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)

We developed a new experimental animal model of human multiple myeloma using immunodeficient NOD/SCID/gammac(null) (NOG) mice. A human myeloma cell line, U266, was intravenously inoculated into 20 NOG mice, all of which developed hind leg paralysis and distress around 6 weeks after transplantation. Pathological studies showed that only the bone marrow was infiltrated with U266 cells, and no cells were present in other organs. Osteolytic lesions in cortical bones and loss of trabecular bones were prominent in U266-transplanted NOG mice. In contrast, U266 cells were not detected in CB17scid or NOD/SCID mice 6 weeks after intravenous inoculation. Human IgE, produced by U266 cells, was detected in the serum of U266-transplanted NOG mice by ELISA. The results indicated that this hu-myeloma NOG model might be useful for studying the pathogenesis of myeloma and related osteolytic lesions, and are suggestive of its applicability to the future development of new drugs.
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PMID:Establishment of a new model of human multiple myeloma using NOD/SCID/gammac(null) (NOG) mice. 1468 54

The NOD/SCID human chimeric animal model was generated by implanting of human fetal bones (FBs) into subcutaneous sites of NOD/SCID mice (NOD/SCID-hu(+)), followed by inoculation of primary bone marrow mononuclear cells (BMNCs) obtained from patients with multiple myeloma (MM) into the FBs. The BMNCs from 30 patients with MM were inoculated, and 28 (93%) of them revealed evidence of tumor growth of myeloma cells (MCs) in the NOD/SCID-hu(+) mice. Intriguingly, 17 (61%) of the 28 patients' BMNCs inoculated developed not only myeloma in the bone marrow of the FBs, but also extramedullary macrotumors (EMTs) along the periosteum of the FBs. The tumor cells in these EMTs had plasmacytoid morphology and preserved antigens and cytogenetics similar, if not identical, to those in the parent MCs. Moreover, small tumor blocks from nine EMTs were transplanted into subcutaneous sites of subsequent recipient NOD/SCID mice without human FBs (NOD/SCID-hu(-)), and all but one grew successfully. Two of the EMTs have been maintained in the animal model for more than 12 months. The NOD/SCID-hu(+) chimeric animal model is highly efficient for growth of primary MCs and presents clinical features of human MM. The engrafted MCs can be maintained subsequently in NOD/SCID-hu(-) mice as in vivo culture.
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PMID:Nonirradiated NOD/SCID-human chimeric animal model for primary human multiple myeloma: a potential in vivo culture system. 1474 78

Bruceantin was first isolated from Brucea antidysenterica, a tree used in Ethiopia for the treatment of cancer, and activity was observed against B16 melanoma, colon 38, and L1210 and P388 leukemia in mice. Phase I and II clinical trials were then initiated, but no objective tumor regressions were observed and clinical development was terminated. Recently, the activity of bruceantin has been studied with a number of leukemia, lymphoma, and myeloma cell lines. Cell differentiation was induced and c-MYC was down-regulated, suggesting a mechanistic correlation between c-MYC down-regulation and induction of cell differentiation or cell death. Treatment of HL-60 and RPMI 8226 cell lines induced apoptosis, and this involved the caspase and mitochondrial pathways. Moreover, an in vivo study using RPMI 8226 human-SCID xenografts demonstrated that bruceantin induced regression in early as well as advanced tumors, and these significant antitumor responses were facilitated in the absence of overt toxicity. Apoptosis was significantly elevated in tumors derived from animals treated with bruceantin. In sum, bruceantin interferes with the growth of leukemia, lymphoma, and myeloma cells in culture and xenograft models. Responses of this type suggest bruceantin should be reinvestigated for clinical efficacy against hematological malignancies.
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PMID:Antitumor activity of bruceantin: an old drug with new promise. 1498 68

HuN901 is a humanized monoclonal antibody that binds with high affinity to CD56, the neuronal cell adhesion molecule. HuN901 conjugated with the maytansinoid N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), a potent antimicrotubular cytotoxic agent, may provide targeted delivery of the drug to CD56 expressing tumors. Based on gene expression profiles of primary multiple myeloma (MM) cells showing expression of CD56 in 10 out of 15 patients (66.6%) and flow cytometric profiles of MM (CD38(bright)CD45(lo)) cells showing CD56 expression in 22 out of 28 patients (79%), we assessed the efficacy of huN901-DM1 for the treatment of MM. We first examined the in vitro cytotoxicity and specificity of huN901-DM1 on a panel of CD56(+) and CD56(-) MM cell lines, as well as a CD56(-) Waldenstrom's macroglobulinemia cell line. HuN901-DM1 treatment selectively decreased survival of CD56(+) MM cell lines and depleted CD56(+) MM cells from mixed cultures with a CD56(-) cell line or adherent bone marrow stromal cells. In vivo antitumor activity of huN901-DM1 was then studied in a tumor xenograft model using a CD56(+) OPM2 human MM cell line in SCID mice. We observed inhibition of serum paraprotein secretion, inhibition of tumor growth, and increase in survival of mice treated with huN901-DM1. Our data therefore demonstrate that huN901-DM1 has significant in vitro and in vivo antimyeloma activity at doses that are well tolerated in a murine model. Taken together, these data provide the framework for clinical trials of this agent to improve patient outcome in MM.
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PMID:In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine against CD56+ multiple myeloma cells. 1523 75

