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

Histone deacetylase inhibitors (HDACIs) constitute a novel class of targeted drugs that alter the acetylation status of histones and other important cellular proteins. These agents modulate chromatin structure leading to transcriptional changes, induce pleiotropic effects on functional pathways and activate cell death signaling in cancer cells. Anti-neoplastic activity in vitro was shown in several experimental models of cancer, but the exact mechanism of cytotoxicity and responses are not clearly understood. Phase I/II clinical trials of various HDACIs as single agents conducted to date have shown substantial activity in cutaneous T cell lymphoma (CTCL), preliminary activity in Hodgkin's disease and modest activity in myeloid neoplasms. Responses have been rare in solid tumors. Several agents are being tested in combination therapy clinical trials, either as chemosensitizers for cytotoxic chemotherapy or radiation therapy, or in association with DNA methylation inhibitors based on in vitro synergy. In this review, we focus on recent basic and clinical data that highlight the anti-neoplastic role of HDACIs.
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PMID:Histone deacetylase inhibitors as anti-neoplastic agents. 1934 75

Histone deacetylase inhibitors (HDACi) represent a novel class of targeted drugs which alter the acetylation status of several cellular proteins. These agents, modulating both chromatin structure through histone acetylation, and the activity of several non-histone substrates, are at the same time able to determine changes in gene transcription and to induce a plethora of biological effects ranging from cell death induction, to differentiation, angiogenesis inhibition or modulation of immune responses. The impressive anticancer activity observed in both in vitro and in vivo cancer models, together with their preferential effect on cancer cells, have led to a huge effort into the identification and development of HDACi with different characteristics. To date, several clinical trials of HDACi conducted in solid tumors and hematological malignancies have shown a preferential clinical efficacy of these drugs in hematological malignancies, and in particular in cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), Hodgkin lymphoma (HL) and myeloid malignancies. Several agents are also beginning to be tested in combination therapies, either as chemo sensitizing agents in association with standard chemotherapy drugs or in combination with DNA methyltransferase inhibitors (DNMTi) in the context of the so-called "epigenetic therapies", aimed to revert epigenetic alterations found in cancer cells. Herein, we will review HDACi data in hematological malignancies questioning the molecular basis of observed clinical responses, and highlighting some of the concerns raised on the use of these drugs for cancer therapy.
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PMID:Histone deacetylases and epigenetic therapies of hematological malignancies. 2021 79

For years chemotherapy regimens were the only possibility of treating malignant lymphoma. Although good responses could be achieved, a substantial proportion of patients are still not cured. Rituximab's development as an anti-CD20 antibody heralded a new era in treatment approaches for non-Hodgkin lymphomas (NHLs). The evolution of rituximab has led to intense interest in this type of therapeutic approach and to development and approval of the radioimmunoconjugates of rituximab and fully humanised antibodies. In recent years, the knowledge of the cellular and molecular biology of distinct types of NHLs have led to the development of a new class of drugs that specifically targets unique disease-specific pathways. Bendamustine and proteasome inhibitors are already approved in the treatment of individual entities of lymphoma. Histone deacetylase inhibitors, idiotype vaccination and other molecules show promising results in the lymphoma research that they are being verified in ongoing clinical trials.
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PMID:[New treatments of malignant lymphoma--a review]. 2088 60

