Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Follicular lymphoma (FL) is the most common form of low-grade non-Hodgkin's lymphoma. Transformation to diffuse large B cell lymphoma (DLBCL) is an important cause of mortality. Using cDNA microarray analysis we identified 113 transformation-associated genes whose expression differed consistently between serial clonally related samples of FL and DLBCL occurring within the same individual. Quantitative RT-PCR validated the microarray results and assigned blinded independent group of 20 FLs, 20 DLBCLs, and five transformed lymphoma-derived cell lines with 100%, 70%, and 100% accuracy, respectively. Notably, growth factor cytokine receptors and p38beta-mitogen-activated protein kinase (MAPK) were differentially expressed in the DLBCLs. Immunohistochemistry of another blinded set of samples demonstrated expression of phosphorylated p38MAPK in 6/6 DLBCLs and 1/5 FLs, but not in benign germinal centers. SB203580 an inhibitor of p38MAPK specifically induced caspase-3-mediated apoptosis in t(14;18)+/p38MAPK+-transformed FL-derived cell lines. Lymphoma growth was also inhibited in SB203580-treated NOD-SCID mice. Our results implicate p38MAPK dysregulation in FL transformation and suggest that molecular targeting of specific elements within this pathway should be explored for transformed FL therapy.
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PMID:Involvement of multiple signaling pathways in follicular lymphoma transformation: p38-mitogen-activated protein kinase as a target for therapy. 1275 97

A (213)Bi-labeled antibody to CD74 was evaluated as a therapeutic agent for B-cell lymphoma. The alpha-particle emission, with a half-life of 46 min, is appropriate for therapy of micrometastases. The labeled Ab retained full immunoreactivity, and was potent at single-cell kill of the Raji B-lymphoma cell line. Approximately 30 decays of cell-bound (213)Bi was required for a cell kill of 99%, and dosimetry calculations suggested that the cGy dose delivered was sufficient to produce the level of toxicity observed. A non-reactive control Ab, labeled similarly, also produced toxicity, due to decays occurring in the medium, but was approximately 3-fold less potent than the reactive Ab. In a SCID mouse xenograft micrometastatic model, Ab injection at day 2 or day 5 after tumor inoculation resulted in strong, specific suppression of tumor growth, with some apparent cures.
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PMID:Experimental therapy of disseminated B-Cell lymphoma xenografts with 213Bi-labeled anti-CD74. 1449 29

To identify molecular features of neoplasms associated with EB virus, human peripheral blood lymphocytes (huPBL) were isolated from healthy volunteer donors and were transplanted intraperitoneally into SCID mice, and then huPBL/SCID mice were infected with EB virus. Serum levels of human IgG were measured by unidirectional immunodiffusion assay. Human Alu sequence and EBER-1 in tumor tissues were detected with PCR and in situ hybridization. Immunohistochemical staining was used to examine leukocyte differentiation antigens (LCA, L26, UCHL1, PS1), viral gene products (LMP1, EBNA2, BZLF1) and cellular oncoproteins (p53, C-myc, Bcl-2 and Bax). The experiments showed that tumors developed in 24 of 34 surviving huPBL/SCID mice by EBV infection. Histopathological and immunohistochemical observations demonstrated that all of the induced tumors in SCID mice were malignant lymphomas derived from human B-lymphocytes. In situ hybridization showed that tumor cells had EBV-encoded small RNA-1 (i.e. EBER-1). Alu sequence could be amplified by PCR from human genome of tumor tissues. Immunohistochemistry detected positive staining of BZLF1-encoded protein in a small population of tumor cells of almost all cases, and positive staining of LMP1 and EBNA2 only in small number of tumor cells. Human IgG could be found in the serum of 12 SCID mice on the 15th day after huPBL engraftment, and then increased with time and with the development of induced tumors in 6 mice. Positive rates of p53, C-myc, Bcl-2 and Bax expression were 83.33%, 100%, 95.83%, 91.67%, respectively, in 24 cases of the EBV-induced lymphomas. The results indicate that molecular lesions associated with the induced B-cell lymphoma involved EBV infection, expression of oncogenic viral genes, and abnormal expression of cellular oncogenes in human xenografts. Human IgG level in the serum of huPBL/SCID mice can be considered as a useful index for tumor development.
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PMID:[Molecular pathological characteristics of human B-cell lymphomas induced by Epstein-Barr virus]. 1451 11

