13 results on '"Kelly WK"'
Search Results
2. Nanoparticles for urothelium penetration and delivery of the histone deacetylase inhibitor belinostat for treatment of bladder cancer.
- Author
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Martin DT, Hoimes CJ, Kaimakliotis HZ, Cheng CJ, Zhang K, Liu J, Wheeler MA, Kelly WK, Tew GN, Saltzman WM, and Weiss RM
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- Animals, Cell Line, Tumor, Drug Carriers metabolism, Drug Delivery Systems, Female, Histone Deacetylase Inhibitors pharmacokinetics, Histone Deacetylase Inhibitors therapeutic use, Humans, Hydroxamic Acids pharmacokinetics, Hydroxamic Acids therapeutic use, Mice, Nanoparticles metabolism, Polyglactin 910 chemistry, Polyglactin 910 metabolism, Sulfonamides pharmacokinetics, Sulfonamides therapeutic use, Urinary Bladder drug effects, Urinary Bladder metabolism, Urinary Bladder pathology, Urinary Bladder Neoplasms metabolism, Urinary Bladder Neoplasms pathology, Urothelium drug effects, Urothelium metabolism, Urothelium pathology, Drug Carriers chemistry, Histone Deacetylase Inhibitors administration & dosage, Hydroxamic Acids administration & dosage, Nanoparticles chemistry, Sulfonamides administration & dosage, Urinary Bladder Neoplasms drug therapy
- Abstract
Nearly 40% of patients with non-invasive bladder cancer will progress to invasive disease despite locally-directed therapy. Overcoming the bladder permeability barrier (BPB) is a challenge for intravesical drug delivery. Using the fluorophore coumarin (C6), we synthesized C6-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs), which were surface modified with a novel cell penetrating polymer, poly(guanidinium oxanorbornene) (PGON). Addition of PGON to the NP surface improved tissue penetration by 10-fold in intravesically-treated mouse bladder and ex vivo human ureter. In addition, NP-C6-PGON significantly enhanced intracellular uptake of NPs compared to NPs without PGON. To examine biological activity, we synthesized NPs that were loaded with the histone deacetylase (HDAC) inhibitor belinostat (NP-Bel-PGON). NP-Bel-PGON exhibited a significantly lower IC50 in cultured bladder cancer cells, and sustained hyperacetylation, when compared to unencapsulated belinostat. Xenograft tumors treated with NP-Bel-PGON showed a 70% reduction in volume, and a 2.5-fold higher intratumoral acetyl-H4, when compared to tumors treated with unloaded NP-PGON., From the Clinical Editor: These authors demonstrate that PLGA nanoparticles with PGON surface functionalization result in greatly enhanced cell penetrating capabilities, and present convincing data from a mouse model of bladder cancer for increased chemotherapy efficacy., (Copyright © 2013 Elsevier Inc. All rights reserved.)
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- 2013
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3. Histone deacetylase inhibitors: biology and mechanism of action.
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Mehnert JM and Kelly WK
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- Angiogenesis Inhibitors physiology, Animals, Antineoplastic Agents therapeutic use, Apoptosis physiology, Cell Cycle physiology, Histone Deacetylases pharmacology, Humans, Neoplasms physiopathology, Enzyme Inhibitors pharmacology, Histone Deacetylase Inhibitors, Histone Deacetylases physiology
- Abstract
Histone deacetylases (HDACs) and histone acetyltransferases are enzymes that regulate chromatin structure and function through the removal and addition, respectively, of the acetyl group from the lysine residues of core nucleosomal histones. This posttranslational modification of histones is an important process in the regulation of gene expression. Aberrant expression and recruitment and disrupted activities of HDACs and histone acetyltransferases have been found in malignant tissues, implicating their involvement in cancer. HDAC inhibitors (HDACIs) function through diverse mechanisms, including the promotion of cell cycle arrest and apoptosis and the inhibition of angiogenesis. Malignant cells appear more sensitive to the proapoptotic effects of HDACIs, underscoring the therapeutic potential of these agents. Multiple HDACIs are currently under investigation in clinical trials, including vorinostat (suberoylanilide hydroxamic acid), which was recently approved by the U.S. Food and Drug Administration for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients with progressive, persistent, or recurrent disease on or after 2 systemic therapies.
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- 2007
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4. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies.
