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)

To improve the complete response (CR) rate in advanced multiple myeloma (MM) without increasing the toxicity of high-dose therapy, we have used a new conditioning regimen. A combination of BE-8 [an anti-interleukin 6 (IL-6) murine monoclonal antibody] and dexamethasone followed by high-dose melphalan (220 mg/m2) and autologous stem cell transplantation was used to treat a series of 16 patients with advanced multiple myeloma. A strong inhibition of IL-6 activity evaluated by quantification of C-reactive protein was observed in all patients and was correlated with the high CR rate achieved with this combination therapy.
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PMID:A combination of anti-interleukin 6 murine monoclonal antibody with dexamethasone and high-dose melphalan induces high complete response rates in advanced multiple myeloma. 1088 21

Cytokines of the interleukin 6 (IL-6) family, which activates the signal transducer gp130, are major survival and growth factors for human multiple myeloma (MM) cells. The signal transduction of gp130 involves the Janus tyrosine kinases (JAK) JAK1, JAK2 and Tyk2 and then the downstream effectors comprising the signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) pathways. We evaluated the effects of the JAK2 inhibitor tyrphostin AG490 on MM cells. We found that AG490 suppressed cell proliferation and induced apoptosis in IL-6-dependent MM cell lines. JAK2 kinase activity, ERK2 and STAT3 phosphorylation were inhibited. These results suggest that the chemical blocking of the gp130 signalling pathway at the JAK level could be a relevant therapeutic approach to MM.
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PMID:JAK2 tyrosine kinase inhibitor tyrphostin AG490 downregulates the mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT) pathways and induces apoptosis in myeloma cells. 1092 36

A 69-year-old man visited our department of neurology with symptoms of paresthesia on the lower extremities and lumbago. Biochemical examination of serum samples showed hypercalcemia (serum concentration 15.6 mg/dl). The levels of intact parathyroid hormone (i-PTH) and 1,25-dihydroxyvitamin D were suppressed, whereas parathyroid hormone-related peptide (PTHrP) was elevated up to 5.4 pM (normal range: below 0.6 pM). Additionally, bone survey revealed a punched-out lesion in radiological examinations of the skull. Bone marrow aspiration demonstrated many atypical plasma cells suggesting multiple myeloma. Nephrogenous cyclic adenosine monophosphate (cAMP), urinary deoxypyridinoline, plasma interleukin 6 (IL-6) and transforming growth factor beta (TGF beta) concentrations were elevated, whereas % of renal tubular reabsorption of phosphate (%TRP) was decreased. The immunohistochemical results demonstrated the expression of PTHrP in atypical plasma cells. These data indicated that hypercalcemia complicating multiple myeloma causes an elevation of renal calcium reabsorption and an increase of bone resorption mediated by PTHrP action.
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PMID:Hypercalcemia induced with the plasma levels of parathyroid hormone-related peptide in multiple myeloma. 1103 Feb 5

Although thalidomide (Thal) was initially used to treat multiple myeloma (MM) because of its known antiangiogenic effects, the mechanism of its anti-MM activity is unclear. These studies demonstrate clinical activity of Thal against MM that is refractory to conventional therapy and delineate mechanisms of anti-tumor activity of Thal and its potent analogs (immunomodulatory drugs [IMiDs]). Importantly, these agents act directly, by inducing apoptosis or G1 growth arrest, in MM cell lines and in patient MM cells that are resistant to melphalan, doxorubicin, and dexamethasone (Dex). Moreover, Thal and the IMiDs enhance the anti-MM activity of Dex and, conversely, are inhibited by interleukin 6. As for Dex, apoptotic signaling triggered by Thal and the IMiDs is associated with activation of related adhesion focal tyrosine kinase. These studies establish the framework for the development and testing of Thal and the IMiDs in a new treatment paradigm to target both the tumor cell and the microenvironment, overcome classical drug resistance, and achieve improved outcome in this presently incurable disease.
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PMID:Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. 1104 70

