The Experts below are selected from a list of 306 Experts worldwide ranked by ideXlab platform
Sara Pellegrino - One of the best experts on this subject based on the ideXlab platform.
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on resin multicomponent 1 3 dipolar cycloaddition of cyclopentanone proline enamines and sulfonylazides as an efficient tool for the synthesis of amidino Depsipeptide mimics
Amino Acids, 2020Co-Authors: Raffaella Bucci, Stefano Pieraccini, Federico Dapiaggi, Helena Macut, Maurizio Sironi, Emanuela Erba, Maria Luisa Gelmi, Sara PellegrinoAbstract:Depsipeptides are biologically active peptide derivatives that possess a high therapeutic interest. The development of Depsipeptide mimics characterized by a chemical diversity could lead to compounds with enhanced features and activity. In this work, an on-resin multicomponent procedure for the synthesis of amidino Depsipeptide mimics is described. This approach exploits a metal-free 1,3-dipolar cycloaddition of cyclopentanone–proline enamines and sulfonylazides. In this reaction, the obtained primary cycloadduct undergoes a ring opening and molecular rearrangement giving access to a linear sulfonyl amidine functionalized with both a peptide chain and a diazoalkane. The so-obtained diazo function “one pot” reacts with the carboxylic group of N-Fmoc-protected amino acids leading to amidino Depsipeptide mimics possessing a C4 aliphatic chain. An important advantage of this procedure is the possibility to easily obtain amidino-functionalized derivatives that are proteolytically stable peptide bond bioisosteres. Moreover, the conformational freedom given by the alkyl chain could promote the obtainment of cyclic Depsipeptide with a stabilized secondary structure as demonstrated with both in silico calculations and experimental conformational studies. Finally, labeled Depsipeptide mimics can be also synthesized using a fluorescent sulfonylazide in the multicomponent reaction.
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On-resin multicomponent 1,3-dipolar cycloaddition of cyclopentanone–proline enamines and sulfonylazides as an efficient tool for the synthesis of amidino Depsipeptide mimics
Amino Acids, 2019Co-Authors: Raffaella Bucci, Stefano Pieraccini, Federico Dapiaggi, Helena Macut, Maurizio Sironi, Emanuela Erba, Maria Luisa Gelmi, Sara PellegrinoAbstract:Depsipeptides are biologically active peptide derivatives that possess a high therapeutic interest. The development of Depsipeptide mimics characterized by a chemical diversity could lead to compounds with enhanced features and activity. In this work, an on-resin multicomponent procedure for the synthesis of amidino Depsipeptide mimics is described. This approach exploits a metal-free 1,3-dipolar cycloaddition of cyclopentanone–proline enamines and sulfonylazides. In this reaction, the obtained primary cycloadduct undergoes a ring opening and molecular rearrangement giving access to a linear sulfonyl amidine functionalized with both a peptide chain and a diazoalkane. The so-obtained diazo function “one pot” reacts with the carboxylic group of N -Fmoc-protected amino acids leading to amidino Depsipeptide mimics possessing a C4 aliphatic chain. An important advantage of this procedure is the possibility to easily obtain amidino-functionalized derivatives that are proteolytically stable peptide bond bioisosteres. Moreover, the conformational freedom given by the alkyl chain could promote the obtainment of cyclic Depsipeptide with a stabilized secondary structure as demonstrated with both in silico calculations and experimental conformational studies. Finally, labeled Depsipeptide mimics can be also synthesized using a fluorescent sulfonylazide in the multicomponent reaction.
Susan E Bates - One of the best experts on this subject based on the ideXlab platform.
