Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitoguazone (methylglyoxal bisguanylhydrazone, methyl-GAG or MGBG) is a synthetic polycarbonyl derivative with activity in patients with Hodgkin's and non-Hodgkin's lymphoma, head and neck cancer, prostate cancer, and esophageal cancer. Mitoguazone has also recently been documented to have activity in patients with AIDS-related lymphoma. Among anticancer drugs, mitoguazone has a unique mechanism of action via interference with the polyamine biosynthetic pathway. Polyamines stabilize DNA structure by non-covalent cross-bridging between phosphate groups on opposite strands. In addition, mitoguazone causes uncoupling of oxidative phosphorylation. In this study, the ability of mitoguazone to induce apoptosis by inhibiting the polyamine pathway was assessed in three Burkitt's lymphoma cell lines (Raji, Ramos and Daudi) and one prostate carcinoma cell line (MPC 3). Additional evaluations were performed in two human breast cancer cell lines (MCF7 with wild-type p53 and VM4K with mutated p53) to determine whether the p53 tumor suppressor gene was required for efficient apoptosis induction. The present study demonstrated that mitoguazone induces apoptosis in all the different human cancer cell lines tested in a concentration- and time-dependent way, and triggers a p53-independent programmed cell death in the human breast cancer MCF7 cell line.
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PMID:Mitoguazone induces apoptosis via a p53-independent mechanism. 977 8

Death-associated protein kinase (DAP-Kinase) is a novel serine/threonine kinase whose expression is required for gamma interferon-induced apoptosis. A previous study suggested that DAP-Kinase expression may be lost epigenetically in cancer cell lines, because treatment of several nonexpressing cell lines with 5-aza-2'-deoxycytidine resulted in the expression of DAP-Kinase. Using methylation-specific polymerase chain reaction (MSP), we examined the DAP-Kinase CpG island for hypermethylation in cancer. Normal lymphocytes and lymphoblastoid cell lines are unmethylated in the 5' CpG island of DAP-Kinase. However, in primary tumor samples, all Burkitt's lymphomas and 84% of the B-cell non-Hodgkin's lymphomas were hypermethylated in the DAP-Kinase CpG island. In contrast, none of the T-cell non-Hodgkin's lymphoma samples and 15% or less of leukemia samples examined had hypermethylated DAP-Kinase alleles. U937, an unmethylated, DAP-Kinase-expressing leukemia cell line, was treated with gamma interferon and underwent apoptosis; however, Raji, a fully methylated, DAP-Kinase nonexpressing Burkitt's lymphoma cell line, only did so when treated with 5-aza-2'-deoxycytidine followed by gamma interferon. Our findings in cell lines and primary tumors suggest that hypermethylation of the DAP-Kinase gene and loss of gamma interferon-mediated apoptosis may be important in the development of B-cell malignancies and may provide a promising biomarker for B-cell-lineage lymphomas.
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PMID:Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. 1084 15

We showed previously that human malignant non-Hodgkin's lymphomas (NHL) degrade extracellular matrix (ECM) components through the action of metalloproteinases and that elevated expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) correlated with a poor clinical outcome in patients with NHL. In the present study we sought to investigate whether there is any correlation between the expression of gelatinases (MMP-2 and MMP-9), TIMP-1, and the expression of cytokines and growth factors such as interleukin-1beta (IL-1beta), IL-6, IL-10, tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGFbeta), and basic fibroblast growth factor (bFGF) in human NHL. In lymphoma tissues obtained from 32 patients, elevated expression of IL-6 correlated significantly with elevated messenger RNA (mRNA) levels of MMP-9, MMP-2, and TIMP-1. Moreover, in human lymphoid cell lines of B- and T-cell origin (Raji, Jurkat, and NC-37), IL-6 stimulated production of MMP-9 and MMP-2 but not TIMP-1. In the Matrigel invasion assay IL-6 significantly upregulated transmigration of Raji and Jurkat cells, which in turn was inhibited by recombinant human TIMP-1 and anti-MMP-9 and MMP-2 antibodies. We postulate that IL-6 may play a role in the clinical aggressiveness of human NHL by stimulating MMP production.
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PMID:Interleukin-6 regulation of matrix metalloproteinase (MMP-2 and MMP-9) and tissue inhibitor of metalloproteinase (TIMP-1) expression in malignant non-Hodgkin's lymphomas. 1047 38

