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)

Twenty-six patients including 11 with metastatic melanoma received cis-dichlorodiammineplatinum(II) at a dose of either 1 mg/kg or 60 mg/m2 given with intensive diuresis over a 6-hour period. This dose was administered twice weekly for the first three to eight courses and then at q3wk intervals. Eighteen patients received the dose schedule of 1 mg/kg and six patients received 60 mg/m2. A complete response was seen in one of four testicular tumors lasting for 6 months; partial responses were seen in three of 11 metastatic melanomas for 1, 1, and 2 months respectively, one of two osteogenic sarcomas for 4 months, one of one multiple myeloma for 2 months, and one of four testicular tumors for 1 month. A transient drop in creatinine clearance to 50%-75% of the baseline level was observed in 21% of the patients. Cytotoxic effects of cis-dichlorodiammineplatinum(II) are probably enhanced by this dose schedule as indicated by the consistent, moderate hematologic toxicity. Renal toxicity is ameliorated.
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PMID:Phase I study of high-dose cis-dichlorodiammineplatinum(II) with forced diuresis. 26 72

Knowledge of the number and kinds of differentiation steps that characterize cells of the osteoblast lineage is inadequate. To further analyze osteoblast differentiation, we generated a series of monoclonal antibodies (MAb) to osteogenic cells. Spleen cells from mice immunized with whole-cell populations enriched for expression of osteoblast-associated properties or bone formation in vitro were fused with the SP2/0 myeloma cell line. Supernatants from growing hybridomas were screened by indirect immunofluorescence on frozen sections of a portion of 21-day fetal rat heads that included the calvaria bone, periosteum, muscle, fibrous connective tissue, and skin. Six MAb were selected with bone-associated staining and limited ability to label other tissues. Either cell surface or cytoplasmic molecules were recognized by five of the MAb; one recognized a molecule detectable both in the cytoplasm, on the cell surface, and in the extracellular matrix. Of the antibodies selected, one identified both preosteoblasts and osteoblasts and has been found to be against alkaline phosphatase. The others recognized the mature osteoblasts, osteocytes, and chondrocytic cells. The pattern and distribution of the labeling in vivo extended to primary cells and cell lines in vivo. These results support earlier observations on molecules differentially expressed by cells at different stages of the osteoblast lineage and extend the available cell surface and cytoplasmic epitopes identifiable as marker molecules.
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PMID:Isolation of monoclonal antibodies recognizing rat bone-associated molecules in vitro and in vivo. 150 71

A patient with peripheral T-cell Lymphoma and acquired, systemic osteosclerosis is described. Bone histology showed a spectacular activation of osteoblasts accompanyed by massive new bone formation. Alkaline phosphatase in serum was elevated and increased to greater than 2000 U/l when the lymphoma became refractory to chemotherapy. In the patient's serum an osteoblast-activating factor could be demonstrated using a rat osteogenic osteosarcoma cell line (ROS 17/2.8). The factor was absent during remission of the tumor. We conclude that osteosclerosis was a paraneoplastic syndrome in this patient due to the secretion of an osteoblast-stimulating factor by the T-cell lymphoma. This situation is similar to the secretion of osteoclast-activating factors described in B-cell lymphomas, particularly multiple myeloma. The characterization of such a factor could be of therapeutic relevance.
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PMID:Evidence for an osteoblast-activating factor in a patient with peripheral T-cell lymphoma and osteosclerosis. 278 45

Monoclonal antibody against an osteogenic-sarcoma cell line (791T) was prepared by production and cloning of a somatic-cell hybrid between the mouse myeloma P3-NS1 and spleen cells from 791T-immunized mice. Three clones of hybridoma producing antibody against 791T, as detected by 125I-labelled Protein A binding, were tested against a range of normal and tumour cell targets to determine the pattern of expression of the antigen detected. The 3 clones had identical activity. They reacted strongly against 791T cells and another osteogenic sarcoma, 788T, and more weakly against a further 2 from a total panel of 10 osteogenic-sarcoma lines. The antibody was negative for fibroblasts from the donor of 791T, and for other fibroblasts, human red blood cells, human peripheral mononuclear cells and sheep red blood cells. When tested against a panel of unrelated tumours, they reacted against individual cell lines derived from carcinomas of colon, lung, bladder and cervix. These cross-reactions were not observed with other colon or lung carcinomas, and it is suggested that the antibody was reacting with a tumour-associated antigen expressed randomly on different tumour types, rather than specifically on osteogenic sarcomas.
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PMID:Antitumour reactions of monoclonal antibody against a human osteogenic-sarcoma cell line. 694 6