During the past decade we have witnessed a number of changes in the field of non-Hodgkin lymphoma (NHL), including new entities added to the classification as well as a better understanding of the biology of diffuse large B-cell lymphoma (DLBCL). An understanding of the epigenetics of NHL is also contributing new agents for the management of this disorder. It has become increasingly clear that DLBCL is a biologically and clinically heterogeneous cell type. Two major categories are now recognized: germinal center B cell and activated B-cell (ABC) types. The former is associated with a good prognosis while the latter is known to have a more adverse outcome. With the use of routine immunohistochemical stains, these two types can be identified. The ABC type is known to be NFK-B dependent. NFK-B is a therapeutic target for bortezomib which is being investigated as treatment for this subtype of DLBCL. Several major changes in the classification will be discussed among which the most important are the recognition of so-called borderline entities. One of the two most common of these is the borderline DLBCL/Burkitt tumor (DLBCL/BL) which has features of both DLBCL and Burkitt's lymphoma. Many of the cases in this DLBCL/BL category contain a translocation of MYC as well as BCL2, so-called "double-hit lymphomas" which have a very aggressive clinical behavior. The second common borderline entity is the mediastinal grey zone NHL (MGZL) which has pathological features intermediate between primary mediastinal B-cell lymphoma and nodular sclerosing Hodgkin lymphoma (NSHL). Overlapping clinical features include young age, male predominance, and localized mediastinal presentation. Anecdotal reports suggest MGZL is relatively resistant to Hodgkin-based chemotherapy. Epigenetic therapy represents a new concept. Histone deacetylase inhibitors (HDACi)and DNA methyltransferase inhibitors constitute a promising new class of antineoplastic agents. They modify the expression of genes related to cancer development. In this review, we discuss the role of HDACi in lymphomagenesis as well as in treatment. To understand the benefits of HDACi in lymphoma treatment, we must appreciate the crucial interplay between BCL6, p53, and STAT3. The STAT3 oncogene is involved in the ABC type of DLBCL, an unfavorable and frequently therapy-refractory lymphoma. STAT3 can be effectively suppressed by several HDACi. We will summarize the results of recent trials with HDACi such as romidepsin, panobinostat and valproic acid that have shown significant preliminary activity in recurrent and refractory lymphomas. Their future role in front-line management remains to be determined.
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PMID:Non-Hodgkin's lymphoma: the old and the new. 2203 56

Histone deacetylase inhibitors (HDACI) have allowed pharmacologic manipulation of deregulated genes in cancer cells and have shown single-agent activity against T cell lymphomas, cutaneous T cell lymphomas, mantle cell lymphomas, and Hodgkin disease. The bigger promise of these agents is in enhancing the activity of other targeted therapies. In addition, the effects of HDACI on the immune system and cytokines indicate that HDACI can be useful in the treatment of immune dysfunction underlying tumorigenesis, autoimmune disorders, and graft-versus-host disease. There is also an effort to determine whether class specificity of HDACI has a biologic significance.
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PMID:Role of histone deacetylase inhibitors in the treatment of lymphomas and multiple myeloma. 2252 Sep 85

Mantle cell lymphoma is a mature B cell neoplasm constituting 5-7% of all non-Hodgkin lymphoma. Overall prognosis with current therapeutics remains poor, thus numerous novel agents are currently under investigation. In this review we focus on early phase trials that have demonstrated promise in mantle cell. Constitutive activation of signaling components downstream of the B cell receptor play an important role in the pathobiology of mantle cell lymphoma. Targeting of this signaling pathway has become a focus with specific agents under development including inhibitors of spleen tyrosine kinase, phosphoinositide 3-kinase and Bruton's tyrosine kinase. Promising data also supports further development of BH-3 mimetics, a crucial component of anti-apoptotic signaling. Histone deacetylase inhibitors have an established role in cutaneous T-cell lymphoma and are now under investigation in mantle cell lymphoma as well. With further understanding of cellular signaling, the armamentarium of treatment options will be enhanced, with the hope of improving the prognosis of this disease.
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PMID:Novel agents in mantle cell lymphoma. 2268 55

Diffuse large B cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma. While the initial treatment strategy is highly effective, relapse occurs in 40% of cases. Histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs but their single agent efficacy against relapsed DLBCL has been variable, ranging from few complete/partial responses to some stable disease. However, most patients showed no response to HDACi monotherapy for unknown reasons. Here we show that sensitivity and resistance to the hydroxamate HDACi, PXD101, can be modeled in DLBCL cell lines. Sensitivity is characterized by G 2/M arrest and apoptosis and resistance by reversible G 1 growth arrest. These responses to PXD101 are independent of several negative prognostic indicators such as DLBCL subtype, BCL2 and MYC co-expression, and p53 mutation, suggesting that HDACi might be used effectively against highly aggressive DLBCL tumors if they are combined with other therapeutics that overcome HDACi resistance. Our investigation of mechanisms underlying HDACi resistance showed that cyclin-dependent kinase inhibitors (CKIs), p21 and p27, are upregulated by PXD101 in a sustained fashion in resistant cell lines concomitant with decreased activity of the cyclin E/cdk2 complex and decreased Rb phosphorylation. PXD101 treatment results in increased association of CKI with the cyclin E/cdk2 complex in resistant cell lines but not in a sensitive line, indicating that the CKIs play a key role in G 1 arrest. The results suggest several treatment strategies that might increase the efficacy of HDACi against aggressive DLBCL.
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PMID:A model of sensitivity and resistance to histone deacetylase inhibitors in diffuse large B cell lymphoma: Role of cyclin-dependent kinase inhibitors. 2398 16