Midkine (MK) was originally cloned as a product of a retinoic acid-responsive gene. The rationale for studying MK expression is based on previous reports showing that it transforms 3T3 cells, and that it acts as an autocrine growth factor in Wilm's tumors, and that its overexpression has been associated with worse outcome in bladder carcinoma. Besides bladder carcinoma, its expression was reported in various solid tumors. We investigated the expression of MK protein and/or MK gene in biopsied specimens from 40 patients with primary malignant lymphoma, 21 with Hodgkin's disease (HD) and 19 with non-Hodgkin's lymphoma (NHL). Reed-Sternberg (R-S) cells were stained positive in 10 of 16 HD cases evaluated by immunohistochemical method, whereas 18 of 19 NHL cases did not stain, and one B-cell NHL stained weakly positive. Immunostaining analysis was extended to established cell lines and to normal lymphocytes with or without lectin stimulation or with EB virus transformation. Among hematopoietic cells examined, erythro- or megakaryoblastic leukemia cell lines (K562, MEG-01 and UT7) were positive, while normal lymphocytes (except the EB virus-transformed one) and most myeloid and lymphoid cell lines (except Raji cells) were negative. On the contrary, solid tumor cell lines showed high and strongly positive staining including cell lines derived from of lung gastric, colon, and a pancreatic cancer. Using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), which is suitable for the detection of weakly expressed mRNA, the relative ratio of MK mRNA to beta-actin mRNA of samples was measured and compared in cases where RNA was available. The mean values of relative ratio (MK/beta-actin) of HD were almost twice as those of NHL samples, peripheral blood T cells, and spleen B cells. Our findings showed that MK is expressed in Reed-Sternberg cells of HD, and that MK might play a role in the pathogenesis of HD.
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PMID:Midkine expression in Reed-Sternberg cells of Hodgkin's disease. 1075 93

Immunotoxins specific for the CD80 and CD86 antigens were prepared by linking three type 1 ribosome-inactivating proteins (RIPs), namely bouganin, gelonin and saporin-S6, to the monoclonal antibodies M24 (anti-CD80) and 1G10 (anti-CD86). These immunotoxins showed a specific cytotoxicity for the CD80/CD86-expressing cell lines Raji and L428. The immunotoxins inhibited protein synthesis by target cells with IC50s (concentration causing 50% inhibition) ranging from 0.25 to 192 pmol/l as RIPs. The anti-CD80 immunotoxins appeared 1-2 log more toxic for target cells than the anti-CD86 ones. Immunotoxins containing saporin and bouganin induced apoptosis of target cells. The toxicity for bone marrow haemopoietic progenitors of these conjugates was also evaluated. Bouganin and related immunotoxins at concentrations up to 100 nmol/l did not significantly affect the recovery of committed progenitors or of more primitive cells. The saporin-containing immunotoxins at concentrations >/= 1 nmol/l showed some toxicity on colony-forming unit cells (CFU-C). The expression of the CD80 and CD86 molecules is prevalently restricted to antigen-presenting cells and is also strong on Hodgkin and Reed-Sternberg cells in Hodgkin's disease. Present results suggest that immunotoxins targeting type 1 ribosome-inactivating proteins to these antigens could be considered and further studied for the therapy of Hodgkin's disease or other CD80/CD86-expressing tumours.
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PMID:In vitro anti-tumour activity of anti-CD80 and anti-CD86 immunotoxins containing type 1 ribosome-inactivating proteins. 1097 92

