Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incidence of follicular lymphoma in Saudi Arabia is very low compared to that in Western countries. We analyzed 22 diagnosed cases, based on conventional morphology examination and immunohistochemistry, to detect the Bcl-2 gene rearrangement by polymerase chain reaction (PCR). The DNA was extracted from formalin-fixed paraffin-embedded lymph node tissues by the standard xylene treatment and proteinase K digestion method. Rearrangement of the major breakpoint region was evident in 8 of the 22 cases (36%), determined by visualization of a discrete band hybridized with a chemiluminescence-labeled specific probe. Although the number of cases is small, we believe it denotes a normal detection rate for PCR analysis, using DNA isolated from fixed tissue. With the exception of follicular lymphoma, non-Hodgkin's lymphoma (NHL) analyzed included diffuse large cell lymphoma, lymphoblastic lymphoma, chronic lymphocytic leukemia, mucosa-associated lymphoid tissue and mantle zone lymphomas. No Bcl-2 gene rearrangement was detected in any of these cases. No evidence of Bcl-2 minor cluster sequence gene rearrangement was detected in any of the 38 NHL cases analyzed.
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PMID:Detection of BCL-2 gene rearrangement in follicular lymphoma by polymerase chain reaction and chemiluminescence technique. 1735 94

Rituximab (chimeric anti-CD20 monoclonal antibody) is the first Food and Drug Administration approved antitumor antibody and is used in the treatment of B-non-Hodgkin's lymphoma (B-NHL). It is used as single monotherapy or in combination with chemotherapy and has improved the treatment outcome of patients with B-NHL. The in vivo mechanisms of rituximab-mediated antitumor effects include antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cell cytotoxicity (CDC), growth-inhibition and apoptosis. A subset of patients does not initially respond to rituximab and several responsive patients develop resistance to further rituximab treatment. The mechanism of rituximab unresponsiveness is not known. Besides the above-postulated mechanisms, rituximab has been shown to trigger the cells via CD-20. Studies performed with B-NHL cell lines as model systems revealed several novel mechanisms of rituximab-mediated effects that are involved in chemo/immunosensitization and the development of resistance to rituximab. Rituximab has been shown to inhibit the p38 mitogen-activated protein kinase, nuclear factor-kappaB (NF-kappaB), extracellular signal-regulated kinase 1/2 (ERK 1/2) and AKT antiapoptotic survival pathways, all of which result in upregulation of phosphatase and tensin homolog deleted on chromosome ten and Raf kinase inhibitor protein and in the downregulation of antiapoptotic gene products (particularly Bcl-2, Bcl-(xL) and Mcl-1), and resulting in chemo/immunosensitization. Further, rituximab treatment inhibits the overexpressed transcription repressor Yin Yang 1 (YY1), which negatively regulates Fas and DR5 expression and its inhibition leads to sensitization to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Rituximab-resistant clones were generated as model to examine the mechanism of in vivo rituximab unresponsiveness. These clones showed reduced expression of CD20 and hyperactivation of the above antiapoptotic signaling pathways and failure of rituximab to trigger the cells leading to inhibition of ADCC, CDC and chemo/immunosensitization. Interference with the hyperactivated pathways with various pharmacological and proteasome inhibitors reversed resistance. Furthermore, the above findings have identified several gene products that can serve as new prognostic/diagnostic biomarkers as well as targets for therapeutic intervention in B-NHL.
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PMID:Rituximab-induced inhibition of antiapoptotic cell survival pathways: implications in chemo/immunoresistance, rituximab unresponsiveness, prognostic and novel therapeutic interventions. 1753 16

Forty cases of oral cavity non-Hodgkin's lymphoma (NHL) were evaluated for sex, age, location, clinical presentation, and World Health Organization (WHO) histological subtype. Fifty-three percent were female and the mean age was 71. The upper jaw (maxilla or palatal bone), mandible, palatal soft tissue, and vestibule and gingivae (maxillary or mandibular soft tissue involvement only) were, respectively, the most common locations. Swelling, ulceration, and radiographic destruction of bone were the most frequent signs. Most of the lymphomas were of B cell lineage (98%), and the majority of these B cell lymphomas (58%) were histologically subtyped as diffuse large B cell lymphoma, which is considered to have an aggressive clinical course. An immunohistochemical panel was used in the majority of cases to confirm the lineage and to help characterize the subtype. B and T cell specific markers were used to show lineage of the neoplastic cells. Additional markers were used to help confirm specific subtypes that characteristically show specific positivity to some of these antibodies. Molecular studies to detect monoclonal immunoglobulin heavy chain (IgH) gene rearrangements and Bcl-1 and Bcl-2 gene translocations were performed in cases in which the diagnosis was in question. The current WHO classification is also reviewed in detail.
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PMID:Oral non-Hodgkin's lymphoma: review of the literature and World Health Organization classification with reference to 40 cases. 1760 60