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O'Connor OA, Heaney ML, Schwartz L, Richardson S, Willim R, MacGregor-Cortelli B, Curly T, Moskowitz C, Portlock C, Horwitz S, Zelenetz AD, Frankel S, Richon V, Marks P, and Kelly WK
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- Administration, Oral, Adult, Aged, Aged, 80 and over, Female, Humans, Hydroxamic Acids adverse effects, Hydroxamic Acids pharmacokinetics, Injections, Intravenous, Male, Middle Aged, Vorinostat, Antineoplastic Agents therapeutic use, Enzyme Inhibitors therapeutic use, Hematologic Neoplasms drug therapy, Histone Deacetylase Inhibitors, Hydroxamic Acids administration & dosage
- Abstract
Purpose: To document the toxicity and activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with pretreated hematologic malignancies., Patients and Methods: Two formulations of SAHA (intravenous [IV] and oral) have been assessed in two consecutive phase I trials. In both trials, dose escalation was performed in parallel and independently in patients with solid tumors and hematologic malignancies. Eligible patients were required to have adequate hepatic and renal function, an absolute neutrophil count > or = 500/microL and a platelet count more than 25,000/mL. All patients provided informed consent for study inclusion., Results: A total of 39 patients with hematologic malignancy were enrolled (14 on IV SAHA and 25 on oral SAHA), of whom 35 were treated. The spectrum of diseases included patients with diffuse large B-cell lymphoma (n = 12), Hodgkin's disease (HD; n = 12), multiple myeloma (n = 2), T-cell lymphoma (n = 3), mantle cell lymphoma (n = 2), small lymphocytic lymphoma (n = 2), and myeloid leukemia (n = 2). Major adverse events with the oral formulation included fatigue, diarrhea, anorexia, and dehydration, whereas myelosuppression and thrombocytopenia were more prominent with the IV formulation. Typically, the hematologic toxicities resolved shortly after SAHA was stopped. There was no neutropenic fever or neutropenic sepsis. Reduction in measurable tumor was observed in five patients. One patient with transformed small lymphocytic lymphoma met criteria for complete response, whereas another met the criteria for partial response (PR). One patient with refractory HD had a PR, whereas three patients had stable disease for up to 9 months., Conclusion: These results suggest that SAHA has activity in hematologic malignancies including HD and select subtypes of non-Hodgkin's lymphoma.
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- 2006
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5. Potential role of histone deacetylase inhibitors in mesothelioma: clinical experience with suberoylanilide hydroxamic acid.
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Krug LM, Curley T, Schwartz L, Richardson S, Marks P, Chiao J, and Kelly WK
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- Administration, Oral, Adult, Aged, Cohort Studies, Drug Administration Schedule, Female, Humans, Male, Mesothelioma diagnostic imaging, Mesothelioma pathology, Middle Aged, Pleural Neoplasms diagnostic imaging, Pleural Neoplasms pathology, Tomography, X-Ray Computed, Treatment Outcome, Vorinostat, Enzyme Inhibitors therapeutic use, Histone Deacetylase Inhibitors, Hydroxamic Acids therapeutic use, Mesothelioma drug therapy, Pleural Neoplasms drug therapy
- Abstract
Background: Histone deacetylase inhibitors are a novel class of therapeutic agents that inhibit deacetylate histones and other proteins involved in the regulation of gene expression and cell cycle progression. Phase I trials of intravenous and oral formulations of one such agent, vorinostat (suberoylanilide hydroxamic acid [SAHA]), have shown that it is safe and tolerable, that it inhibits histone deacetylation in peripheral blood mononuclear cells, and that it has a broad range of antitumor activity., Patients and Methods: Thirteen patients with mesothelioma were included in a phase I trial of oral SAHA. All but one had previously been treated with chemotherapy., Results: Four patients completed > or = 6 cycles of therapy; 2 patients demonstrated a partial response. The toxicities in this cohort of patients were similar to those observed in the entire phase I trial: primarily fatigue, dehydration, nausea, and vomiting., Conclusion: Given the dearth of treatment options for patients with advanced mesothelioma who have progressed after first-line chemotherapy, these results are encouraging. A placebo-controlled, randomized phase III study of oral SAHA is now open for patients with mesothelioma in whom treatment with pemetrexed has failed.
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- 2006
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6. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer.