The association of Epstein-Barr virus (EBV) with various lymphoid malignancies has been reported. The precise pathogenesis of EBV in malignancies has not yet been elucidated. Latent membrane protein-1 (LMP-1) and Epstein-Barr nuclear antigen-2 (EBNA-2) genes are suspected to be tumorigenic genes. Previous studies suggest that a deletion within the LMP-1 gene may increase the oncogenic potential of EBV. In this study, we analyzed the sequence within the carboxy terminal end of the LMP-1 gene in paraffin-embedded specimens from T-cell lymphomas, Hodgkin's disease (HD), and the buffy coat of peripheral blood from healthy individuals in Japan. Polymerase chain reaction (PCR) was performed using primers spanning the carboxy terminal region of the LMP-1 gene, and sequence analysis was performed to show the exact location of the deletion. The PCR product of the Raji cell line was 161 base pairs (bp), and the LMP-1 gene with deletion was 30 bp shorter in a direct sequence of PCR products. The 30-bp deletion was located in position 168285-168256 of the Raji cell. A deletion within the LMP-1 gene was found in 4 of 25 cases (16%) of EBV-positive T-cell lymphomas, 4 of 10 cases (40%) of EBV-positive HD cases, and 2 of 13 specimens (15%) with amplified PCR products from 49 healthy individuals. The incidence of the 30-bp deletion within the LMP-1 gene in HD was comparable to that of subjects in the United States and Brazil, but the deletion was not found in a high proportion of EBV-positive T-cell lymphoid malignancies. No statistical significance was found regarding the clinical outcome between patients with a deletion within the LMP-1 gene and patients with wild-type LMP. This deletion cannot be considered as simply causing the pathogenesis of EBV-associated lymphoid malignancies in Japan.
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PMID:Frequency of a 30-base pair deletion in the latent membrane protein-1 gene in Epstein-Barr virus-associated lymphomas in Japan. 1103 71

Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Studies of HCV replication and pathogenesis have so far been hampered by the lack of an efficient tissue culture system for propagating HCV in vitro. Although HCV is primarily a hepatotropic virus, an increasing body of evidence suggests that HCV also replicates in extrahepatic tissues in natural infection. In this study, we established a B-cell line (SB) from an HCV-infected non-Hodgkin's B-cell lymphoma. HCV RNA and proteins were detectable by RNase protection assay and immunoblotting. The cell line continuously produces infectious HCV virions in culture. The virus particles produced from the culture had a buoyant density of 1.13 to 1.15 g/ml in sucrose and could infect primary human hepatocytes, peripheral blood mononuclear cells (PBMCs), and an established B-cell line (Raji cells) in vitro. The virus from SB cells belongs to genotype 2b. Single-stranded conformational polymorphism and sequence analysis of the viral RNA quasispecies indicated that the virus present in SB cells most likely originated from the patient's spleen and had an HCV RNA quasispecies pattern distinct from that in the serum. The virus production from the infected primary hepatocytes showed cyclic variations. In addition, we have succeeded in establishing several Epstein-Barr virus-immortalized B-cell lines from PBMCs of HCV-positive patients. Two of these cell lines are positive for HCV RNA as detected by reverse transcriptase PCR and for the nonstructural protein NS3 by immunofluorescence staining. These observations unequivocally establish that HCV infects B cells in vivo and in vitro. HCV-infected cell lines show significantly enhanced apoptosis. These B-cell lines provide a reproducible cell culture system for studying the complete replication cycle and biology of HCV infections.
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PMID:Establishment of B-cell lymphoma cell lines persistently infected with hepatitis C virus in vivo and in vitro: the apoptotic effects of virus infection. 1252 48

The activation of the NF-kappaB family of transcription factors plays a crucial role in oncogenesis. The IkappaB family has the ability to retain the NF-kappaB in an inactive complex in the cytoplasm. Recently, mutations of the IkappaBalpha gene were found in Hodgkin's lymphoma, which allows NF-kappaB proteins to translocate into the nucleus in an active form. In this report, we describe a mutational analysis of IkappaBalpha for primary tumor cells obtained from patients with a variety of hematologic malignancies (acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, hairy cell leukemia, adult T-cell leukemia, and mantle cell lymphoma) as well as 15 leukemia, lymphoma, and myeloma cell lines (HL60, U937, HEL, K562, NALM1, Jurkat, JM, MOLT4, Raji, KS1, OKM2T, OKM3T, F6T, Su9T01, and C2-2). RT-PCR, followed by direct sequencing, was performed and all samples expressed IkappaBalpha. One missense mutation was identified in a primary effusion lymphoma cell line, KS1. However, NF-kappaB (p65) protein was absent from the nucleus of KS1 immunohistochemically, suggesting that the mutation did not alter the function of IkappaBalpha in this case. Taken together, although it is not clear whether normal IkappaBalpha protein was expressed in hematologic malignancies, mutations of IkappaBalpha could be rare events in these diseases, except for Hodgkin's lymphoma. Alterations of other members of NF-kappaB/ IkappaB family proteins might act on the development of hematologic malignancies.
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PMID:Mutational analysis of IkappaBalpha in hematologic malignancies. 1252 85