Bortezomib, an inhibitor of the 26S proteasome, is currently approved for treatment of multiple myeloma and is being studied for therapy of non-Hodgkin's lymphoma. We found that Epstein-Barr virus (EBV)-positive B cells with type III latency were more susceptible to killing by bortezomib than those with type I latency. Bortezomib induced apoptosis of EBV lymphoblastoid cell lines (LCLs) by inducing cleavage of caspases 8 and 9; apoptosis was inhibited by pretreatment with a pan-caspase inhibitor. Bortezomib reduced the levels of the p50 and p65 components of the canonical NF-kappaB pathway and reduced the level of p52 in the noncanonical NF-kappaB pathway, which is induced by EBV LMP1. Bortezomib inhibited expression of cIAP-1, cIAP-2, and XIAP, which are regulated by NF-kappaB and function as inhibitors of apoptosis. Bortezomib did not inhibit expression of several other antiapoptotic proteins, including Bcl-2 and Bcl-XL. Finally, bortezomib significantly prolonged the survival of severe combined immunodeficiency mice inoculated with LCLs. These findings suggest that bortezomib may represent a novel strategy for the treatment of certain EBV-associated lymphomas.
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PMID:Bortezomib induces apoptosis of Epstein-Barr virus (EBV)-transformed B cells and prolongs survival of mice inoculated with EBV-transformed B cells. 1762 72

DLBCL (diffuse large B-cell lymphoma) is the most common subtype of non-Hodgkin's lymphoma. Current therapy for patients includes chemotherapy and monoclonal antibodies. Although oncogene-targeted therapy is dramatically successful for patients with certain kinds of leukaemias, there are no such agents yet for DLBCL. One reason for this is that several key oncogenes involved in DLBCL pathogenesis are transcription factors, which are difficult to therapeutically target with small molecules. Recent advances in the structural and functional characterization of DLBCL oncogenes have facilitated design of CPPs (cellpenetrating peptides) with potent inhibitory effects on DLBCL and other aggressive lymphomas. CPPs targeting the Bcl (B-cell lymphoma)-6, Bcl-2, Myc and NF-kappaB (nuclear factor kappaB) oncogenic pathways, among others, could improve efficacy and reduce toxicity of anti-lymphoma therapy. Another barrier towards effective therapy in DLBCL is its profound molecular heterogeneity. Combinatorial administration of oncogene-targeted CPPs based on the molecular profiles of individual patient tumours could allow individualized targeted therapy regimens to be developed.
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PMID:Targeting aggressive B-cell lymphomas with cell-penetrating peptides. 1763 52

Mantle cell lymphoma (MCL) represents only 6% of non-Hodgkin's lymphoma but is one of the most active fields of clinical investigation. Front-line therapy appears to benefit from intensification either through high-dose therapy with stem cell transplant consolidation or dose-intense chemotherapy with hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and rituximab. Unfortunately, no standard therapy has been defined, and most patients eventually relapse. An impressive number of novel agents are currently being tested, the bulk of which are biologic agents or targeted therapies. Bortezomib is the first in class of proteasome inhibitors and the first new agent to be approved in relapsed/refractory MCL. Other small molecules have shown encouraging activity, including mTOR and Bcl-2 inhibitors, novel antibodies, and new cytotoxic agents. Future trials will also benefit from new molecular approaches through pharmacogenomics.
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PMID:Mantle cell lymphoma: evolving novel options. 1770 68

Non-Hodgkin lymphoma is a diverse group of lymphoid malignancies treated historically with cytotoxic chemotherapy. Recent technologic advances have enabled the development of new therapies specifically targeted to inhibit various pathways involved in disease pathophysiology. Led by the anti-CD20 monoclonal antibody rituximab, these agents are expected to revolutionize patient care. Several new drugs might have limited single-agent activity but could combine with other targeted therapies to produce significant effects. Although the current level of understanding makes this sort of rational combination challenging, there is evidence that certain combinations might be very effective. Examples include the combination of rituximab with other monoclonal antibodies, immunomodulatory drugs, Bcl-2 inhibitors, and bortezomib. All of these agents face the challenge of optimal integration with rituximab. The strategies most likely to produce initial success will be those that incorporate rituximab in sensitive patients, as well as those that target patient populations with rituximab-refractory disease. Ideally, these studies will incorporate biologic correlates, such that the mechanisms of action and the patients most likely to benefit can be better defined. We discuss several combinations, their rationale, and the clinical evidence that justifies further evaluation.
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PMID:Targeted therapies for non-Hodgkin lymphoma: rationally designed combinations. 1787 44

