 subcutaneous tumors (5/5) and several pathological features of plasmacytomas. There were neither obvious increase in lambda light chain and calcium levels, nor spread of human MM cells to murine bone marrow and no radiological evidence of skeletal lesions. The intravenously injected animal model had relative low efficiency for growth of tumors (4/7) but MM cells could engraft and proliferate in murine bone marrow. The human lambda light chain could be detected in serum as early as 3 weeks after inoculation. Myeloma-bearing mice had high level of lambda light chain and high calcium in serum and resorption of the murine bone. Furthermore, the concentrations of BDNF were increased with the tumor growth in both models with (73 +/- 11) pg/ml and (105 +/- 18) pg/ml in plasma respectively at 9 weeks after inoculation. It is concluded that two appropriate MM xenograft NOD/SCID animal models were established, both of which show high BDNF levels in the plasma. Therefore, two valuable in vivo systems to explore novel therapeutic target (BDNF/TrkB) in MM have been set up successfully.
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PMID:[Establishment of multiple myeloma mouse models expressing brain derived neurotrophic factor]. 1795 71

Drug resistance remains a critical problem in the treatment of patients with multiple myeloma. Recent studies have determined that Notch signaling plays a major role in bone marrow (BM) stroma-mediated protection of myeloma cells from de novo drug-induced apoptosis. Here, we investigated whether pharmacologic inhibition of Notch signaling could affect the viability of myeloma cells and their sensitivity to chemotherapy. Treatment with a gamma-secretase inhibitor (GSI) alone induced apoptosis of myeloma cells via specific inhibition of Notch signaling. At concentrations toxic for myeloma cell lines and primary myeloma cells, GSI did not affect normal BM or peripheral blood mononuclear cells. Treatment with GSI prevented BM stroma-mediated protection of myeloma cells from drug-induced apoptosis. The cytotoxic effect of GSI was mediated via Hes-1 and up-regulation of the proapoptotic protein Noxa. In vivo experiments using xenograft and SCID-hu models of multiple myeloma demonstrated substantial antitumor effect of GSI. In addition, GSI significantly improved the cytotoxicity of the chemotherapeutic drugs doxorubicin and melphalan. Thus, this study demonstrates that inhibition of Notch signaling prevents BM-mediated drug resistance and sensitizes myeloma cells to chemotherapy. This may represent a promising approach for therapeutic intervention in multiple myeloma.
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PMID:Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. 1803 53

APRIL (a proliferation-inducing Ligand) and BLyS/BAFF (B-lymphocyte stimulator/B-cell-activating factor of the TNF (tumor necrosis factor) family have been shown to be the survival factors for certain myeloma cells in vitro. BAFF binds to the TNF-related receptors such as B-cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) and BAFFR, whereas APRIL binds to TACI and BCMA and to heparan sulfate proteoglycans (HSPG) such as syndecan-1. TACI gene expression in myeloma reportedly can distinguish tumors with a signature of microenvironment dependence (TACI(high)) versus a plasmablastic signature (TACI(low)). We tested the effect of atacicept (formerly TACI-Ig, which blocks APRIL and BAFF) and BAFFR-Ig (which blocks BAFF only) on primary myeloma growth in the SCID-hu model and in coculture with osteoclasts. With only few exceptions, atacicept and to a lesser extent BAFFR-Ig, inhibited growth of TACI(high) but not TACI(low) myeloma samples in vivo and ex vivo, and the response rate was inversely correlated with TACI expression. Most TACI(high) myeloma cells were molecularly classified as being low risk with our recently described 70-gene model. APRIL and BAFF were highly expressed by osteoclasts and were upregulated in myeloma cells after coculture with osteoclasts. Our findings suggest that APRIL plays an essential role in the survival of TACI(high) bone marrow-dependent myeloma cells and TACI gene expression may be a useful predictive marker for patients who could benefit from atacicept treatment.
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PMID:Atacicept (TACI-Ig) inhibits growth of TACI(high) primary myeloma cells in SCID-hu mice and in coculture with osteoclasts. 1804 46