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Kelly WK, O'Connor OA, Krug LM, Chiao JH, Heaney M, Curley T, MacGregore-Cortelli B, Tong W, Secrist JP, Schwartz L, Richardson S, Chu E, Olgac S, Marks PA, Scher H, and Richon VM
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- Administration, Oral, Adult, Aged, Biological Availability, Drug Administration Schedule, Enzyme Inhibitors pharmacokinetics, Female, Hematologic Neoplasms metabolism, Humans, Hydroxamic Acids pharmacokinetics, Male, Maximum Tolerated Dose, Middle Aged, Neoplasms metabolism, Vorinostat, Enzyme Inhibitors administration & dosage, Hematologic Neoplasms drug therapy, Histone Deacetylase Inhibitors, Hydroxamic Acids administration & dosage, Neoplasm Recurrence, Local drug therapy, Neoplasms drug therapy
- Abstract
Purpose: To determine the safety, dosing schedules, pharmacokinetic profile, and biologic effect of orally administered histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with advanced cancer., Patients and Methods: Patients with solid and hematologic malignancies were treated with oral SAHA administered once or twice a day on a continuous basis or twice daily for 3 consecutive days per week. Pharmacokinetic profile and bioavailibity of oral SAHA were determined. Western blots and enzyme-linked immunosorbent assays of histones isolated from peripheral-blood mononuclear cells (PBMNCs) pre and post-therapy were performed to evaluate target inhibition., Results: Seventy-three patients were treated with oral SAHA and major dose-limiting toxicities were anorexia, dehydration, diarrhea, and fatigue. The maximum tolerated dose was 400 mg qd and 200 mg bid for continuous daily dosing and 300 mg bid for 3 consecutive days per week dosing. Oral SAHA had linear pharmacokinetics from 200 to 600 mg, with an apparent half-life ranging from 91 to 127 minutes and 43% oral bioavailability. Histones isolated from PBMNCs showed consistent accumulation of acetylated histones post-therapy, and enzyme-linked immunosorbent assay demonstrated a trend towards a dose-dependent accumulation of acetylated histones from 200 to 600 mg of oral SAHA. There was one complete response, three partial responses, two unconfirmed partial responses, and 22 (30%) patients remained on study for 4 to 37+ months., Conclusions: Oral SAHA has linear pharmacokinetics and good bioavailability, inhibits histone deacetylase activity in PBMNCs, can be safely administered chronically, and has a broad range of antitumor activity.
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- 2005
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7. Drug insight: Histone deacetylase inhibitors--development of the new targeted anticancer agent suberoylanilide hydroxamic acid.
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Kelly WK and Marks PA
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- Cell Death, Chromatin genetics, Clinical Trials as Topic, Gene Expression Regulation, Histones, Humans, Neoplasms genetics, Neoplasms physiopathology, Protein Processing, Post-Translational, Vorinostat, Enzyme Inhibitors therapeutic use, Histone Deacetylase Inhibitors, Hydroxamic Acids therapeutic use, Neoplasms drug therapy
- Abstract
This review focuses on the discovery and development of the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA). Post-translational modifications of the histones of chromatin are important factors in regulating gene expression--so-called epigenetic gene regulation. Acetylation and deacetylation of lysine residues in histone tails, controlled by the activities of HDACs and histone acetyltransferases, are among the most studied post-translational modification of histones. In addition to chromatin protein, transcription factors, cell-signaling regulatory proteins, and proteins regulating cell death are substrates of HDACs and may be altered in function by HDAC inhibitors. HDAC inhibitors have several remarkable aspects. For instance, despite HDACs being ubiquitously distributed through chromatin, SAHA selectively alters the transcription of relatively few genes, and normal cells are at least 10-fold more resistant than transformed cells to SAHA and related HDAC inhibitor-induced cell death. HDAC inhibitors represent a relatively new group of targeted anticancer compounds, which are showing significant promise as agents with activity against a broad spectrum of neoplasms, at doses that are well tolerated by cancer patients. SAHA is one of the HDAC inhibitors most advanced in development. It is in phase I and II clinical trials for patients with both hematologic and solid tumors.
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- 2005
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8. Histone deacetylase inhibitors.