VS38 is a mouse monoclonal antibody which recognizes an intracytoplasmic antigen of 64 kilodaltons present in normal and neoplastic cells. It was reported to be of potential value in identifying myeloma or plasmacytoma in bone marrow or other tissues. During diagnostic analysis of bone marrow biopsies we noticed a consistent staining of osteoblasts with VS38. This led us to investigate the immunoreactivity in a range of bone lesions. 58 lesions were examined in the current study, including benign and malignant tumors as well as tumor like lesions and processes with reactive bone formation. The Streptavidin-peroxidase complex technique was applied on paraffin embedded sections, with 3-amino-9-ethylcarbazole serving as chromogen. All osteoblasts of reactive origin and part of the osteoblasts of benign neoplasms showed positive immunostaining. The antibody stained stroma cells in 81.25% (13/16) of the cases of benign osteogenic tumors and in 82.35% (14/17) of the osteosarcomas. Additionally, VS38 labelling was observed in bone tumors of fibrohistiogenic origin such as nonossifying fibroma and giant cell tumor, the histogenesis of which is still being debated. On the whole, it can be concluded that antibody VS38 lacks specificity as a plasma cell marker. It shows, however, a striking affinity to osteoblasts and in part also to stroma cells of osteogenic and fibrohistiogenic bone tumors.
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PMID:Expression of VS38 in osteoblasts and stroma cells of bone tumors. 952 Oct 19

Interleukin-6 (IL-6) is an important growth and survival factor for myeloma cells. However, the identity of the cells producing IL-6 in vivo remains unclear. Myeloma cells are found closely associated with sites of active bone turnover, and cells of the osteogenic lineage, including bone marrow osteoprogenitors, osteoblasts and bone lining cells, may therefore be ideally placed to synthesize IL-6. We have examined the possibility that human osteogenic cells may produce IL-6 in response to stimulation by myeloma cells. Primary human osteoblasts (hOBs) were isolated from normal donors, co-cultured with the human myeloma cell lines, JJN-3, RPMI-8226 and NCI-H929, and the amount of IL-6 released was determined by enzyme-linked immunosorbent assay (ELISA). All myeloma cells stimulated a significant increase in the production of IL-6 when cultured with hOBs (P < 0.05). Prior fixation of hOBs completely abrogated release of IL-6 in the co-cultures. In contrast, fixed myeloma cells retained the ability to induce IL-6 production, suggesting that hOBs were the principal source of IL-6. Physical separation of myeloma cells from hOBs using transwell inserts caused a partial inhibition of IL-6 release (P < 0.05), whereas the addition of media conditioned by myeloma cells to cultures of hOBs stimulated a significant increase in IL-6 production (P < 0.05). hOBs secreted greater amounts of IL-6 than human bone marrow stromal cells (hBMSCs) (2.2- to 3.5-fold, P < 0.05), but incubating hBMSCs with dexamethasone to stimulate osteoblastic differentiation resulted in an increase in their ability to produce IL-6 (1.7- to 4. 8-fold, P < 0.05) and to respond to myeloma cells (P < 0.05). These data clearly indicate that cells of the osteoblast lineage release significant amounts of IL-6 in response to stimulation by myeloma cells and may contribute to the IL-6 that promotes the proliferation and survival of myeloma cells in vivo.
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PMID:Human myeloma cells promote the production of interleukin 6 by primary human osteoblasts. 1069 69

Human mesenchymal stem cells (hMSCs) from bone marrow are a source of osteoblast progenitors in vivo, and under appropriate conditions they differentiate into osteoblasts ex vivo. The cells provide a convenient cell culture model for the study of osteogenic tissue repair in an experimentally accessible system. Recent advances in the field of skeletal development and osteogenesis have demonstrated that signaling through the canonical wingless (Wnt) pathway is critical for the differentiation of progenitor cell lines into osteoblasts. Inhibition of such signals can predispose hMSCs to cell cycle entry and prevent osteogenesis. Our investigation of the role of Wnt signaling in osteogenesis by hMSCs ex vivo has demonstrated that osteogenesis proceeds in response to bone morphogenic protein 2 stimulation and is sustained by Wnt signaling. In the presence of Dkk-1, an inhibitor of Wnt signaling, the cascade is disrupted, resulting in inhibition of osteogenesis. Peptide mapping studies have provided peptide Dkk-1 agonists and the opportunity for the production of blocking antibodies. Anti-Dkk-1 strategies are clinically relevant since high serum levels of Dkk-1 are thought to contribute to osteolytic lesion formation in multiple myeloma and possibly some forms of osteosarcoma. Specific inhibitors of glycogen synthetase kinase 3beta (GSK3beta), which mimic Wnt signaling, may also have a therapeutic benefit by enhancing in vitro osteogenesis despite the presence of Dkk-1. Antibodies that block Dkk-1 and GSK3beta inhibitors may provide novel opportunities for the enhancement of bone repair in a variety of human diseases such as multiple myeloma and osteosarcoma.
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PMID:How Wnt signaling affects bone repair by mesenchymal stem cells from the bone marrow. 1596 10

