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)

In recent years considerable progress has been made in the treatment of patients with B-cell non-Hodgkin lymphoma (NHL). Although responses can be achieved with combination chemotherapy regimens, a substantial proportion of patients are still not cured. In recent years, the knowledge of the cellular and molecular biology of distinct types of B-cell NHL have led to the development of a new class of drugs that specifically targets unique disease-specific pathways. This review will focus on novel therapies that are being developed for the treatment of B-cell NHL including those targeting the B-cell receptor signaling pathway, the proteasome, epigenetic lesions, novel anti-apoptotic drugs, new monoclonal antibodies and immunomodulatory drugs.
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PMID:Emerging therapies for B-cell non-Hodgkin lymphoma. 1976 34

Combinations with proteasome inhibitors are currently being investigated to improve the therapy of hematological malignancies. We previously found that proteasome inhibition by bortezomib failed to sensitize anti-CD30 antibody (Ab)-based lymphoma cell killing. In this study, we demonstrate in L540 Hodgkin's lymphoma cells that proteasome inhibition not only communicates apoptosis but also more rapidly causes a loss of CD30 antigen from cell membrane and a simultaneous release of soluble CD30, a targeting competitor. This shedding was catalyzed by the tumor necrosis factor (TNF)-alpha-converting enzyme (TACE, ADAM17) and blocked by the ADAM17-selective inhibitor, Ro32-7315. In parallel with CD30 shedding, bortezomib caused the generation of reactive oxygen species (ROS). As apoptosis and shedding were inhibited by the radical scavenger, N-acetyl-L-cysteine, ROS might have a pivotal function in both effects. In contrast, the pan-caspase inhibitor, zVAD-fmk, blocked bortezomib-induced apoptosis but not CD30 shedding, and Ro32-7315 blocked shedding but allowed apoptosis. This suggests independent terminal signaling pathways that are conflicting in Ab-based immunotherapy. Consequently, shedding inhibition substantially improved the synergistic antitumor efficacy of the human anti-CD30 Ab, MDX-060, and bortezomib. As proteasome inhibition also stimulated loss of TNF receptors, interleukin-6 receptor and syndecan-1 in different leukemia and lymphoma cell lines, we concluded that proteasome inhibition might impede targeted therapy against antigens susceptible to shedding.
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PMID:TNF-alpha-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive oxygen species. 1989 Mar 73

Mantle cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin lymphomas characterized by the chromosomal translocation t(11;14)(q13;q32) and nuclear cyclin D1 overexpression in the vast majority of cases. Most patients present with advanced stage disease, often with extranodal dissemination, and pursue an aggressive clinical course in the majority of cases. Recent improvement has been achieved by the successful introduction of monoclonal antibodies and dose-intensified approaches including autologous stem cell transplantation (ASCT) strategies. With the exception of allogeneic hematopoietic stem cell transplantation, current treatment approaches are non-curative and the corresponding survival curves are characterized by a delayed, but continuous decline and a median survival of 4 to 6 years. However, recently a subset (15%) of long-term survivors have been identified with a rather indolent clinical course even after conventional treatment strategies only. Emerging strategies such as proteasome inhibitors, IMIDs, mTOR inhibitors and others are based on the dysregulated control of cell cycle machinery and impaired apoptotic pathways. Monotherapy of these compounds achieves efficacy comparable to conventional chemotherapy in relapsed MCL, and combination strategies are currently being investigated in numerous trials; however, their introduction into clinical practice and current treatment algorithms remains a challenge.
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PMID:Current treatment standards and emerging strategies in mantle cell lymphoma. 2000 39

Mantle cell lymphoma (MCL) is a distinct histologic subtype of B cell non-Hodgkins lymphoma (NHL) associated with an aggressive clinical course. Inhibition of the ubiquitin-proteasome pathway modulates survival and proliferation signals in MCL and has shown clinical benefit in this disease. This has provided rationale for exploring combination regimens with B-cell selective immunotherapies such as rituximab. In this study, we examined the effects of combined treatment with bortezomib and rituximab on patient-derived MCL cell lines (Jeko, Mino, SP53) and tumor samples from patients with MCL where we validate reversible proteasome inhibition concurrent with cell cycle arrest and additive induction of apoptosis. When MCL cells were exposed to single agent bortezomib or combination bortezomib/rituximab, caspase dependent and independent apoptosis was observed. Single agent bortezomib or rituximab treatment of Mino and Jeko cell lines and patient samples resulted in decreased levels of nuclear NFkappaB complex(es) capable of binding p65 consensus oligonucleotides, and this decrease was enhanced by the combination. Constitutive activation of the Akt pathway was also diminished with bortezomib alone or in combination with rituximab. On the basis of in vitro data demonstrating additive apoptosis and enhanced NFkappaB and phosphorylated Akt depletion in MCL with combination bortezomib plus rituximab, a phase II trial of bortezomib-rituximab in patients with relapsed/refractory MCL is underway.
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PMID:Combination bortezomib and rituximab treatment affects multiple survival and death pathways to promote apoptosis in mantle cell lymphoma. 2004 72

