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)

Monoclonal antibodies (mAb) directed against CD20, either unmodified or in radiolabeled forms, have been successfully exploited in clinic as effective therapeutic agents in the management of non-Hodgkin's B-cell lymphoma. The antibody fragment is a potential agent in image and therapy of tumor. To further improve the soluble expression of anti-CD20 antibody Fab' fragment, PCR was used to mutate the anti-CD20 VL and VH genes and its biological activity was identified. The expression vector of chimeric antibody Fab' was constructed and expressed in E. coli. The data of mutant clone DNA sequence showed that the amino acid of light chain gene of the parent anti-CD20 antibody (H47) was successful mutated as Ser (GAG)-Asn (CAG). The soluble expression of mutated anti-CD20 Fab' (CD20-7) was 3.8 mg/g dry cell weight, while the parent (CD20-2) was 1.3 mg/g dry cell weight. The affinity constant Ka of CD20-7 was 2.2 x 10(9) L/mol. The primary results of competitive assays by FACS showed that CD20-7 could partially block the sites through which parent antibody (HI47) bind to Raji cells. There was difference in the Raji cells (CD20+)-binding activity between the mutant CD20-7 and parent CD20-2. The site mutation of anti-CD20 Fab' gene make it possible that the anti-CD20 antibody fragment was succeeded to obtain higher expression. In this thesis, we succeeded in completing mutation and expression of anti-CD20 Fab' genes, distinguishing its biological activity, and obtaining its highly expression. These period results will lay a foundation for development of other kind of anti-CD20 engineering antibody (for instance: Fab' Diabody and miniantibody), and make it possible for anti-CD20 antibody to be applied to tumor therapy in civil in the future.
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PMID:[One amino acid mutation in an anti-CD20 antibody fragment that affects the yield bacterial secretion and the affinity]. 1596 5

Antibody-targeted liposomal anticancer drugs combine the specificity of antibodies with large payloads of entrapped drugs. We previously showed that liposomal doxorubicin (DXR) targeted via anti-CD19 monoclonal antibodies (mAb) or their Fab' fragments against the B-cell antigen CD19 led to improved therapeutic effects in murine B-cell lymphoma models relative to non-targeted liposomal DXR. We now are examining the use of anti-CD19 single chain fragments of the antibody variable region (scFv) as a targeting moiety, to test the hypothesis that scFv have advantages over full-sized mAb or Fab' fragments. We expressed two different anti-CD19 scFv constructs, HD37-C and HD37-CCH in E. coli, and purified the scFvs using two different methods. The HD37-CCH construct was selected for coupling studies due to its relative stability and activity in comparison to HD37-C. When coupled to liposomes, the HD37-CCH scFv showed increased binding in vitro to CD19-positive Raji cells, compared to non-targeted liposomes. Cytotoxicity data showed that HD37-CCH scFv-targeted liposomes loaded with DXR were more cytotoxic than non-targeted liposomal DXR. Our results suggest that anti-CD19 scFv constructs should be explored further for their potential in treating B-lymphoid leukemias and lymphomas.
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PMID:Expression and purification of two anti-CD19 single chain Fv fragments for targeting of liposomes to CD19-expressing cells. 1704 11

To investigate the roles of interferon regulatory factor 4 (IRF4) in B-cell development, we established germinal center B cell-derived Burkitt's lymphoma cell lines that exogenously express IRF4. Daudi-IRF4 expressed IRF4 in the presence of doxycycline (inducible expression), and Raji-IRF4 constitutively expressed an IRF4-estrogen receptor chimeric protein, which was activated by 4-hydroxytamoxifen. Expression or activation of IRF4 resulted in growth inhibition accompanied by accumulation of cells in G0/G1. Upregulation of the plasma cell markers CD38 and CD138 and downregulation of the germinal center cell marker B-cell lymphoma 6 (BCL6) were also observed. Furthermore, mRNAs for BCL6 and paired box gene 5 (PAX5) were decreased and those for B-lymphocyte-induced maturation protein-1 (BLIMP1)/PR domain containing 1 (PRDM1) and X-box binding protein 1 (XBP1) were increased, which corresponds to the characteristic changes in transcription factor expression in B cells differentiating toward plasma cells. Impairment in proliferation and differentiation toward plasma cells induced by IRF4 were not inhibited by enforced expression of BCL6. These results suggest that IRF4 inhibits cell cycle progression of germinal center B cell-derived Burkitt's lymphoma cells and induces terminal differentiation toward plasma cells through mechanisms independent of BCL6 downregulation.
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PMID:IRF4 negatively regulates proliferation of germinal center B cell-derived Burkitt's lymphoma cell lines and induces differentiation toward plasma cells. 1765 61