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cardiac studies in patients treated with Depsipeptide fk228 in a phase ii trial for t cell lymphoma
Clinical Cancer Research, 2006Co-Authors: Richard Piekarz, Tito Fojo, John J Wright, Robin A Frye, Seth M Steinberg, David J Liewehr, Douglas R Rosing, Vandana Sachdev, Susan E BatesAbstract:Purpose: The histone deacetylase inhibitor Depsipeptide (FK228) has activity in patients with cutaneous or peripheral T-cell lymphoma. Electrocardiogram abnormalities, thought to be a class effect, were observed in preclinical animal studies and phase I testing and led to the incorporation of intensive cardiac monitoring in an ongoing efficacy trial. Patients and Methods: This report summarizes the cardiac monitoring of 42 patients enrolled and treated on a phase II trial with Depsipeptide. Cardiac evaluations included serial electrocardiograms to evaluate T-wave, ST segment, and QT interval effects and serial serum cardiac troponin I levels and left ventricular ejection fraction (LVEF) evaluations to exclude myocardial damage. Results: Cardiac studies from 282 cycles and 736 doses of Depsipeptide included 2,051 electrocardiograms and 161 LVEF evaluations. Although T-wave flattening (grade 1) or ST segment depression (grade 2) was observed in more than half of the electrocardiograms obtained posttreatment, these electrocardiogram abnormalities were not associated with elevation of cardiac troponin I or with altered left ventricular function. No significant changes in LVEF were observed, even in 16 patients treated for ≥6 months and regardless of prior anthracycline exposure. Posttreatment electrocardiograms had a mean heart rate–corrected QT interval prolongation of 14.4 milliseconds compared with baseline. Electrolyte replacement has been instituted to mitigate potential untoward effects. Conclusion: The data obtained in this study show that the administration of Depsipeptide is not associated with myocardial damage or impaired cardiac function. The potential effect of heart rate–corrected QT interval prolongation remains under study.
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increased mdr1 expression in normal and malignant peripheral blood mononuclear cells obtained from patients receiving Depsipeptide fr901228 fk228 nsc630176
Clinical Cancer Research, 2006Co-Authors: Robert W Robey, Richard Piekarz, Zhirong Zhan, Ganesh Kayastha, Tito Fojo, Susan E BatesAbstract:The increased expression of markers associated with a differentiated phenotype, such as P-glycoprotein (Pgp), follows treatment with histone deacetylase inhibitors. Because Depsipeptide (FR901228, FK228, NSC630176) is a substrate for Pgp, up-regulation of the gene that encodes it, MDR1 , would mean that Depsipeptide induces its own mechanism of resistance. To examine the effect of Depsipeptide on expression of ATP-binding cassette transporters associated with multidrug resistance, the kidney cancer cell lines 108, 121, 127, and 143 were treated with Depsipeptide and evaluated by quantitative reverse transcription-PCR. Increased levels of MDR1 (1.3- to 6.3-fold) and ABCG2 (3.2- to 11.1-fold) but not MRP1 (0.9- to 1.3-fold) were observed. The induced Pgp transported the fluorescent substrates rhodamine 123, bisantrene, calcein-AM, BODIPY-vinblastine, and BODIPY-paclitaxel. In normal peripheral blood mononuclear cells (PBMC) and circulating tumor cells obtained from patients receiving Depsipeptide, increased levels of histone H3 acetylation were found. We next examined MDR1 levels in normal and malignant PBMCs obtained from 15 patients enrolled in clinical trials with Depsipeptide and detected up to a 6-fold increase in normal PBMCs and up to an 8-fold increase in circulating tumor cells after Depsipeptide administration. In one patient with Sezary syndrome, increased MDR1 gene expression was accompanied by increased cell surface Pgp expression in circulating Sezary cells as determined by measurement of MRK-16 staining by flow cytometry. These studies suggest that Depsipeptide induces its own mechanism of resistance and thus provide a basis for clinical trials evaluating Depsipeptide in combination with a Pgp inhibitor.