Simvastatin and pravastatin are inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, and are used as antihypercholesterolemia drugs. Simvastatin, but not pravastatin, binds to the inserted domain of leukocyte function antigen (LFA)-1 and inhibits the function of LFA-1, including adhesion and costimulation of lymphocytes. Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) express high levels of LFA-1 on their surface and grow in tight clumps. Here we show that simvastatin (2 microM) inhibits clump formation and induces apoptosis of EBV-transformed LCLs. The apoptosis-inducing effect of simvastatin depends on binding to the inserted domain of LFA-1. Simvastatin, but not pravastatin, dissociates EBV latent membrane protein 1 from lipid rafts of LCLs, resulting in down-regulation of nuclear factor kappaB activity and induction of apoptosis. Analysis of multiple EBV-positive and -negative cell lines indicated that both LFA-1 and EBV latent membrane protein 1 expression were required for simvastatin's effects. Administration of simvastatin to severe combined immunodeficiency mice followed by inoculation with LCLs resulted in delayed development of EBV lymphomas and prolonged survival of animals. To our knowledge, this is the first report in which a drug that targets LFA-1 has been used to treat B cell lymphoma. These data suggest that simvastatin may have promise for treatment or prevention of EBV-associated lymphomas that occur in immunocompromised persons.
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PMID:Simvastatin induces apoptosis of Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines and delays development of EBV lymphomas. 1504 42

Xenoengraftment of human cells in mice with severe combined immunodeficiency (SCID) has been used as a model system to study the mechanisms of B-cell lymphomagenesis. In the study reported here, we determined that SCID mice can also be used as a model to study angiogenesis in B-cell lymphomas. The C.B-17 scid/scid mice were xenotransplanted with Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCL), and we determined whether CD31, a marker found on endothelial cells, was detected in the human B-cell lymphomas that developed in these mice. Microvessel formation was identified by use of immunohistochemical staining for CD31. To assess possible mechanisms of angiogenic stimulus, we analyzed the expression of interleukin 8 (IL-8), a chemokine documented to promote angiogenesis, in non-small-cell lung cancer and bronchogenic carcinomas. We observed that a panel of LCL and LCL-lymphomas expressed IL-8 mRNA and protein. Neutralization of IL-8, however, did not inhibit lymphomagenesis, suggesting that IL-8 is not essential for angiogenesis in this model. To examine other parameters of angiogenesis, we identified expression of vascular endothelial growth factor in the lymphomas. These data suggest that angiogenesis accompanies EBV-associated B-cell lymphoma development, but IL-8 is not essential for this process. Thus, the SCID mouse model is amenable to testing of anti-angiogenic factors.
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PMID:Model of angiogenesis in mice with severe combined immunodeficiency (SCID) and xenoengrafted with Epstein-Barr virus-transformed B cells. 1513 68