PDX (10-propargyl-10-deazaaminopterin) is a novel anti-folate with improved membrane transport and polyglutamylation in tumor cells. In prior studies, PDX exhibited enhanced efficacy over methotrexate (MTX) in lung and breast carcinoma xenografts. Because MTX is active in the treatment of aggressive non-Hodgkin's lymphoma (NHL), we compared the efficacy of PDX and MTX against five lymphoma cell lines: RL (transformed follicular lymphoma), HT, SKI-DLBCL-1 (diffuse large B cell), Raji (Burkitt's), and Hs445 (Hodgkin's disease). After 5-day continuous in vitro exposure, PDX demonstrated > 10-fold greater cytotoxicity than MTX in all cell lines (IC50PDX = 3-5 nM, IC50MTX = 30-50 nM). We then compared the in vivo effects of anti-folates against three established human NHL xenografts in NOD/SCID mice. Tumor bearing animals were treated with saline (control) or the maximum tolerated doses of MTX (40 mg/kg) or PDX (60 mg/kg) via an intraperitoneal route twice weekly for 2 weeks. Almost 90% of HT lymphomas treated with PDX completely regressed, whereas, those treated with MTX treatment had only modest growth delays. In two other xenografts, tumor bearing mice had complete regression rates of 56% (RL) and 30% (SKI-DLBCL-1) after PDX therapy. No regressions and only minor growth inhibition was noted after MTX therapy. RT-PCR analysis for the expression of genes involved in folate metabolism demonstrated that increased sensitivity to PDX correlated with higher RFC-1 gene expression with no difference in FPGS or FPGH levels, suggesting that measurement of tumor RFC-1 gene expression level may be a predictor of response to PDX. These results demonstrate that the PDX has markedly greater potential activity against human NHL than MTX and warrants further preclinical and clinical evaluation.
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PMID:Activity of a novel anti-folate (PDX, 10-propargyl 10-deazaaminopterin) against human lymphoma is superior to methotrexate and correlates with tumor RFC-1 gene expression. 1285 5

Chromosomal translocations and somatic mutations occurring in the 5' noncoding region of the BCL6 gene, encoding a transcriptional repressor, are most frequent genetic abnormalities associated with non-Hodgkin B-cell lymphoma and result in deregulated expression of BCL6. However, the significance of deregulated expression of BCL6 in lymphomagenesis and its effect on clinical outcomes of lymphoma patients have remained elusive. In the present study, we established Daudi and Raji B-cell lymphoma cell lines that overexpress BCL6 or its mutant, BCL6-Ala333/343, in which serine residues required for degradation through the proteasome pathway in B-cell receptor-stimulated cells are mutated. BCL6 overexpression did not have any significant effect on cell proliferation, but significantly inhibited apoptosis caused by etoposide, which induced a proteasome-dependent degradation of BCL6. BCL6-Ala333/343 was not degraded after etoposide treatment and strongly inhibited apoptosis. In these lymphoma cell lines, etoposide increased the generation of reactive oxygen species (ROS) and reduced mitochondria membrane potential, both of which were inhibited by the antioxidant N-acetyl-L-cysteine (NAC). NAC also inhibited apoptosis. Furthermore, BCL6 overexpression was found to inhibit the increase in ROS levels and apoptosis in response to etoposide and other chemotherapeutic reagents. These results raise the possibility that deregulated expression of BCL6 may endow lymphoma cells with resistance to chemotherapeutic reagents, most likely by enhancing the antioxidant defense systems.
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PMID:BCL6 overexpression prevents increase in reactive oxygen species and inhibits apoptosis induced by chemotherapeutic reagents in B-cell lymphoma cells. 1288 2


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