Clinically and biologically relevant animal models are indispensable to evaluate both the pathophysiology and strategies for diagnosis and treatment of multiple myeloma (MM). We examined the tumorigenicity of MM cell lines KMM-1 and U-266 in an in vivo cell proliferation model using NOD/SCID/gammacnull (NOG) mice. Two cell lines were inoculated either subcutaneously (s.c.) in the post-auricular region or intravenously (i.v.) in the tail of NOG mice. The KMM-1 cell line produced a progressively growing large tumor with infiltration of the cells expressing human lambda-chain in various organs of all NOG mice, while the U-266 cell line failed to do so. Tumor cells grown in NOG mice maintained the original histomorphology, as well as expression patterns of tumor markers human lambda Ig light chain and VEGF. Tumor progression in mice also correlated with elevation of serum human soluble IL-6R and gp130. Tumor cells sustained a strong NF-kappaB activity in vivo and induced NF-kappaB components were indistinguishable from those in cells cultured in vitro. The rapid and efficient engraftment of the MM cell line in NOG mice suggests that this is a very useful animal model which could provide a novel system in which to clarify the mechanism of growth of cancer cells, as well as to develop new therapeutic regimens against MM.
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PMID:Prompt tumor formation and maintenance of constitutive NF-kappaB activity of multiple myeloma cells in NOD/SCID/gammacnull mice. 1524 91

Autologous stem cell transplantation, in the setting of hematologic malignancies such as lymphoma, improves disease-free survival if the graft has undergone tumor purging. Here we show that flowing hematopoietic cells through pulsed electric fields (PEFs) effectively purges myeloma cells without sacrificing functional stem cells. Electric fields can induce irreversible cell membrane pores in direct relation to cell diameter, an effect we exploit in a flowing system appropriate for clinical scale. Multiple myeloma (MM) cell lines admixed with human bone marrow (BM) or peripheral blood (PB) cells were passed through PEFs at 1.35 kV/cm to 1.4 kV/cm, resulting in 3- to 4-log tumor cell depletion by flow cytometry and 4.5- to 6-log depletion by tumor regrowth cultures. Samples from patients with MM gave similar results by cytometry. Stem cell engraftment into nonobese diabetic-severe combined immunodeficient (NOD/SCID)/beta2m-/- mice was unperturbed by PEFs. Flowing cells through PEFs is a promising technology for rapid tumor cell purging of clinical progenitor cell preparations.
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PMID:Flowing cells through pulsed electric fields efficiently purges stem cell preparations of contaminating myeloma cells while preserving stem cell function. 1529 69

The humanized anti-CD74 monoclonal antibody (mAb) hLL1 is under evaluation as a therapeutic agent. The effects of hLL1-at times in comparison with the CD20 mAb rituximab-were assessed on non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) cell lines and in tumor-bearing SCID mice. In vitro, hLL1 caused growth inhibition and induction of apoptosis in B-cell lines when cross-linked with an antihuman immunoglobulin G (IgG) second antibody. The sensitivity profile of the cell lines was different for hLL1 and rituximab, and antiproliferative activity was augmented when the 2 mAbs were combined. Unlike rituximab, hLL1 did not induce antibody-dependent cellular cytotoxicity or complement-mediated cytotoxicity. In xenograft models of NHL and MM, treatment with hLL1 yielded significant survival benefits without cross-linking agents. Efficacy was greater in the MM model, in which median survival time was increased more than 4.5-fold. Thus, hLL1 has therapeutic potential as a naked mAb for B-cell malignancies because of high antigen expression on malignant cells, specifically MM, with limited expression on normal tissue, and because of its antiproliferative activity. Further, hLL1 may be a therapeutic candidate for rituximab-resistant disease because the 2 antibodies apparently act through distinct mechanisms and exhibit different expression and sensitivity profiles, and activity can be augmented when the mAbs are combined.
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PMID:Antiproliferative activity of a humanized anti-CD74 monoclonal antibody, hLL1, on B-cell malignancies. 1529 17