In mouse models and cell lines, murine double minute 2 (MDM2) and MDM4 have been shown to synergistically promote proteasome-mediated degradation of p21 and p53. MDM4 also inhibits p53-mediated transcriptional activation of p21. p53 expression results in increased p21 expression, a negative cell-cycle regulatory protein and an inhibitor of cyclin D1. As mantle cell lymphoma is characterized by cyclin D1 overexpression, we assessed for human homolog of MDM4 (HDM4) expression and its effect on p21 in mantle cell lymphoma. Using immunohistochemical methods, in reactive lymph nodes (n=19) germinal center cells strongly expressed HDM4 in the nucleus and the cytoplasm, but mantle zone B-cells were only dimly positive. In mantle cell lymphoma tumors, aberrant HDM4 nuclear expression was observed in 18 of 19 (95%) cases. In contrast, HDM4 in other B-cell non-Hodgkin lymphoma types retained its normal pattern of expression. To further characterize the differential upregulation of HDM4 in mantle cell lymphoma, HDM4 was assessed by quantitative real-time polymerase chain reaction in four mantle cell lymphoma cell lines (Granta 519, Z-138, SP-53, and Mino) and six mantle cell lymphoma tumors. Both the splicing variant HDM4-S, containing only the p53-binding domain, and full length HDM4 were increased compared with normal CD19+ B-cells (P<0.05). Using small interfering RNA to inhibit HDM4 in the SP53 and Mino cell lines showed increased p21 and active caspase-3, the latter indicating increased apoptosis. Our results show that HDM4 is overexpressed in mantle cell lymphoma and, at least in part, exerts its effect by suppressing p21 expression, thereby enhancing cell-cycle progression. Inhibition of HDM4 may serve as a potential approach in the design of therapy for patients with mantle cell lymphoma.
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PMID:HDM4 is overexpressed in mantle cell lymphoma and its inhibition induces p21 expression and apoptosis. 2006 13

Mantle cell lymphoma (MCL) is a rare non-Hodgkin lymphoma (NHL) entity. The translocation between chromosomes 11 and 14 is the cytogenetics hallmark of MCL. This translocation leads to the dysregulation of the CCDN1 gene, and overexpression of cyclin D1 which promotes cell cycling. Despite a classical phenotype (CD19+, CD20+, CD5+, CCND1+, CD10-, CD23-, Bcl-2+, Ig at the membrane, mainly IgM), MCL is not a homogeneous disease and several cytological, phenotypic, cytogenetic and clinical variants have been described. MCL represents 5 % of NHLs with its incidence constantly increasing over the last years. Median age at diagnosis is 68 years. Stage III-IV disease is observed in more than 80 % of patients at presentation, with intestinal and bone marrow being the most frequently involved organs, while the spleen is enlarged in half of cases. Intensive strategies including high-dose chemotherapy, followed by autologous stem cell transplantation have significantly improved the outcome of MCL patients. Median overall survival rate increased from 3 to 5 years during the last decade. At present, induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard regimen in younger patients. However, most of MCL patients will experience relapse. Thus, close monitoring of minimal residual disease (currently under evaluation) may represent a valuable tool for assessment of disease response during follow-up. Future innovative therapies that are being presently investigated in prospective trials include transduction pathways inhibitors, proteasome inhibitors, pro-apoptotic molecules, immunotherapy and/or radiolabeled immunotherapy, and will likely open a new era for targeted therapies in MCL.
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PMID:[Mantle cell lymphoma: an overview from diagnosis to future therapies]. 2048 92

