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)

Monoclonal antibodies were produced in vitro by fusing mouse myeloma cells (SP2) with spleen cells derived from Balb/c mice immunized with purified measles virus. Fifteen independent hybrid cell lines, isolated from two separate fusions, were maintained in culture for up to 5 months without loss of their antibody-secreting activity. Radioimmunoprecipitation and polyacrylamide gel electrophoresis showed that in five of the hybrid lines the antibodies were directed against haemagglutinin, in two against the nucleoprotein, and in one against L protein. The remaining seven hybridomas did not precipitate viral antigens under the experimental conditions employed even though they gave positive immunofluorescence against measles virus-infected cells. Monoclonal haemagglutinin antibodies displayed anti-haemagglutinating activity and neutralized measles virus infectivity but not canine distemper virus (CDV).
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PMID:Monoclonal antibodies against measles virus. 728 10

Conditionally replicating viruses are promising agents for the treatment of malignancy. Here it is shown that the live attenuated Edmonston-B vaccine strain of measles virus (MV-Edm) replicates selectively in human myeloma cells and has potent antitumor activity. In vitro, replication of MV-Edm was restricted in phytohemagglutinin (PHA)-stimulated peripheral blood lymphocytes (PBLs) but proceeded efficiently in a panel of 6 myeloma cell lines-ARH-77, RPMI 8226, JJN-3, MM1, KAS-6/1, and KMS-11-and in primary myeloma cells isolated by CD138 sorting from the bone marrow aspirates of 6 patients. MV-Edm infection induced potent cytopathic effects in these myeloma cells, resulting in the formation of multinucleated syncytia that eventually became nonviable. In contrast, syncytial formation in PHA-stimulated PBLs was minimal after MV-Edm infection. In vivo, MV-Edm was antitumorigenic and inhibited the establishment of myeloma cells as xenografts in immunocompromised mice. When injected directly into ARH-77 myeloma xenografts in the mice, MV-Edm caused complete regression of these xenografts. MV-Edm administered intravenously into the tail veins of mice also showed significant antineoplastic activity against established RPMI 8226 and ARH-77 xenografts. In particular, the ARH-77 myeloma xenografts were exquisitely sensitive to MV-Edm therapy, and tumors in all mice regressed completely. In light of its selectivity for myeloma cells and its potent antineoplastic activity against myeloma xenografts in vivo, MV-Edm merits further development for the treatment of multiple myeloma.
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PMID:Systemic therapy of myeloma xenografts by an attenuated measles virus. 1156 82

We investigated the presence of the measles virus genome in order to identify asymptomatic infections in the adult population. Bone-marrow aspirates were obtained from 179 patients, 20-96 years of age, for the diagnosis of malignant diseases (29 with malignant lymphoma, 28 with acute leukaemia, 21 with myelodysplastic syndrome, five with multiple myeloma and 96 with other diseases). The measles virus genome was detected in 17 (9.5%) of 179 individuals by RT-PCR and 28 (15.6%) through hybridization. The genomes detected in bone marrow were all in the same cluster, D5, the strain circulating during the study period, and no evidence of persistent infection was obtained. We conclude that asymptomatic infections of measles virus are common in adults and the presence of the measles virus genome would not be related to the pathogenesis of illness.
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PMID:Detection of measles virus genome in bone-marrow aspirates from adults. 1223 31

Live attenuated measles virus (MV-Edm) has potent oncolytic activity against myeloma xenografts in mice. Therapy of multiple myeloma, a disseminated plasma cell malignancy, would require systemic administration of the virus. Thus, the virus should ideally be targeted to infect only myeloma cells to minimize collateral damage to normal tissues: viral binding to its natural receptors must be ablated and a new specificity domain that targets entry into myeloma cells be added. This study covers 2 critical steps toward generating such a retargeted virus: (1) a new specificity domain against the plasma cell marker CD38 was constructed in the form of a single-chain antibody (scFv) and (2) display of that scFv on the measles viral envelope glycoprotein successfully redirected virus entry through CD38 expressed on target cells devoid of the natural MV receptors. The anti-CD38 scFv was tethered to the C-terminus of the hemagglutinin (H) glycoprotein of MV-Edm through a Factor Xa protease cleavable linker. Immunoblot analysis demonstrated that the scFv was efficiently incorporated into recombinant viral particles. Replication of MV-alpha CD38 was not hindered by the scFv, reaching titers comparable to MV-Edm. Chinese hamster ovary (CHO) cells were resistant to infection by MV-Edm and MV-alpha CD38. In contrast, CHO cells expressing CD38 became susceptible to infection by MV-alpha CD38 but not MV-Edm. Removal of the displayed scFv rendered MV-alpha CD38 noninfectious on CHO-CD38 cells. Tumorigenicity of CHO-CD38 cells in immunocompromised mice was significantly attenuated by MV-alpha CD38, resulting in enhanced survival of these mice compared with the control group.
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PMID:Oncolytic measles viruses displaying a single-chain antibody against CD38, a myeloma cell marker. 1243 86