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

Recently, it has been found that inappropriate expression of microRNAs (miRNAs) is strongly associated with carcinogenesis. In this study, we demonstrated that the expression of miRNAs (miRs) -143 and -145, the levels of which were previously shown to be reduced in colon cancers and various kinds of established cancer cell lines, was also decreased in most of the B-cell malignancies examined, including chronic lymphocytic leukemias (CLL), B-cell lymphomas, Epstein-Barr virus (EBV)-transformed B-cell lines, and Burkitt lymphoma cell lines. All samples from 13 CLL patients and eight of nine B-cell lymphoma ones tested exhibited an extremely low expression of miRs-143 and -145. The expression levels of miRs-143 and -145 were consistently low in human Burkitt lymphoma cell lines and were inversely associated with the cell proliferation observed in the EBV-transformed B-cell lines. Moreover, the introduction of either precursor or mature miR-143 and -145 into Raji cells resulted in a significant growth inhibition that occurred in a dose-dependent manner and the target gene of miRNA-143 was determined to be ERK5, as previously reported in human colon cancer DLD-1 cells. Taken together, these findings suggest that miRs-143 and -145 may be useful as biomarkers that differentiate B-cell malignant cells from normal cells and contribute to carcinogenesis in B-cell malignancies by a newly defined mechanism.
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PMID:Downregulation of microRNAs-143 and -145 in B-cell malignancies. 1789 14

CD19 and CD21 (CR2) are co-receptors found on B-cells and various B-cell lymphomas, including non-Hodgkin lymphoma. To evaluate their suitability as targets for therapy of such lymphomas using internalization-dependent antibody-drug conjugates [such as antibody-4-(N-maleimidomethyl)cyclohexane-1-carboxylate, (N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine) (MCC-DM1) conjugates, which require lysosomal degradation of the antibody moiety for efficacy], we examined uptake of antibodies to CD19 and CD21 in a panel of B-cell lines. Anti-CD21 antibodies were not sufficiently internalized even in the highest CD21-expressing Raji cells, resulting in lack of efficacy with anti-CD21-MCC-DM1 conjugates. Anti-CD19 antibody uptake was variable, and was unexpectedly negatively correlated with CD21 expression. Thus, high CD21-expressing Raji, ARH77 and primary B-cells only very slowly internalized anti-CD19 antibodies, while CD21-negative or low expressing cells, including Ramos and Daudi, rapidly internalized these antibodies in clathrin-coated vesicles followed by lysosomal delivery. Anti-CD19-MCC-DM1 caused greater cytotoxicity in the faster anti-CD19-internalizing cell lines, implying that the rate of lysosomal delivery and subsequent drug release is important. Furthermore, transfection of Ramos cells with CD21 impeded anti-CD19 uptake and decreased anti-CD19-MCC-DM1 efficacy, suggesting that CD21-negative tumours should respond better to such anti-CD19 conjugates. This may have possible clinical implications, as anti-CD21 immunohistochemistry revealed only approximately 30% of 54 diffuse large B-cell lymphoma patients lack CD21 expression.
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PMID:High CD21 expression inhibits internalization of anti-CD19 antibodies and cytotoxicity of an anti-CD19-drug conjugate. 1799

To determine the most robust and reproducible parameters for noninvasively estimating tumor cell burden in a murine model, we used real-time in vivo bioluminescent imaging to assess the growth kinetics and dissemination of luciferase-transfected Raji B-cell lymphoma. Bioluminescent signals were acquired every minute for 40 minutes after luciferin injection every other day post-tumor injection. The total 40-minute area under the curve (AUC) of photon intensity (photons/second) was calculated and compared with simplified fixed time point observations (every 5 minutes from 5 to 40 minutes after substrate injection). There was substantial variability in the shape of the time signal intensity curves at different stages of tumor growth in both the intravenous and subcutaneous models. The coefficient of variance in the AUC was 0.27 (intravenous) and 0.36 (subcutaneous) as values determined by fitting the curve, whereas the 20-minute time point measurement varied at 0.29 (intravenous) and 0.37 (subcutaneous). In both the subcutaneous and intravenous models, single time point measurements at 20 minutes had the highest correlation value with AUC. This simplified single time point measurement appears appropriate to estimate the total tumor burden in this model, but the substantial variance at each measurement must be considered in experimental designs.
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PMID:How reproducible is bioluminescent imaging of tumor cell growth? Single time point versus the dynamic measurement approach. 1809 16