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t cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy impact of Depsipeptide on molecular markers therapeutic targets and mechanisms of resistance
Blood, 2004Co-Authors: Richard Piekarz, Robert W Robey, Zhirong Zhan, Ganesh Kayastha, Anousheh Sayah, Amina H Abdeldaim, Sonia Torrico, Susan E BatesAbstract:Depsipeptide (FK228) is a novel histone deacetylase inhibitor currently in clinical trials and the first to demonstrate clinical activity in patients. Responses have been observed in patients with T-cell lymphomas, despite prior treatment with multiple chemotherapeutic agents. To better understand the effects of histone deacetylase inhibitors on T-cell lymphoma, the human T-cell lymphoma cell line HUT78 was tested for sensitivity and molecular response to Depsipeptide. Treatment with Depsipeptide, as well as other histone deacetylase inhibitors, caused induction of histone acetylation, induction of p21 expression, and substantial apoptosis without significant cell cycle arrest. Treatment with the caspase inhibitor z-VAD-fmk significantly inhibited Depsipeptide-induced apoptosis, enabling detection of cell cycle arrest. Treatment with Depsipeptide increased expression of the interleukin-2 (IL-2) receptor, and combination with the IL-2 toxin conjugate denileukin diftitox resulted in more than additive toxicity. Cells selected for resistance to Depsipeptide overexpressed the multidrug resistance pump, P-glycoprotein (Pgp). However, cells selected for resistance to Depsipeptide in the presence of a Pgp inhibitor had a Pgp-independent mechanism of resistance. These studies confirm the activity of Depsipeptide in a T-cell lymphoma model and suggest a general sensitivity of T-cell lymphoma to histone deacetylase inhibitors, an emerging new class of anticancer agents. (Blood. 2004;103:4636-4643)
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inhibitor of histone deacetylation Depsipeptide fr901228 in the treatment of peripheral and cutaneous t cell lymphoma a case report
Blood, 2001Co-Authors: Richard Piekarz, Rob Robey, Victor Sandor, Susan Bakke, Wyndham H Wilson, Laila Dahmoush, Douglas M Kingma, Maria L Turner, Rosemary Altemus, Susan E BatesAbstract:Depsipeptide, FR901228, has demonstrated potent in vitro and in vivo cytotoxic activity against murine and human tumor cell lines. In the laboratory, it has been shown to be a histone deacetylase (HDAC) inhibitor. In a phase I trial of Depsipeptide conducted at the National Cancer Institute, 3 patients with cutaneous T-cell lymphoma had a partial response, and 1 patient with peripheral T-cell lymphoma, unspecified, had a complete response. Sezary cells isolated from patients after treatment had increased histone acetylation. These results suggest that inhibition of HDAC is a novel and potentially effective therapy for patients with T-cell lymphoma.
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low concentrations of the histone deacetylase inhibitor Depsipeptide fr901228 increase expression of the na i symporter and iodine accumulation in poorly differentiated thyroid carcinoma cells
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Masaki Kitazono, Zhirong Zhan, Susan E Bates, Rob Robey, Nicholas J Sarlis, Monica C Skarulis, Takashi Aikou, Tito FojoAbstract:Thyroid carcinoma accounts for the majority of deaths from endocrine cancers. A major cause of treatment failure is the inability to trap iodine. Chemotherapeutic agents with differentiating properties have been tried in an attempt to increase iodine uptake. We examined the ability of the novel histone deacetylase (HDAC) inhibitor, Depsipeptide (FR901228), to modulate the expression of thyroid-specific genes. Four cell lines, two derived from follicular thyroid carcinomas (FTC 133 and FTC 236) and two derived from anaplastic thyroid carcinomas (SW-1736 and KAT-4) were used. In these four cell lines, a very low concentration of Depsipeptide (1 ng/mL) increased histone acetylation and expression of both thyroglobulin and the Na+/I− symporter messenger RNAs. After 3 days, messenger RNA levels approached those of a normal thyroid control. Depsipeptide induced increases in 125I accumulation indicated that a functional Na+/I− symporter protein was induced. Transient transfections indicate that the effects are m...
Raffaella Bucci - One of the best experts on this subject based on the ideXlab platform.
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on resin multicomponent 1 3 dipolar cycloaddition of cyclopentanone proline enamines and sulfonylazides as an efficient tool for the synthesis of amidino Depsipeptide mimics
Amino Acids, 2020Co-Authors: Raffaella Bucci, Stefano Pieraccini, Federico Dapiaggi, Helena Macut, Maurizio Sironi, Emanuela Erba, Maria Luisa Gelmi, Sara PellegrinoAbstract:Depsipeptides are biologically active peptide derivatives that possess a high therapeutic interest. The development of Depsipeptide mimics characterized by a chemical diversity could lead to compounds with enhanced features and activity. In this work, an on-resin multicomponent procedure for the synthesis of amidino Depsipeptide mimics is described. This approach exploits a metal-free 1,3-dipolar cycloaddition of cyclopentanone–proline enamines and sulfonylazides. In this reaction, the obtained primary cycloadduct undergoes a ring opening and molecular rearrangement giving access to a linear sulfonyl amidine functionalized with both a peptide chain and a diazoalkane. The so-obtained diazo function “one pot” reacts with the carboxylic group of N-Fmoc-protected amino acids leading to amidino Depsipeptide mimics possessing a C4 aliphatic chain. An important advantage of this procedure is the possibility to easily obtain amidino-functionalized derivatives that are proteolytically stable peptide bond bioisosteres. Moreover, the conformational freedom given by the alkyl chain could promote the obtainment of cyclic Depsipeptide with a stabilized secondary structure as demonstrated with both in silico calculations and experimental conformational studies. Finally, labeled Depsipeptide mimics can be also synthesized using a fluorescent sulfonylazide in the multicomponent reaction.