Multiple myeloma (MM) is a malignancy of antibody-secreting plasma cells. B-cell plasmacytomas stimulate bone resorption and angiogenesis, resulting in osteolytic lesions in the skeleton which persist upon successful treatment of the malignancy with chemotherapy. We found that an interaction between MM cells and mesenchymal stem cells (MSCs) from bone marrow stroma results in the formation and persistence of osteolytic bone lesions. It is known that MM cells activate osteoclast activity and secrete high levels of the Wnt inhibitor, Dickkopf-1, which prevents MSCs from differentiating into osteoblasts. We show that the Wnt signaling activator 6-bromoindirubin-3'-monoxime (BIO) releases MSCs from the osteoinhibitory effects of Dickkopf-1, whereas LiCl treatment does not. Additionally, we show that the >5-kDa fraction of MSC-conditioned medium promotes the proliferation of Dickkopf-1-secreting MM cells and that an interleukin-6 (IL-6)-neutralizing antibody blocks this effect. IL-6 expression levels were higher in undifferentiated MSCs than in MSCs treated with osteogenic medium, remained high in the presence of Dkk1, and were reduced by BIO treatment. Therefore, BIO treatment reduces the MSC-stimulated proliferation of MM cells and may enable MSCs to repair existing osteolytic lesions.
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PMID:A crosstalk between myeloma cells and marrow stromal cells stimulates production of DKK1 and interleukin-6: a potential role in the development of lytic bone disease and tumor progression in multiple myeloma. 1629 76

The microenvironment plays a critical role in facilitating cancer progression and metastasis. We previously demonstrated the ability of osteoclasts to support primary myeloma plasma cell (MM PC) growth. Our study on the role of the bone marrow (BM) microenvironment in myeloma, using global gene expression profiling, has identified fibroblast activation protein (FAP) as one of 28 genes significantly overexpressed in cocultured osteoclasts. Because FAP has been previously implicated in tumorigenesis and shown to be selectively expressed by the reactive stroma of epithelial tumours, we focused our study on the role of this serine protease in myeloma. Using quantitative polymerase chain reaction amplification, we demonstrated upregulation of FAP by cocultured osteoclasts and mesenchymal stem cells, and in whole myelomatous human bone in SCID-hu mice. Immunohistochemical analysis of myelomatous bone sections revealed FAP expression by osteoclasts, osteogenic cells, fibrotic stroma and certain adipocytes and vascular endothelial cells. FAP was not expressed in PCs by all these methods. Inhibition of FAP expression with the use of small-interference RNA reduced MM PC survival in cocultures. Our results indicate that FAP is critical for the interaction of MM cells with the BM microenvironment--a potential therapeutic target in myeloma.
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PMID:Fibroblast activation protein (FAP) is upregulated in myelomatous bone and supports myeloma cell survival. 1651 33

The study was purposed to explore the role of mesenchymal stem cells (MSCs) in the pathogenesis of bone disease particularly observed in multiple myeloma (MM), the biological features of marrow derived MSCs from patients with MM have been investigated. Marrow aspirates were harvested from 11 newly diagnosed patients with MM and 5 normal adults and MSCs were isolated and culture-expanded by the cell properties of adherence to plastic flasks, The phenotype was analyzed by flow cytometric technique. The proliferation of MSCs was observed by MTT assay and their differentiation capacities into osteoblasts and adipoblasts were assessed with lineage-specific histochemical staining. The concentrations of IL-6 and SCF in the culture supernatant were detected by enzyme-linked immunosorbent assay (ELISA). MSC culture supernatants were collected and MTT assay was performed to evaluate their support on the proliferation of an MM cell line SKO007 cells. The results showed that bone marrow-derived MSCs from MM patients were homogeneously positive for CD29, CD73, CD166 and HLA-ABC and negative for hematopoietic cell marker CD45 and endothelial cell marker CD31, the phenotype of which was similar to that of marrow counterparts from normal adults. MTT assay indicated that MSCs from MM patients or normal adults proliferated at similar rates. MSCs from MM patients occupied in vitro osteogenic and adipogenic capacity as those from normal adults. The levels of IL-6 and SCF in culture supernatant were greatly up-regulated in MM patients by ELISA assay. Furthermore, MSC culture supernatants from MM bone marrow displayed enhanced activity to promote the proliferation of SKO007 cells. It is concluded that marrow-derived MSCs from bone marrow of MM patients are normal in their proliferation and differentiation capacities, and myeloma bone disease may not be ascribed to the differentiation of MSCs while the elevated secretion of IL-6 and SCF may provide necessary cues for the survival of malignant myeloma cells.
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PMID:[Biological properties of mesenchymal stem cells derived from bone marrow of patients with multiple myeloma]. 1720 80


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