The breakthrough discovery of the anti-angiogenic effects of thalidomide gave impetus to a series of clinical trials in patients with solid tumors and hematologic malignancies. Thalidomide has been shown to block the activity of angiogenic substances like bFGF, VEGF and interleukin 6. This drug also down-regulates TNF alpha. Thalidomide has shown clinical antitumor activity in single-agent, phase II clinical trials in AIDS-related Kaposi sarcoma, glioma, multiple myeloma refractory to chemotherapy, and hormone-refractory prostate cancer. In contrast, thalidomide was inactive in breast, lung and kidney cancer. The dose-limiting toxicity of thalidomide is sedation. Other adverse effects include skin rash, constipation, dry mouth and liver function abnormalities, along with peripheral neuropathy and the drug's well-known teratogenic potential. The advantages of thalidomide include the convenience of the oral route of administration, the drug's toxicity profile--substantially milder than that of chemotherapy--and its low cost. The potential role of thalidomide in the treatment of human neoplasia will be confirmed by means of randomized clinical trials.
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PMID:[Thalidomide. Clinical trials in cancer]. 1118 34

Originating from a post-switch memory B cell or plasma cell compartment in peripheral lymphoid tissues, malignant myeloma cells accumulate in the bone marrow of patients with multiple myeloma. In this favorable microenvironment their growth and survival are dependent upon both soluble factors and physical cell-to-cell and cell-to-extracellular matrix contacts. In this report we show that hyaluronan (HA), a major nonprotein glycosaminoglycan component of the extracellular matrix in mammalian bone marrow, is a survival and proliferation factor for human myeloma cells. The effect of HA is mainly mediated through a gp 80-interleukin 6 (IL-6) receptor pathway by a CD44-independent mechanism, suggesting that HA retains and concentrates IL-6 close to its site of secretion, thus favoring its autocrine activity. In addition, we show that HA-mediated survival and proliferation of myeloma cells is associated with a down-regulation in the expression of p27(kip1) cyclin-dependent kinase inhibitor and a hyperphosphorylation of the retinoblastoma protein (pRb). These data suggest that HA could be an important component in the myeloma cell physiopathology in vivo by potentiating autocrine and/or paracrine IL-6 activities.
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PMID:Hyaluronic acid induces survival and proliferation of human myeloma cells through an interleukin-6-mediated pathway involving the phosphorylation of retinoblastoma protein. 1127 72

Multiple myeloma (MM) remains incurable and novel treatments are urgently needed. Preclinical in vitro and in vivo evaluations were performed to assess the potential therapeutic applications of human recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand/Apo2 ligand (TRAIL/Apo2L) in MM. TRAIL/Apo2L potently induced apoptosis of MM cells from patients and the majority of MM cell lines, including cells sensitive or resistant to dexamethasone (Dex), doxorubicin (Dox), melphalan, and mitoxantrone. TRAIL/Apo2L also overcame the survival effect of interleukin 6 on MM cells and did not affect the survival of peripheral blood and bone marrow mononuclear cells and purified B cells from healthy donors. The status of the TRAIL receptors (assessed by immunoblotting and flow cytometry) could not predict TRAIL sensitivity of MM cells. The anti-MM activity of TRAIL/Apo2L was confirmed in nu/xid/bg mice xenografted with human MM cells; TRAIL (500 microg intraperitoneally daily for 14 days) was well tolerated and significantly suppressed the growth of plasmacytomas. Dox up-regulated the expression of the TRAIL receptor death receptor 5 (DR5) and synergistically enhanced the effect of TRAIL not only against MM cells sensitive to, but also against those resistant to, Dex- or Dox-induced apoptosis. Nuclear factor (NF)-kappaB inhibitors, such as SN50 (a cell-permeable inhibitor of the nuclear translocation and transcriptional activity of NF-kappaB) or the proteasome inhibitor PS-341, enhanced the proapoptotic activity of TRAIL/Apo2L against TRAIL-sensitive MM cells, whereas SN50 reversed the TRAIL resistance of ARH-77 and IM-9 MM cells. Importantly, normal B lymphocytes were not sensitized to TRAIL by either Dox, SN50, or PS-341. These preclinical studies suggest that TRAIL/Apo2L can overcome conventional drug resistance and provide the basis for clinical trials of TRAIL-based treatment regimens to improve outcome in patients with MM. (Blood. 2001;98:795-804)
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PMID:TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. 1146 81