The present study was undertaken to explore the effect of administration of high doses of sodium selenite on the expression of Bcl-2 in patients with non-Hodgkin's lymphoma (NHL). Fifty patients with newly diagnosed NHL were randomly divided into two groups. Group A-I received standard chemotherapy whereas group A-II received adjuvant sodium selenite 0.2 mg kg-1 day-1 for 30 days in addition to chemotherapy. Enzyme-linked immunosorbent assay was used to assess Bcl-2 at the time of diagnosis and after therapy in the two groups. Sodium selenite administration resulted in significant decline of Bcl-2 level after therapy in group A-II (8.6 +/- 6.9 ng/ml vs 3 6.9 +/- 7.9 ng/ml, P < 0.05). Also, complete response reached 60% in group A-II compared to 40% in group A-I. Significant increase in CD4/CD8 ratio was noticed in group A-II compared to group A-I after therapy (1.45 +/- 0.36 vs 1.10 +/- 0.28 p 0.04). Overall survival time in months was significantly longer in complete remission patients in group A-II (21.87 +/- 1.41) compared to group A-I (19.70 +/- 1.95) (p = 0.01). It is concluded that sodium selenite administration at the dosage and duration chosen acts as a down regulator of Bcl-2 and improves clinical outcome.
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PMID:The impact of high-dose sodium selenite therapy on Bcl-2 expression in adult non-Hodgkin's lymphoma patients: correlation with response and survival. 1791 49

Anti-apoptotic proteins Bcl-2 and Bcl-xL are overexpressed in 80% of non Hodgkin's lymphoma cells and are thought to play an important role in the resistance of lymphoma cells to current chemotherapeutic agents. Gossypol, an orally-active polyphenolic aldehyde derived from the cotton plant, has been known to have potential anti-neoplastic activity. Recently, gossypol was found to bind to the BH3 binding groove of Bcl-xL and with lesser affinity to Bcl-2. The present study was conducted to determine whether gossypol increases the sensitivity of non-Hodgkin's lymphoma cells to the actions of chemotherapeutic agents by potentiating treatment-induced apoptosis. The interactions observed between gossypol and chemotherapeutic drugs were analyzed using the median effect principle (CalcuSyn analysis). Our data showed that treatment of Ramos cells with gossypol not only induced cell arrest on the G(0)/G(1) phase, but also augmented apoptosis and growth inhibition induced by etoposide (VP-16), doxorubicin hydrochloride (ADM), vincristine (VCR), and paclitaxel (taxol). However, when gossypol was combined with cisplatin (DDP) an antagonistic effect was observed. Gossypol-induced cell cycle arrest was accompanied by decreased expression of cyclin D1 in Ramos cells. In addition, the peroxisome proliferator-activated receptor (PARP) pathway is, at least in part, involved in the gossypol-induced apoptosis when combined with VP-16. These data indicate that single-agent gossypol is effective in inhibiting growth of non-Hodgkin's lymphoma cells in vitro and combination studies with certain secondary chemotherapeutic agents further demonstrate it's synergistic cytotoxicity. These findings support future preclinical and clinical studies of gossypol in the treatment of non-Hodgkin's lymphoma.
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PMID:Synergistic cytotoxicity of Bcl-xL inhibitor, gossypol and chemotherapeutic agents in non-Hodgkin's lymphoma cells. 1834 25

Primary central nervous system (PCNS) diffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin's lymphoma whose growth is restricted to the central nervous system and eye. Primary CNS DLBCL has a poor prognosis relative to other extranodal DLBCL. Recently DLBCL has been subclassified as germinal and non-germinal center B-cell types using microarray. Germinal center B-cell DLBCL is associated with better prognosis compared to non-germinal center B-cell group. The objective of the study was to subcategorize the PCNS DLBCL into germinal center and non-germinal center DLBCL using immunohistochemistry and to correlate its prognostic significance. 21 immunocompetent patients were diagnosed with PCNS DLBCL over last 20 years at William Beaumont Hospital. Clinical data on outcome were collected and their specimens were retrieved. Immunohistochemical staining was done using markers, CD20, CD10, Bcl-6, MUM-1, MIB-1, Bcl-2 and by molecular analysis of the immunoglobulin heavy chain gene (IgH) variable region. Immunohistochemistry showed 1/21 (positive cases/examined cases) for CD10, 19/21 for Bcl-6, 19/21 for MUM-1 and 15/21 for Bcl-2. The expression pattern of CD10(-) MUM-1(+) is corresponded to the non-germinal center DLBCL. The MIB-1 index ranged from 40--80% with a mean of 57%, indicating a high proliferation of lymphoma cells. The IgH gene variable region analysis showed monoclonality in 15 of 21 cases (71%). Primary CNS DLBCL has a non-germinal center B-cell phenotype in majority of cases and has a high Bcl-2 positivity and MIB-1 index. These features might be associated with poor prognosis.
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PMID:Activated B-cell immunophenotype might be associated with poor prognosis of primary central nervous system lymphomas. 1825 70


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