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Kelly WK
- Subjects
- Clinical Trials as Topic, Disease Progression, Drug Therapy, Combination, Enzyme Inhibitors adverse effects, Enzyme Inhibitors pharmacology, Humans, Neoplasms physiopathology, Enzyme Inhibitors therapeutic use, Histone Deacetylase Inhibitors, Histone Deacetylases metabolism, Neoplasms drug therapy
- Published
- 2004
9. Histone deacetylase inhibitors.
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Marks PA, Richon VM, Miller T, and Kelly WK
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- Acetylation drug effects, Acetyltransferases physiology, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Cell Cycle drug effects, Clinical Trials as Topic, Drug Evaluation, Preclinical, Drug Synergism, Enzyme Inhibitors chemistry, Enzyme Inhibitors therapeutic use, Female, Gene Expression Regulation, Neoplastic drug effects, Histone Acetyltransferases, Histone Deacetylases physiology, Humans, Male, Mice, Models, Molecular, Neoplasm Proteins physiology, Protein Processing, Post-Translational drug effects, Antineoplastic Agents pharmacology, Enzyme Inhibitors pharmacology, Histone Deacetylase Inhibitors, Neoplasm Proteins antagonists & inhibitors
- Abstract
The base sequence of DNA provides the genetic code for proteins. The regulation of expression or suppression of gene transcription is largely determined by the structure of the chromatin--referred to as epigenetic gene regulation (Agalioti et al., 2002; Jenuwein and Allis, 2001; Richards and Elgin, 2002; Spotswood and Turner, 2002; Zhang and Reinberg, 2001). Posttranslational modifications of the histones of chromatin play an important role in regulating gene expression. Some of the most extensively studied epigenetic modifications involve acetylation/deacetylation of lysines in the tails of the core histones, which is controlled by the action of histone deacetylases (HDACs) and histone acetyltransferases (HATs). A controlled balance between histone acetylation and deacetylation appears to be essential for normal cell growth (Waterborg, 2002). Alterations in the structure or expression of HATs and HDACs occur in many cancers (Jones and Baylin, 2002; Marks et al., 2001, 2003; Timmermann et al., 2001; Wang et al., 2001). A structurally diverse group of molecules has been developed that can inhibit HDACs (HDACi) (Arts et al., 2003; Bouchain and Delorme, 2003; Curtin and Glaser, 2003; Johnstone and Licht, 2003; Marks et al., 2003; Remiszewski, 2003; Richon et al., 1998; Yoshida et al., 2003). These inhibitors induce growth arrest, differentiation, and?or apoptosis of cancer cells in vitro and in in vivo tumor-bearing animal models. Clinical trials with several of these agents have shown that certain HDACi have antitumor activity against various cancers at doses that are well tolerated by patients (Gottlicher et al., 2001; Kelly et al., 2002a,b; Piekarz et al., 2001; Wozniak et al., 1999).
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- 2004
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10. Histone deacetylase inhibitors: assays to assess effectiveness in vitro and in vivo.
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Richon VM, Zhou X, Secrist JP, Cordon-Cardo C, Kelly WK, Drobnjak M, and Marks PA
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- Animals, Blotting, Western, Cells, Cultured, Electrophoresis, Polyacrylamide Gel, Enzyme Inhibitors therapeutic use, Histones analysis, Humans, Immunohistochemistry, Male, Enzyme Inhibitors pharmacology, Histone Deacetylase Inhibitors, Histone Deacetylases metabolism
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- 2004
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11. Histone deacetylase inhibitors: development as cancer therapy.
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Marks PA, Richon VM, Kelly WK, Chiao JH, and Miller T
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- Histone Deacetylases classification, Humans, Laryngeal Neoplasms drug therapy, Lung pathology, Lung Neoplasms drug therapy, Lung Neoplasms secondary, Histone Deacetylase Inhibitors, Neoplasms drug therapy
- Abstract
Histone deacetylase (HDAC) inhibitors represent a new class of targeted anticancer agents. A number of structural classes of HDAC inhibitors have been developed of which several are in clinical trials, including phenylbutyrate (PB) and related compounds; the hydroxamic acids, suberoylanilide hydroxamic acid (SAHA) and depsipeptide (FK-228); and the benzamides, MS-275 and C1-994. This review will focus on our studies with the hydroxamic acid HDAC inhibitors, of which SAHA is the lead agent. X-ray crystallographic studies with a HDAC homologue (HDLP) demonstrated that the hydroxamic acid group, most of the aliphatic chain and part of the phenyl amino group of SAHA inserts into the pocket-like catalytic site of the enzyme, at the base of which is a zinc molecule. SAHA inhibits the activity of class I and II HDACs and is selective in altering gene expression. SAHA is synergistic in its anticancer activity with radiation, kinase inhibitors, cytotoxic agents and differentiating agents. In phase I clinical trial with orally administered SAHA the agent caused accumulation of acetylated histones in peripheral mononuclear cells and tumour cells, has excellent bioavailability and has shown antitumour activity in patients with haematologic and solid tumours.