The Edmonston vaccine strain of measles virus (MV-Edm) propagates efficiently in a broad range of human tumor cells, killing them selectively. However, the oncolytic potency of MV-Edm in different human tumor xenograft therapy models is highly variable and there is no convenient way to map the distribution of virus-infected tissues in vivo. To enhance the oncolytic potency of MV-Edm against radiosensitive malignancies and to facilitate noninvasive imaging of infected tissues, we generated a recombinant MV-Edm encoding the human thyroidal iodide symporter (NIS). MV-NIS replicated almost as efficiently as unmodified MV-Edm, and human tumor cells efficiently concentrated radioiodine when infected with MV-NIS. Intratumoral spread of MV-NIS was noninvasively demonstrated by serial gamma-camera imaging of iodine-123 (123I) uptake both in MV-sensitive KAS-6/1 myeloma xenografts, which regressed completely after a single intravenous dose of MV-NIS, and in MM1 myeloma xenografts, which were unresponsive to MVNIS therapy. However, MV-resistant MM1 tumors regressed completely when 131I was administered 9 days after a single intravenous injection of MV-NIS (radiovirotherapy). 131I alone had no effect on MM1 tumor growth. While the potential hematopoietic toxicity of this new therapy requires further evaluation, image-guided radiovirotherapy is a promising new approach to the treatment of multiple myeloma, an incurable but highly radiosensitive plasma cell malignancy. Testing in other radiosensitive cancers is warranted.
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PMID:Image-guided radiovirotherapy for multiple myeloma using a recombinant measles virus expressing the thyroidal sodium iodide symporter. 1460 66

Targeting tumor-associated vascular endothelium by replication-competent viral vectors is a promising strategy for cancer gene therapy. Here we describe the development of a viral vector based on the Edmonston vaccine strain of measles virus targeted to integrin alpha(v)beta3, which is expressed abundantly on activated but not quiescent vascular endothelium. We displayed a disintegrin, M28L echistatin that binds with a high affinity to integrin alpha(v)beta3 on the COOH terminus of the viral attachment (H) protein and rescued the replication-competent recombinant virus by reverse genetics. The new targeted virus was named measles virus echistatin vector (MV-ERV). Its native binding to CD46 was purposefully retained to allow virus infection of tumor cells expressing this receptor. MV-ERV correctly displayed echistatin on the outer surface of its envelope and produced interesting ring formation phenomena due to cell detachment upon infection of susceptible Vero cells in vitro. MV-ERV grew to 10(6) plaque-forming units/mL, slightly lower than the parental Edmonston strain of measles virus (MV-Edm), but it selectively infected Chinese hamster ovary cells expressing integrin alpha(v)beta3. It also selectively infected both bovine and human endothelial cells on matrigels and unlike MV-Edm, MV-ERV infected newly formed blood vessels in chorioallantoic membrane assays. In animal models, MV-ERV but not the control MV-Edm caused the regression of s.c. xenografts of resistant multiple myeloma tumors (MM1) in severe combined immunodeficient mice. The tumors were either completely eradicated or their growth was significantly retarded. The specificity, potency, and feasibility of MV-ERV infection clearly show the potential use of MV-ERV in gene therapy for targeting tumor-associated vasculature for the treatment of solid tumors.
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PMID:Targeted measles virus vector displaying echistatin infects endothelial cells via alpha(v)beta3 and leads to tumor regression. 1595 76

A recombinant measles virus (MV) expressing the sodium iodide symporter (NIS) is being considered for therapy of advanced multiple myeloma. Auger electrons selectively damage cells in which the isotope decays. We hypothesized that the Auger electron emitting isotope 125I can be used to control viral proliferation. MV was engineered to express both carcinoembryonic antigen and NIS (MV-NICE). Cells were infected with MV-NICE and exposed to 125I with appropriate controls. MV-NICE replication in vitro is inhibited by the selective uptake of 125I by cells expressing NIS. Auger electron damage is partly mediated by free radicals and abrogated by glutathione. In myeloma xenografts, control of MV-NICE with 125I was not possible under the conditions of the experiment. MV-NICE does not replicate faster in the presence of radiation. Auger electron emitting isotopes effectively stop propagation of MV vectors expressing NIS in vitro. Additional work is necessary to translate these observations in vivo.
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PMID:Interaction of measles virus vectors with Auger electron emitting radioisotopes. 1617 77