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On-resin multicomponent 1,3-dipolar cycloaddition of cyclopentanone–proline enamines and sulfonylazides as an efficient tool for the synthesis of amidino Depsipeptide mimics
Amino Acids, 2019Co-Authors: Raffaella Bucci, Stefano Pieraccini, Federico Dapiaggi, Helena Macut, Maurizio Sironi, Emanuela Erba, Maria Luisa Gelmi, Sara PellegrinoAbstract:Depsipeptides are biologically active peptide derivatives that possess a high therapeutic interest. The development of Depsipeptide mimics characterized by a chemical diversity could lead to compounds with enhanced features and activity. In this work, an on-resin multicomponent procedure for the synthesis of amidino Depsipeptide mimics is described. This approach exploits a metal-free 1,3-dipolar cycloaddition of cyclopentanone–proline enamines and sulfonylazides. In this reaction, the obtained primary cycloadduct undergoes a ring opening and molecular rearrangement giving access to a linear sulfonyl amidine functionalized with both a peptide chain and a diazoalkane. The so-obtained diazo function “one pot” reacts with the carboxylic group of N -Fmoc-protected amino acids leading to amidino Depsipeptide mimics possessing a C4 aliphatic chain. An important advantage of this procedure is the possibility to easily obtain amidino-functionalized derivatives that are proteolytically stable peptide bond bioisosteres. Moreover, the conformational freedom given by the alkyl chain could promote the obtainment of cyclic Depsipeptide with a stabilized secondary structure as demonstrated with both in silico calculations and experimental conformational studies. Finally, labeled Depsipeptide mimics can be also synthesized using a fluorescent sulfonylazide in the multicomponent reaction.
John C Byrd - One of the best experts on this subject based on the ideXlab platform.
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A phase 1 and pharmacodynamic study of Depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia
Blood, 2005Co-Authors: John C Byrd, Mark R. Parthun, Jim J. Xiao, Mollie Moran, Thomas S. Lin, Amy R. Sklenar, Shujun Liu, Guido Marcucci, Rebecca B. Klisovic, Melanie E. DavisAbstract:Preclinical studies with the histone deacetylase (HDAC) inhibitor Depsipeptide (FK228) in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) have demonstrated that it effectively induces apoptosis at concentrations at which HDAC inhibition occurs. We initiated a minimum effective pharmacologic dose study of Depsipeptide, targeting an in vivo dose at which acetylation of histone proteins H3 and H4 increased by 100% or more in vitro. Ten patients with CLL and 10 patients with AML were treated with 13 mg/m(2) Depsipeptide intravenously days 1, 8, and 15 of therapy. Neither life-threatening toxicities nor cardiac toxicities were noted, although the majority of patients experienced progressive fatigue, nausea, and other constitutional symptoms that prevented repeated dosing. Several patients had evidence of antitumor activity following treatment, but no partial or complete responses were noted by National Cancer Institute criteria. HDAC inhibition and histone acetylation increases of at least 100% were noted, as well as increases in p21 promoter H4 acetylation, p21 protein, and 1D10 antigen expression. We conclude that Depsipeptide effectively inhibits HDAC in vivo in patients with CLL and AML, but its use in the current schedule of administration is limited by progressive constitutional symptoms. Future studies with Depsipeptide should examine alternative administration schedules.