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- 2004
12. Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously.
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Kelly WK, Richon VM, O'Connor O, Curley T, MacGregor-Curtelli B, Tong W, Klang M, Schwartz L, Richardson S, Rosa E, Drobnjak M, Cordon-Cordo C, Chiao JH, Rifkind R, Marks PA, and Scher H
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- Acetylation, Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacokinetics, Area Under Curve, Biopsy, Dose-Response Relationship, Drug, Female, Histones metabolism, Humans, Hydroxamic Acids pharmacokinetics, Infusions, Intravenous, Male, Middle Aged, Skin pathology, Time Factors, Treatment Outcome, Vorinostat, Hematologic Neoplasms drug therapy, Histone Deacetylase Inhibitors, Hydroxamic Acids administration & dosage
- Abstract
Purpose: To evaluate the safety, pharmacokinetics, and biological activity of suberoylanilide hydroxamic acid (SAHA) administered by 2-h i.v. infusion in patients with advanced cancer., Experimental Design: SAHA was administered for 3 days every 21 days in part A and 5 days for 1-3 weeks in part B. Dose escalation proceeded independently in patients with solid tumor and hematological malignancies (part B only). Pharmacokinetic studies were performed along with assessment of acetylated histones in peripheral blood mononuclear cells and tumor tissues., Results: No dose-limiting toxicities were observed in 8 patients enrolled in part A (75, 150, 300, 600, and 900 mg/m(2)/day). Among 12 hematological and 17 solid tumor patients enrolled in part B (300, 600, and 900 mg/m(2)/day), therapy was delayed > or = 1 week for grade 3/4 leukopenia and/or thrombocytopenia in 2 of 5 hematological patients at 600 mg/m(2)/day x 5 days for 3 weeks. The maximal-tolerated dose was 300 mg/m(2)/day x 5 days for 3 weeks for hematological patients. One solid patient on 900 mg/m(2)/day x 5 days for 3 weeks developed acute respiratory distress and grade 3 hypotension. The cohort was expanded to 6 patients, and no additional dose-limiting toxicities were observed. Mean terminal half-life ranged from 21 to 58 min, and there was dose-proportional increase in area under the curve. An accumulation of acetylated histones in peripheral blood mononuclear cells up to 4 h postinfusion was observed at higher dose levels. Posttherapy tumor biopsies showed an accumulation of acetylated histones by immunohistochemistry. Four (2 lymphoma and 2 bladder) patients had objective tumor regression with clinical improvement in tumor related symptoms., Conclusions: Daily i.v. SAHA is well tolerated, inhibits the biological target in vivo, and has antitumor activity in solid and hematological tumors.
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- 2003
13. Histone deacetylase inhibitors: from target to clinical trials.
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Kelly WK, O'Connor OA, and Marks PA
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- Benzamides therapeutic use, Clinical Trials as Topic, Humans, Hydroxamic Acids therapeutic use, Peptides, Cyclic therapeutic use, Antineoplastic Agents therapeutic use, Enzyme Inhibitors therapeutic use, Histone Deacetylase Inhibitors, Neoplasms drug therapy
- Abstract
Transformed cells, characterised by inappropriate cell proliferation, do not necessarily lose the capacity to undergo growth arrest under certain stimuli. DNA, genetic information, is packaged in chromatin proteins, for example, histones. The structure of chromatin may be altered by post-translational modifications (e.g., acetylation, phosphorylation, methylation and ubiquitylation) which play a role in regulating gene expression. Two groups of enzymes, histone deacetylases (HDACs) and acetyl transferases, determine the acetylation status of histones. This review focuses on compounds that inhibit HDAC activity. These agents have been shown to be active in vitro and in vivo in causing cancer cell growth arrest, differentiation and/or apoptosis. Several HDAC inhibitors are currently in clinical trials as anticancer agents and, in particular, hydroxamic acid-based HDAC inhibitors have shown activity against cancers at well-tolerated doses.
- Published
- 2002
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