Ethical and scientific concerns regarding the use of human fetal bones in the SCID-hu model of primary human myeloma prompted us to develop a novel system that uses rabbit bones implanted subcutaneously in unconditioned SCID mice. Immunohistochemical analysis of the implanted bone revealed that the majority of bone marrow (BM) microenvironment cells such as blood vessels, osteoclasts and osteoblasts were of rabbit origin. The implanted bones were directly injected with myeloma cells from 28 patients. Successful engraftment of unseparated BM cells from 85% of patients and CD138-selected myeloma plasma cells from 81% of patients led to the production of patients' M-protein isotypes and typical myeloma manifestations (osteolytic bone lesions and angiogenesis of rabbit origin). Myeloma cells grew exclusively in the rabbit bone, but were able to metastasize into another bone at a remote site in the same mouse. Cells from patients with extramedullary disease also grew along the outer surface of the rabbit bones. This demonstrates the ability of SCID-rab model, marked by a nonmyelomatous, nonhuman, and nonfetal microenvironment, to support the growth of CD138-expressing myeloma cells. This system can now be widely used to study the biology of myeloma and its manifestations and to develop novel therapeutic approaches for this disease.
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PMID:The SCID-rab model: a novel in vivo system for primary human myeloma demonstrating growth of CD138-expressing malignant cells. 1538 29

Multiple myeloma (MM) is a fatal lymphoid malignancy that is incurable with conventional modalities of chemotherapy. Strong and constitutive activation of nuclear factor kappa B (NF-kappaB) is a common characteristic of MM cells. In our study we successfully target NF-kappaB with a novel NF-kappaB inhibitor dehydroxymethylepoxyquinomycin (DHMEQ). DHMEQ completely abrogates constitutive NF-kappaB activity and induces apoptosis of MM cells, whereas control peripheral blood mononuclear cells (PBMC) are resistant to NF-kappaB inhibition and apoptosis by DHMEQ treatment. DHMEQ inhibition of NF-kappaB triggers activation of caspases 8 and 9, as well as G0/G1 cell cycle arrest accompanied by downregulation of antiapoptotic genes Bcl-XL and c-FLIP and cell cycle progression gene cyclins D1 and D2. DHMEQ-mediated inhibition of vascular endothelial growth factor (VEGF) production in MM cells raises the possibility that DHMEQ abrogates the autocrine VEGF loop and enhances its antitumor effects by inhibiting neovascularization in the bone marrow. Using an in vivo NOD/SCID/gammac(null) (NOG) mice model, we show that DHMEQ has a potent inhibitory effect on the growth of MM cells. Compared to other compounds having the potential to inhibit NF-kappaB, DHMEQ is a unique compound that blocks the translocation of NF-kappaB p65 into the nucleus and selectively targets NF-kappaB activated in tumor cells. Therefore, our study presents a new molecular target therapy in MM.
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PMID:A novel NF-kappaB inhibitor DHMEQ selectively targets constitutive NF-kappaB activity and induces apoptosis of multiple myeloma cells in vitro and in vivo. 1552 84

Despite new treatment options, including autologous and allogeneic stem cell transplants, multiple myeloma remains an incurable disease. The authors developed and characterized a murine anti-human ICAM-1 (CD54) monoclonal antibody, UV3, which is highly effective in SCID mice with advanced human myeloma xenografts (SCID/ARH-77). To improve the effector functions and pharmacokinetic parameters and to reduce its immunogenicity in humans, the authors engineered this monoclonal antibody into a mouse/human IgG1kappa chimeric (c) antibody, cUV3. Following coexpression and purification of the genetically spliced heavy and light chain constructs, the authors compared cUV3 and UV3 in various in vitro assays, including relative cell-binding affinities and effector functions, namely antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. The authors compared their in vivo retention times and biodistribution patterns in normal mice. In each assay, the authors found that cUV3 was essentially equivalent to UV3. Finally, these antibodies were tested in a SCID/ARH-77 model of advanced myeloma, with daily treatments of 4 mug/g for 4 consecutive days commencing 14 days after tumor cell inoculation. cUV3 was at least as effective as UV3; 40% and 20% of the mice, respectively, were cured, with no sign of disease at day 150. The authors intend to evaluate the efficacy of cUV3 further in SCID/ARH-77 mice using other doses and dosing schedules to try to improve the cure rate. Eventually, they hope to test the efficacy of cUV3 in patients with multiple myeloma.
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PMID:The generation and anti-myeloma activity of a chimeric anti-CD54 antibody, cUV3. 1553 85


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