A systematic study was designed to elucidate differences in cytostatic activity in vitro between HPMA-based doxorubicin conjugates synthesized using different polymerization techniques and differing in peptidyl side chain. A polymer-drug conjugate containing doxorubicin (DOX) bound to HPMA copolymer backbone through the enzymaticaly non-cleavable sequence GlyGly shows low but significant cytotoxicity in vitro in seven cancer cell lines of mouse (EL4, 38C13, 3T3, BCL1) and human (SW620, Raji, Jurkat) origin. The low cytotoxicity can be considerably increased by the presence of additional drug-free GlyPheLeuGly side chains. P1 conjugate, i.e. non-targeted HPMA copolymer bearing doxorubicin bound via a biodegradable GlyPheLeuGly sequence, synthesized by direct copolymerization of HPMA with monomeric doxorubicin and thus without additional drug-free GlyPheLeuGly sequences is less effective compared to PK1 synthesized by polymer analogous reaction and thus containing extra drug-free GlyPheLeuGly sequences. Significant activity-enhancing effect was not seen with other amino acid/oligopeptide sequences (e.g., Gly or GlyGly). The activity-enhancing effect of GlyPheLeuGly sequences is more obvious in the conjugate containing doxorubicin bound to HPMA through GlyGly sequence. Derivatization of the terminal carboxyl group of the extra GlyPheLeuGly side chains (amide, N-substituted amide, free carboxyl) does not significantly influence the cytotoxicity of the conjugates. The presence of the GlyPheLeuGly sequence in the conjugate structure increases its rate of intracellular accumulation. Normal cells (Balb/c splenocytes) accumulate less polymer-doxorubicin conjugate compared to cancer cells (T cell lymphoma EL4, B cell lymphoma Raji and T cell leukemia JURKAT).
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PMID:Doxorubicin release is not a prerequisite for the in vitro cytotoxicity of HPMA-based pharmaceuticals: in vitro effect of extra drug-free GlyPheLeuGly sequences. 1832 18

Despite the effectiveness of the anti-CD20 monoclonal antibody (mAb) Rituximab (C2B8) in the treatment of B-cell lymphoma, its efficacy remains variable and often modest. It seems likely that a combination of multiple mechanisms, such as complement-dependent cytotoxicity (CDC) and apoptotic signaling, underlies the therapeutic success of anti-CD20 mAbs. Unfortunately, all the current anti-CD20 mAbs effective in CDC are relatively inactive in signaling cell death and vice versa. In this study, we developed two genetically engineered tetravalent antibodies (TetraMcAb) respectively derived from the anti-CD20 mAbs C2B8 and 2F2. TetraMcAbs, with a molecular mass only 25 kDa higher than native divalent antibodies (DiMcAb), were shown not only to be as effective in mediating CDC and antibody-dependent cellular cytotoxicity against B-lymphoma cells as DiMcAbs but also to have antiproliferative and apoptosis-inducing activity markedly superior to that of DiMcAbs. Interestingly, whereas 2F2 and C2B8 were equally effective in inducing cell growth arrest and apoptosis, the functions of their tetravalent versions, 2F2(ScFvHL)(4)-Fc and C2B8(ScFvHL)(4)-Fc, were significantly different. 2F2(ScFvHL)(4)-Fc exhibited exceptionally more potent antiproliferative and apoptosis-inducing activity than that of C2B8(ScFvHL)(4)-Fc. Immunotherapeutic studies further showed that 2F2(ScFvHL)(4)-Fc was far more effective in prolonging the survival of severe combined immunodeficient mice bearing systemic Daudi or Raji tumors than C2B8, 2F2, and C2B8(ScFvHL)(4)-Fc, suggesting that it might be a promising therapeutic agent for B-cell lymphoma.
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PMID:Development of novel tetravalent anti-CD20 antibodies with potent antitumor activity. 1838 48

Rituximab, a CD20-reactive chimeric monoclonal antibody (mAb), induces apoptosis of lymphoma cells and promotes phagocytosis by dendritic cells and produces a cellular immunoresponse by cross-presentation of tumor antigens to T cells. Heat-stressed tumor cells also stimulate dendritic-cell maturation and induce specific cytotoxic T cells against tumor cells by inducing expression of heat-shock proteins. In this study, we used heat-stressed and rituximab-coated CD20+ lymphoma cells as antigens to load onto immature dendritic cells, and found that rituximab-coated CD20+ Raji cells could promote phagocytosis by dendritic cells, and that rituximab-coated or heat-stressed and then rituximab-coated CD20+ Raji cells resulted in increased dendritic cell maturation. Moreover, only CD20+ Raji cells treated with heat and rituximab effectively enhanced the immunostimulating functions of dendritic cells. Thus, our data indicate that rituximab and heat-shock proteins have synergistic effects, resulting in increased induction of cytotoxic T cells against B-cell lymphoma.
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PMID:Enhancement of anti-lymphoma immuno-effects mediated by dendritic cells pulsed with heat-stressed and rituximab-coated CD20+ lymphoma cells. 1841 83


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