The role of angiogenesis in lymphoproliferative diseases is not well established. We demonstrate here that human lymphoma cells secrete vascular endothelial growth factor (VEGF) and express VEGF receptor 1 (VEGFR-1) and VEGFR-2. Proliferation of non-Hodgkin lymphoma (NHL) cells under serum-free conditions was enhanced by the addition of VEGF and was blocked by VEGFR-1- and VEGFR-2-specific antibodies. To differentiate between VEGF-mediated autocrine and paracrine effects on lymphoma growth, NOD/SCID mice engrafted with human diffuse large B-cell lymphoma (DLBCL) were treated with species-specific antibodies against human VEGFR-1 (6.12), human VEGFR-2 (IMC-1C11), murine VEGFR-1 (MF-1), or murine VEGFR-2 (DC101). Treatment with 6.12 or DC101 (targeting tumor VEGFR-1 and host VEGFR-2) reduced established DLBCL xenograft growth, whereas treatment with IMC-1C11 or MF-1 (targeting tumor VEGFR-1 and host VEGFR-1) had no effect. Decreased tumor volumes after 6.12 and DC101 treatment correlated with increased tumor apoptosis and reduced vascularization, respectively, supporting the presence of autocrine VEGFR-1- and paracrine VEGFR-2-mediated pathways in lymphomagenesis. Inhibition of paracrine VEGF interactions (DC101) in these models was equivalent to their inhibition with rituximab. Combining DC101 with therapeutic agents (rituximab, 6.12, methotrexate) consistently improved tumor responses over those of single-agent therapy. These data support the further clinical development of VEGFR-targeted approaches for the therapy of aggressive DLBCL.
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PMID:Targeting autocrine and paracrine VEGF receptor pathways inhibits human lymphoma xenografts in vivo. 1523 24

Kaposi's sarcoma-associated herpesvirus/human herpesvirus type-8 (KSHV/HHV-8) is associated with primary effusion lymphomas (PEL), a rare form of B-cell lymphoma. PEL cell lines infected with HHV-8, but negative for Epstein-Barr virus (EBV), were analyzed for their tumorigenic potential in a small animal model system. Inoculation of PEL cell lines into non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice results in efficient engraftment and tumorigenesis in vivo. PEL-engrafted NOD/SCID (PEL/SCID) mice displayed malignant ascites development with notable abdominal distension, consistent with the clinical manifestations of PEL in humans. Azidothymidine (AZT, zidovudine) and interferon-alpha (IFN-alpha) induce apoptosis in HHV-8+/EBV- PEL cells in culture, by induction of a tumor necrosis factor-related apoptosis inducing ligand (TRAIL) mediated suicide program and has been proposed as a therapy for herpesvirus-associated lymphomas. Daily injection of AZT and IFN-alpha significantly increased mean survival time (MST) of PEL/SCID mice suggesting that induction of apoptosis in PEL cells in vivo may be exploited as an effective relatively non-toxic therapy targeting HHV-8 infected PEL. These data demonstrate that the PEL/SCID mouse is an important preclinical model to characterize efficacy and anti-tumor mechanisms of new therapeutic targets in vivo and will be useful in the design and testing of agents in viral lymphoproliferative diseases.
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PMID:Inhibition of HHV-8/KSHV infected primary effusion lymphomas in NOD/SCID mice by azidothymidine and interferon-alpha. 1575 7

Antibodies (Abs) conjugated to 177Lu, a relatively low-energy beta-particle emitter, were evaluated in vitro for their cytotoxic activity and in vivo for their therapeutic activity against disseminated B-cell lymphoma xenografts in SCID mice. 177Lu was compared with other beta-particle emitters ((131)I and 90Y), and also with emitters of low-energy electrons (LEEs, meaning Auger and conversion electrons of < 50 keV). The Abs used reacted with CD20, CD74 or HLA-DR, and the target cell was the Raji B lymphoma. Like the other beta-particle emitters, 177Lu was a potent and specific toxic agent in vitro, when conjugated to Abs recognizing high-density antigens. It appeared to be slightly less potent than (131)I per decay, but this difference was relatively small, and would not be a major factor in the selection of the optimal radionuclide for clinical use. The nonspecific toxicity from 177Lu was less than from 90Y, but 177Lu still produced greater nonspecific toxicity in vitro than LEE emitters. The maximum tolerated dose (MTD) of 177Lu-anti-CD74 in SCID mice was 1.81 MBq (49 microCi)/mouse. When this dose was administered on day 5 after tumor inoculation, significant protection was obtained, but considerably less than the protection obtained in previous experiments with LEE emitters (111)In and 67Ga. In conclusion, 177Lu has advantages over other available beta-particle emitters as a therapeutic agent, but its efficacy in the treatment of micrometastases seems to be less than that of LEE emitters, due to greater nonspecific toxicity. This conclusion, however, may not apply to therapy of macroscopic tumors.
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PMID:177Lu-antibody conjugates for single-cell kill of B-lymphoma cells in vitro and for therapy of micrometastases in vivo. 1582 Jul 62