CD200 is an immunosuppressive molecule overexpressed in multiple hematologic malignancies such as B cell chronic lymphocytic leukemia, multiple myeloma, and acute myeloid leukemia. We previously demonstrated that up-regulation of CD200 on tumor cells suppresses antitumor immune responses and that antagonistic anti-human CD200 mAbs enabled human PBMC-mediated tumor growth inhibition in xenograft NOD/SCID human (hu)-mouse models. Ab variants with effector function (IgG1 constant region (G1)) or without effector function (IgG2/G4 fusion constant region (G2G4)) exhibited high antitumor activity in a human tumor xenograft model in which CD200 was expressed. In this report, we seek to select the best candidate to move forward into the clinic and begin to decipher the mechanisms of tumor cell killing by comparing anti-CD200-G1 vs anti-CD200-G2G4 in two related animal models. In a CD200-expressing xenograft NOD/SCID hu-mouse model where CD200 ligand/receptor interactions are already established before initiating treatment, we find that anti-CD200-G1 is a less effective Ab compared with anti-CD200-G2G4. Separately, in a model that evaluates the effect of the Abs on the immune cell component of the xenograft NOD/SCID hu-mouse model distinctly from the effects of binding to CD200 on tumor cells, we find that the administration of anti-CD200-G1 Abs completely abolished human PBMC-mediated tumor growth inhibition. Along with supporting in vitro studies, our data indicate that anti-CD200-G1 Abs efficiently mediate Ab-dependent cellular cytotoxicity of activated T cells, critical cells involved in immune-mediated killing. These studies suggest important implications regarding the selection of the constant region in anti-CD200 immunotherapy of cancer patients.
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PMID:Blockade of CD200 in the presence or absence of antibody effector function: implications for anti-CD200 therapy. 1817 7

The interaction between multiple myeloma (MM) cells and the bone marrow (BM) microenvironment induces proliferation and survival of MM cells, as well as osteoclastogenesis. This study investigated the therapeutic potential of novel p38 mitogen-activated protein kinase (p38MAPK) inhibitor LY2228820 (LY) in MM. Although cytotoxicity against MM cell lines was modest, LY significantly enhanced the toxicity of bortezomib by down-regulating bortezomib-induced heat shock protein 27 phosphorylation. LY inhibited interleukin-6 secretion from long term cultured-BM stromal cells and BM mononuclear cells (BMMNCs) derived from MM patients in remission. LY also inhibited macrophage inflammatory protein-1alpha secretion from patient MM cells and BMMNCs as well as normal CD14 positive osteoclast precursor cells. Moreover, LY significantly inhibited in vitro osteoclastogenesis from CD14 positive cells induced by macrophage-colony stimulating factor and soluble receptor activator of nuclear factor-kappaB ligand. Finally, LY also inhibited in vivo osteoclatogenesis in a severe combined immunodeficiency mouse model of human MM. These results suggest that LY represents a promising novel targeted approach to improve MM patient outcome both by enhancing the effect of bortezomib and by reducing osteoskeletal events.
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PMID:p38 mitogen-activated protein kinase inhibitor LY2228820 enhances bortezomib-induced cytotoxicity and inhibits osteoclastogenesis in multiple myeloma; therapeutic implications. 1839 45

The interleukin-12 (IL-12) receptor (R) B2 gene acts as tumor suppressor in human acute and chronic B-cell leukemias/lymphomas and IL-12rb2-deficient mice develop spontaneously localized plasmacytomas. With this background, we investigated the role of IL-12R beta 2 in multiple myeloma (MM) pathogenesis. Here we show the following: (1) IL-12R beta 2 was expressed in primary MM cells but down-regulated compared with normal polyclonal plasmablastic cells and plasma cells (PCs). IL-6 dampened IL-12R beta 2 expression on polyclonal plasmablastic cells and MM cells. (2) IL-12 reduced the proangiogenic activity of primary MM cells in vitro and decreased significantly (P = .001) the tumorigenicity of the NCI-H929 cell line in SCID/NOD mice by inhibiting cell proliferation and angiogenesis. The latter phenomenon was found to depend on abolished expression of a wide panel of proangiogenic genes and up-regulated expression of the antiangiogenic genes IFN-gamma, IFN-alpha, platelet factor-4, and TIMP-2. Inhibition of the angiogenic potential of primary MM cells was related to down-regulated expression of the proangiogenic genes CCL11, vascular endothelial-cadherin, CD13, and AKT and to up-regulation of an IFN-gamma-related antiangiogenic pathway. Thus, IL-12R beta 2 directly restrains MM cell growth, and targeting of IL-12 to tumor cells holds promise as new therapeutic strategy.
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PMID:Constitutive expression of IL-12R beta 2 on human multiple myeloma cells delineates a novel therapeutic target. 1847 25