The soluble interleukin 6 receptor alpha is an agonistic molecule of interleukin 6 (IL-6) and is important in the biology of multiple myeloma. More precisely, it potentiates the deleterious effects of IL-6 during tumour progression, facilitating angiogenesis and bone resorption. Because the mechanisms involved in the shedding of the interleukin 6 receptor alpha (IL-6Ralpha) in multiple myeloma are not known, we have investigated them in the XG-6 human myeloma cell line. Here we provide evidence that PMA-induced IL-6Ralpha shedding is controlled by a metalloproteinase and by protein kinase C (PKC) isoenzymes that do not require Ca(2+) for their activation. We show that XG-6 cells express PKC-delta, -eta and -zeta isoenzymes. However, after stimulation with PMA, only PKC-delta and PKC-eta are activated, as shown by their translocation to the membrane. Treatment with PMA induces an increase in PKC-delta phosphorylation in its active loop. In addition, by using rottlerin, a specific inhibitor of PKC-delta, we demonstrate that PKC-delta is involved in the PMA-induced shedding of IL-6Ralpha. With the use of UO126, a specific inhibitor of the mitogen-activated protein kinase (MAPK) pathway, we show that the PMA-induced IL-6Ralpha shedding is mediated in part by the MAPK pathway. Finally, whereas GF109203X, a general PKC inhibitor, inhibits the activation of ERK1/2 (extracellular signal-regulated protein kinase 1/2), rottlerin has no inhibitory effect, indicating that the Ras/MAPK activation is PKC-dependent but PKC-delta-independent. Taken together, these results suggest that the PMA-induced shedding of IL-6Ralpha is mediated by a PKC isoenzyme network.
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PMID:Protein kinase C delta and eta isoenzymes control the shedding of the interleukin 6 receptor alpha in myeloma cells. 1148 67

Thalidomide (Thal) is a drug with anti-angiogenic properties. To explore whether the effect of Thal on angiogenesis is associated with a reduction of angiogenic cytokine levels in progressive multiple myeloma (MM), plasma levels of basic fibroblast growth factor, vascular endothelial growth factor, interleukin 6, tumour necrosis factor-alpha and hepatocyte growth factor (HGF) were measured in 51 patients at 0, 3 and 6 months of Thal therapy. After 6 months of treatment, 26 patients were considered to be responsive to Thal therapy, including 17 minimal responses, eight partial responses and one complete response. Only HGF (decreasing, P = 0.02) in the group of responsive patients showed a statistically significant change over a period of 6 months. Because HGF levels are known to correlate to MM tumour burden, we conclude that the mechanism of action of Thal in MM is not caused by a specific inhibition of angiogenic cytokine secretion.
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PMID:Response to thalidomide in progressive multiple myeloma is not mediated by inhibition of angiogenic cytokine secretion. 1235 38

Study of the network of cytokines has helped identify cell growth factors in multiple myeloma. Plasma cells themselves may produce autocrine interleukin 6 (IL-6) while IL-6 production by bone marrow stromal cells may operate a paracrine mechanism. Involvement of IL-6 in multiple myeloma is indicated by its ability to induce the differentiation of myeloma plasmablasts into mature malignant plasma cells. Differential diagnosis between multiple myeloma and monoclonal gammopathies of undetermined significance (MGUS) is generally based on clinical and laboratory parameters. Nevertheless, evaluation of the serum level of IL-6, C reactive protein, soluble IL-6 receptor, soluble IL-2 receptor together with the activity exerted by IL-3 and IL-4 on some cellular subsets constitutes an additional element in the differential diagnosis of border-line cases. Serum levels of IL-6, soluble IL-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R) and the expression of membrane-bound IL-2 receptors, both on bone marrow plasma cells and on peripheral blood mononuclear cells are correlated with disease activity and disease stage. In addition, IL-6 and sIL-6R serum levels correlate with the duration of survival, as high values at the time of diagnosis correlate with short duration of survival.
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PMID:Interleukin-6 and the network of several cytokines in multiple myeloma: an overview of clinical and experimental data. 1174 46


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