Interleukin-6 (IL-6) plays a central role in the pathogenesis of several autoimmune and inflammatory diseases as well as B-cell lymphoproliferative disorders. This work describes the effects of the recombinant or adenovirally-delivered IL-6 superantagonist Sant7, anti-IL-6 and IL-6 receptor monoclonal antibodies in a severe murine model of human B-cell lymphoma induced in SCID mice by transplantation of an LCL-41 cell line variant (isotype-switched IgM>IgG). Survival of 60% of the animals treated with anti-gp130 was observed up to day 33, while about 20% of the animals survived with anti-gp80 and Sant7 treatment. No survival was observed with the anti-IL-6 monoclonal antibody treatment. No significant change in serum and peritoneal levels of human IL-6 (hIL-6) and soluble human IL-6 receptor (shIL-6R) was observed in the recombinant Sant7-treated group towards the control group. The anti-gp80 monoclonal antibody induced significant increase of both hIL-6R and hIL-6 in serum and peritoneum. The anti-gp130 monoclonal antibody treatment determined a reduction of the seric shIL-6R and a significant increase of the seric hIL-6. Anti-IL-6 monoclonal antibody administration resulted in a reduction of serum and in an increase of peritoneal hIL-6. Treatment with adenoviral Sant7 was associated with a reduction of circulating shIL-6R, hIgG and mSAP. However, only marginal anti-tumor efficacy of the adenoviral Sant7 was observed. Overall, the present data suggest a potential for anti-hIL-6 therapy in B-cell lymphomas. Less severe animal models might be useful to better evaluate Sant7 efficacy alone or in combination with other anti-IL-6 therapeutics.
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PMID:Comparative activity of Sant7 and anti-IL-6, IL-6R monoclonal antibodies in a murine model of B-cell lymphoma. 1606 91

FTY720 is an immunosuppressant developed to prevent organ transplant rejection. Recent studies indicate an additional role for FTY720 in inducing cell apoptosis. We demonstrate here that FTY720 mediates toxic effects in cell lines representing different B-cell malignancies and primary B cells from patients with chronic lymphocytic leukemia (CLL). In contrast to previous reports in T-cell lines, FTY720-induced toxicity in the Raji cell line and primary CLL B cells is independent of activation of caspases or poly(ADP-ribose) polymerase processing. Further, pancaspase inhibitor Z-VAD-fmk failed to rescue these cells from apoptosis mediated by FTY720. FTY720 induced down-regulation of Mcl-1 but not Bcl-2 in CLL B cells. Overexpression of Bcl-2 failed to protect transformed B cells from FTY720-induced apoptosis, suggesting a Bcl-2-independent mechanism. Interestingly, FTY720 induced protein phosphatase 2a (PP2a) activation and downstream dephosphorylation of ERK1/2, whereas okadaic acid at concentrations that inhibited the FTY720-induced PP2a activation also resulted in inhibition of FTY720-mediated apoptosis and restoration of baseline ERK1/2 phosphorylation in primary CLL cells, indicating a role for PP2a activation in FTY720-induced cytotoxicity. Further, FTY720 treatment resulted in significant prolonged survival in a xenograft severe combined immunodeficiency (SCID) mouse model of disseminated B-cell lymphoma/leukemia. These results provide the first evidence for the potential use of FTY720 as a therapeutic agent in a variety of B-cell malignancies, including CLL.
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PMID:FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma. 1776 20


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