Measles virus (MV) has shown promise as an oncolytic virus in the treatment of different tumor models for human B-cell lymphoma, multiple myeloma, ovarian cancer, and glioma. We have shown that, in a phase I clinical trial, MV vaccine induces tumor regression in cutaneous T-cell lymphoma (CTCL) patients. Here, we investigated in detail, the effect of recombinant MV (rMV) vaccine strain in CTCL cell cultures, and in vivo in established CTCL xenografts in nude mice. The susceptibility of three CTCL cell lines, originating from patients, to rMV was tested by determination of cell surface expression of MV receptors. All cell lines expressed the receptors CD150 and CD46 and were easily infected by rMV and induced complete cell lysis. The cytoreductive activity was apparent in cells forming aggregates, indicating a cell-to-cell spread of MV and cytolysis owing to virus infection. Intratumoral (i.t.) injection of rMV, expressing enhanced green fluorescent protein induced complete regression of large established human CTCL tumors in nude mice, whereas tumors with control treatment progressed exponentially. Immunohistochemical analysis of tumor biopsies, after i.t. treatment, for MV-NP protein complex demonstrated replication of MV within the tumors. The data demonstrate the potential of MV as a therapeutic agent against CTCL.
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PMID:Recombinant measles virus induces cytolysis of cutaneous T-cell lymphoma in vitro and in vivo. 1704 18

Neutralizing antiviral antibodies (Abs) can hinder systemic virotherapy. Here, we used activated T cells as carriers to deliver oncolytic measles viruses (MV) to multiple myeloma xenografts in the presence of anti-MV antibodies (Abs). Virus-infected T cells expressing measles H/F fusogenic envelope glycoproteins could efficiently transfer MV infection by heterofusion, even after exposure to virus-inactivating anti-MV antisera. Severe-combined immunodeficiency (SCID) mice bearing subcutaneous or disseminated human myeloma xenografts were given MV-luciferase (MV-Luc) or MV-Luc-infected T cells intravenously. Indium111 labeling indicated that 1-2% of the virus-infected T cells trafficked to tumors. Preinfected T cells fused with tumor cells in vivo and transferred MV-Luc to tumor xenografts where intratumoral viral spread was monitored non-invasively using bioluminescent imaging. In mice passively immunized with high titers of measles immune serum, intravenous virus and cell delivery were both inhibited. Decreasing the amount of measles immune serum given to mice permitted tumor infection by virus-infected T cells and cell-free virus. In conclusion, virus-loaded T cells may facilitate systemic measles virotherapy in the presence of antiviral Abs and they warrant further investigation as potential MV cell carriers.
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PMID:Evaluation of T cells as carriers for systemic measles virotherapy in the presence of antiviral antibodies. 1705 Dec 48

The innate antiviral responses of tumor cells are often impaired but may still be sufficient to impede the intratumoral spread of an oncolytic virus. Here, we establish that the oncolytic measles virus (MV-eGFP) induces interferon (IFN) production in human myeloma and ovarian cancer cells. In addition, MV gene expression and virus progeny production were inhibited by IFN treatment of these tumor cells. The P gene of wild-type measles virus encodes P/V/C proteins known to antagonize IFN induction and/or response. We therefore engineered MV-eGFP for IFN evasion and more efficient intratumoral spread by arming it with the P gene from wild-type IC-B strain MV, thus generating MV-eGFP-Pwt. The chimeric virus exhibited reduced IFN sensitivity and diminished capacity to induce IFN in BJAB lymphoma, ARH-77 myeloma cells, and activated peripheral blood mononuclear cells. Interestingly, unlike the wild-type MV, MV-eGFP-Pwt was unable to shut down IFN induction completely. In immunocompromised mice bearing human myeloma xenografts, intravenously administered MV-eGFP-Pwt showed significantly enhanced oncolytic potency compared to MV-eGFP. These results indicate that oncolytic viruses are subject to control by the innate immune defenses of human tumor cells and may therefore be more effective if their natural ability to combat innate immunity is maintained.
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PMID:Engineering oncolytic measles virus to circumvent the intracellular innate immune response. 1724 55


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