Hodgkin lymphoma (HL) relapsing after an autologous hematopoietic cell transplant (HCT) poses a therapeutic challenge. In this setting, salvage chemotherapy (for example, gemcitabine-based, ifosfamide-containing and others) or immunotherapy (for example, brentuximab vedotin) is essential as a bridging-cytoreduction strategy to an allogeneic HCT. Myeloablative allogeneic hematopoietic cell transplantation in relapsed HL is associated with high rates of non-relapse mortality. In carefully selected patients with chemosensitive disease, allografting following lower-intensity conditioning regimens can provide durable disease control rates of about 25-35%. Promising early results with haploidentical and umbilical cord transplantation are noteworthy and are expanding this procedure to patients for whom HLA-matched related or unrelated donors are not available. Unfortunately, a significant number of HL patients relapsing after an autologous HCT are not candidates for allografting because of the presence of resistant disease, donor unavailability or comorbidities. Brentuximab vedotin is approved for HL relapsing after a prior autograft. Rituximab and bendamustine are also active in this setting, albeit with short durations of remission. Histone deacetylase inhibitors (for example, panobinostat, mocetinostat), mTOR inhibitors (for example, everolimus) and immunomodulatory agents (lenalidomide) have shown activity in phase II trials, but currently are not approved for this indication. Second autologous HCT are rarely performed but this approach should not be considered standard practice at this time. The need for effective agents for post autograft failures of HL largely remains unmet. Continuous efforts to ensure early referral of such patients for allogeneic HCT or investigational therapies are the key to improving outcomes of this not-so-good lymphoma.
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PMID:Managing Hodgkin lymphoma relapsing after autologous hematopoietic cell transplantation: a not-so-good cancer after all! 2444 46

Cutaneous T cell lymphomas (CTCL) represent rare extranodal non-Hodgkin's lymphomas, which are characterised by pleomorphic skin lesions and distinct T-cell markers. CTCL is a relatively benign disease in its early stages, but survival rates decrease significantly with progression. Histone deacetylase inhibitors (HDACi) have recently emerged as a new class of targeted anticancer therapies for CTCL, which have been shown to induce growth inhibition, terminal differentiation and apoptosis in various cancers in vitro and in vivo. In addition to the intrinsic anticancer properties of HDACi, recent studies have demonstrated its ability to synergise with phototherapy. In particular, we examine the therapeutic potential of HDACi in combination with ultraviolet A (UV-A) phototherapy, employing a halogenated DNA minor groove binding ligand called UVASens as a photosensitiser. In vitro studies have demonstrated that UVASens is approximately 1000-fold more potent than current psoralens. The extreme photopotency of UVASens allows the use of lower radiation doses minimising the carcinogenic risks associated with the long-term use of phototherapy. Considering, previous findings using the photosensitiser UVASens and potential synergy of HDACi with phototherapy, it was hypothesised that HDACi will augment photochemotherapy-induced cytotoxicity in CTCL MyLa cells. The findings indicated that combinations of UVASens/UV-A photochemotherapy and HDACi significantly decreased cell viability and increased apoptosis and DNA double-strand breaks in MyLa cells.
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PMID:Histone deacetylase inhibitors potentiate photochemotherapy in cutaneous T-cell lymphoma MyLa cells. 2451 45

HB22.7, an anti-CD22 monoclonal antibody has shown consistent preclinical activity against non-Hodgkin lymphoma (NHL). Histone deacetylase inhibitors (HDACi) have demonstrated efficacy in lymphoma and can modulate cell surface receptor expression. To augment the lymphomacidal activity of HB22.7 we examined the combination of AR42 (an HDACi) and HB22.7 in vitro and in vivo. The combination resulted in 10-fold increased potency in 6 NHL cell lines when compared to either drug alone. Both drugs reduced tumor progression in xenografts, but the combination was significantly more efficacious and resulted in regression of established tumors, without toxicity. AR42 inhibited HB22.7-mediated CD22 internalization, suggesting that increased efficacy could be due to higher availability of CD22. Overall, the synergistic effects of HB22.7 and AR42 on in vitro cytotoxicity and in vivo anti-tumor activity make this combination an attractive option for further pre-clinical and clinical evaluation.
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PMID:Histone deacetylase inhibition enhances the lymphomacidal activity of the anti-CD22 monoclonal antibody HB22.7. 2524 Dec 75


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