Mantle cell lymphoma (MCL) is a well-recognized lymphoma subtype that accounts for about 5% of all patients with non-Hodgkin lymphoma. The clinical course of MCL ranges from an indolent disease to a rapidly progressive malignancy, with a poor prognosis and a median overall survival (OS) of about 3-5 years reported in earlier data sets. Knowledge of its biology has increased in the last few years. Unfortunately, this progress has not yet brought any major improvements in therapeutic approaches, which still remain highly unsatisfactory. Recent improvement has been achieved by the successful introduction of monoclonal antibodies and dose-intensified approaches including autologous stem cell transplantation strategies. However, with the exception of allogeneic hematopoietic stem cell transplantation, current treatment approaches are non-curative, and the corresponding survival curves are characterized by a delayed but continuous decline and a median survival of 4-6 years. In recent years, new insights into the biology of MCL have been obtained which have provided the rationale for the development of novel therapeutic strategies. Emerging new drugs such as bendamustine, proteasome inhibitors, antibodies, mTOR inhibitors, and immunomodulatory drugs and others are based on the dysregulated control of cell cycle machinery and impaired apoptotic pathways. The efficacy of these agents as monotherapy was demonstrated to be comparable to conventional chemotherapy in relapsed MCL, and combination strategies are currently being investigated in clinical trials.
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PMID:Current treatment strategy and new agents in mantle cell lymphoma. 2053 41

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma characterized by CD5 expression and a t(11;14) cytogenetic translocation that results in overexpression of the cyclin D1 gene. Currently, there is no standard of care for the treatment of MCL, and patient prognosis is poor. Traditional treatments for MCL rely on conventional chemotherapy agents, including cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The addition of the immunotherapeutic agent rituximab to this regimen (CHOP-R) has helped to improve patient response to treatment. These treatments often provide good initial responses that are difficult to sustain. Therefore, a number of newer agents and combinations have been investigated to produce more durable benefit. Several of these advances were reported at the 51st American Society of Hematology (ASH) Annual Meeting and Exposition, held December 5-8, 2009 in New Orleans, Louisiana. In this clinical roundtable monograph, new strategies in the treatment of MCL are discussed. Some of the drug classes examined here are proteasome inhibitors, inhibitors of the protein mammalian target of rapamycin (mTOR), the unique alkylating agent bendamustine, and immunomodulatory agents.
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PMID:Clinical roundtable monograph: Recent advances in the treatment of mantle cell lymphoma: a post-ASH 2009 discussion. 2053 72

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma characterized by CD5 expression and a t(11;14) cytogenetic translocation that results in overexpression of the cyclin D1 gene. Currently, there is no standard of care for the treatment of MCL, and patient prognosis is poor. Traditional treatments for MCLrely on conventional chemotherapy agents, including cyclophosphamide, doxorubicin, vincristine, and prednisone(CHOP). The addition of the immunotherapeutic agent rituximab to this regimen (CHOP-R) has helped to improve patient response to treatment. These treatments often provide good initial responses that are difficult to sustain. Therefore, a number of newer agents and combinations have been investigated to produce more durable benefit. Several of these advances were reported at the 51st American Society of Hematology (ASH)Annual Meeting and Exposition, held December 5-8, 2009 in New Orleans, Louisiana. In this clinical roundtable monograph, new strategies in the treatment of MCL are discussed. Some of the drug classes examined here are proteasome inhibitors, inhibitors of the protein mammalian target of rapamycin (mTOR), the unique alkylating agent bendamustine, and immunomodulatory agents.
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PMID:Recent advances in the treatment of mantle cell lymphoma: a post-ASH 2009 discussion. 2055 50

The treatment of lymphoproliferative diseases has changed dramatically during the last decades. The improved therapeutic results for this disease group are included among the most important achievements of modern oncohaematology. They are due to better disease staging, use of new markers for risk assessment, patient stratification in separate risk groups, implementation of highly effective chemotherapy (CHT), progress of targeted therapies using monoclonal antibodies, proteasome inhibitors, modern radiation therapy (RT) and supportive care. The achieved progress, especially in the treatment of Hodgkin's disease (HD), is an example of the fundamental dependence of clinical practice on the scientific achievements, mainly in the field of diagnostics and in the two pure anticancer therapeutic modalities: chemo- and radiotherapy. The aim of this article was to discuss the basic variants of RT in the multimodal treatment of HD and the clinical experience accumulated during the last decades. The experience gained in the area of involved field RT (IFRT) and extended field RT (EFRT), both alone or as a part of the combined-therapy protocols, is considered in detail. The role of RT is also discussed as a part of the dose-escalated CHT combined programmes for patients recurring, progressing or partially responding to treatment, carried out mainly as IFRT, total lymphoid irradiation (TLI) or total body irradiation (TBI). Regardless of the already attained achievements of the combined treatment at the present stage of development of oncological knowledge, there is still no consensus with respect to the optimal therapy of HD in children and in adult patients. New trials addressing issues of the best modality, best RT technique, optimal dose of RT, optimal number of cycles and timing of CHT are still needed. The contemporary challenge is to optimize treatment so that it can be accomplished with the least toxicity, lowest cost, and greatest efficiency possible.
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PMID:Radiation therapy in Hodgkin's disease - decades of steady progress. 2065 14


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