We have previously described the development and testing of a monoclonal anti-human CD54 antibody (UV3) in SCID mice xenografted with human multiple myeloma, lymphoma, and melanoma cell lines. In all 3 cases, UV3 was highly effective at slowing the growth of tumors and/or prolonging survival. Since CD54 (ICAM-1) is up-regulated on many different types of cancer cells, we have now investigated the anti-tumor activity of UV3 in several other CD54(+) epithelial tumors. A panel of 16 human breast, prostate, non-small cell (NSC) lung, and pancreatic tumor cell lines was examined for reactivity with UV3, and 13 were positive. A representative CD54(+) cell line from each cancer was grown subcutaneously in SCID mice. Once the tumors were established, UV3 was administered using different dose regimens. UV3 slowed the growth of all 4 tumors, although it was not curative. When UV3 or gemcitabine were administered to SCID mice xenografted with a NSC lung tumor cell line or a pancreatic tumor cell line, UV3 was as effective as the chemotherapy alone. When gemcitabine and UV3 were administered together, the best anti-tumor responses were observed. UV3 has been chimerized (cUV3) and both toxicology studies and clinical trials are planned to assess the safety and activity of cUV3 in patients with one or more of these tumors.
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PMID:The antitumor activity of an anti-CD54 antibody in SCID mice xenografted with human breast, prostate, non-small cell lung, and pancreatic tumor cell lines. 1875 48

This study was aimed to further explore whether brain derived neurotrophic factor (BDNF) pathway is a potential therapeutic target in multiple myeloma (MM) and whether anti-BDNF monoclonal antibody can prevent the development of this disease. The in vivo antitumor effect of anti-BDNF monoclonal antibody (McAb) on a human myeloma xenograft animal model was evaluated. The model of xenograft tumors was established in the nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice by subcutaneous injection of human myeloma cell line RPMI8226. The antibodies were injected intraperitoneally at a dose of 20 microg/mouse at day 1, 2, 3 after inoculation or at a dose of 100 microg/mouse once a week after tumors were detected. The microvascular densities in tumors were analyzed by immunohistochemistry study. The effect of anti-BDNF McAb on the proliferation of RPMI8226 cells in vitro and on endothelial cells network formation in the co-culture system were determined by using a (3)H-thymidine incorporation assay and a Matrigel network formation assay, respectively. The results showed that multiple injections of anti-BDNF McAb reduced the tumor size, decreased the microvascular density and significantly prolonged tumor-free time and survival time. Moreover, the proliferation of RPMI8226 cells was inhibited in vitro by anti-BDNF McAb, but not by the control IgG. Anti-BDNF McAb also inhibited RPMI8226-induced network formation in endothelial cells in vitro. It is concluded that anti-BDNF monoclonal antibody can inhibit cell growth and angiogenesis in subcutaneous plasmacytoma.
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PMID:Antitumor effect of anti-brain derived neurotrophic factor monoclonal antibody in human multiple myeloma xenograft animal model. 1892 97

HM1.24 antigen (CD317) was originally identified as a cell surface protein that is preferentially overexpressed on multiple myeloma cells. Immunotherapy using anti-HM1.24 antibody has been performed in patients with multiple myeloma as a phase I study. We examined the expression of HM1.24 antigen in lung cancer cells and the possibility of immunotherapy with anti-HM1.24 antibody which can induce antibody-dependent cellular cytotoxicity (ADCC). The expression of HM1.24 antigen in lung cancer cells was examined by flow cytometry as well as immunohistochemistry using anti-HM1.24 antibody. ADCC was evaluated using a 6-h (51)Cr release assay. Effects of various cytokines on the expression of HM1.24 and the ADCC were examined. The antitumor activity of anti-HM1.24 antibody in vivo was examined in SCID mice. HM1.24 antigen was detected in 11 of 26 non-small cell lung cancer cell lines (42%) and four of seven (57%) of small cell lung cancer cells, and also expressed in the tissues of lung cancer. Anti-HM1.24 antibody effectively induced ADCC in HM1.24-positive lung cancer cells. Interferon-beta and -gamma increased the levels of HM1.24 antigen and the susceptibility of lung cancer cells to ADCC. Treatment with anti-HM1.24 antibody inhibited the growth of lung cancer cells expressing HM1.24 antigen in SCID mice. The combined therapy with IFN-beta and anti-HM1.24 antibody showed the enhanced antitumor effects even in the delayed treatment schedule. HM1.24 antigen is a novel immunological target for the treatment of lung cancer with anti-HM1.24 antibody.
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PMID:HM1.24 (CD317) is a novel target against lung cancer for immunotherapy using anti-HM1.24 antibody. 1897 97


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