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a phase 1 and pharmacodynamic study of Depsipeptide fk228 in chronic lymphocytic leukemia and acute myeloid leukemia
Blood, 2004Co-Authors: John C Byrd, Mark R. Parthun, Jim J. Xiao, Amy R. Sklenar, Melanie E. Davis, Guido Marcucci, Rebecca B. Klisovic, Mollie E Moran, David M Lucas, Beth FischerAbstract:Preclinical studies with the histone deacetylase (HDAC) inhibitor Depsipeptide (FK228) in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) have demonstrated that it effectively induces apoptosis at concentrations at which HDAC inhibition occurs. We initiated a minimum effective pharmacologic dose study of Depsipeptide, targeting an in vivo dose at which acetylation of histone proteins H3 and H4 increased by 100% or more in vitro. Ten patients with CLL and 10 patients with AML were treated with 13 mg/m2 Depsipeptide intravenously days 1, 8, and 15 of therapy. Neither life-threatening toxicities nor cardiac toxicities were noted, although the majority of patients experienced progressive fatigue, nausea, and other constitutional symptoms that prevented repeated dosing. Several patients had evidence of antitumor activity following treatment, but no partial or complete responses were noted by National Cancer Institute criteria. HDAC inhibition and histone acetylation increases of at least 100% were noted, as well as increases in p21 promoter H4 acetylation, p21 protein, and [1D10][1] antigen expression. We conclude that Depsipeptide effectively inhibits HDAC in vivo in patients with CLL and AML, but its use in the current schedule of administration is limited by progressive constitutional symptoms. Future studies with Depsipeptide should examine alternative administration schedules. [1]: /lookup/external-ref?link_type=PDB&access_num=1D10&atom=%2Fbloodjournal%2F105%2F3%2F959.atom
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Depsipeptide fr901228 a novel therapeutic agent with selective in vitro activity against human b cell chronic lymphocytic leukemia cells
Blood, 1999Co-Authors: John C Byrd, Charlotte Shinn, Rajani Ravi, Carl R Willis, Jamie K Waselenko, Ian W Flinn, Nancy A Dawson, Michael R GreverAbstract:Therapy of B-cell chronic lymphocytic leukemia (CLL) has been limited by both the nonselectivity of therapeutic agents toward normal residual immune cells and inherent drug resistance. Identification of agents that spare normal immune effector cells, thus facilitating addition of immune-based therapies, and that modulate factors associated with drug resistance in CLL might represent a major therapeutic advance. Depsipeptide (FR901228) is a novel agent entering clinical trials that has selective in vitro activity against resistant leukemia cell lines. To assess its in vitro activity in CLL, we exposed peripheral mononuclear cells from CLL patients (n = 10) to varying concentrations of this agent. Viability of the CLL cells was reduced by 50% (LC 50 ) at 4 hours, 24 hours, and 4 days at Depsipeptide concentrations of 0.038, 0.024, and 0.015 μmol/L, respectively. Depsipeptide had marked selective cytotoxicity when compared with normal blood mononuclear cells, in which the LC 50 was 3.44 μmol/L at 4 hours ( P = .03), 0.965 μmol/L at 24 hours ( P = .01), and 0.0318 μmol/L at 96 hours ( P = .04). Inhibition of bone marrow progenitor cell growth was also minimal after incubation with 0.015 μmol/L (19% inhibition of colony forming unit-granulocyte-macrophage [CFU-GM]; 17% inhibition burst forming unit-erythroid [BFU-E]) and 3.44 μmol/L (24% inhibition of CFU-GM; 57% inhibition BFU-E) of Depsipeptide for 4 hours, followed by a 14-day incubation period. Expression of apoptotic proteins after Depsipeptide exposure (0.015 μmol/L) included no change in bcl-2, elevation of bax, and decreased expression of p27. These data demonstrate that Depsipeptide has significant selective in vitro activity against human CLL cells concurrent with favorable alterations of the bcl-2:bax protein ratio and decrease in p27 expression. Such findings strongly support the early introduction of Depsipeptide into clinical trials for patients with CLL.
Melanie E. Davis - One of the best experts on this subject based on the ideXlab platform.
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A phase 1 and pharmacodynamic study of Depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia
Blood, 2005Co-Authors: John C Byrd, Mark R. Parthun, Jim J. Xiao, Mollie Moran, Thomas S. Lin, Amy R. Sklenar, Shujun Liu, Guido Marcucci, Rebecca B. Klisovic, Melanie E. DavisAbstract:Preclinical studies with the histone deacetylase (HDAC) inhibitor Depsipeptide (FK228) in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) have demonstrated that it effectively induces apoptosis at concentrations at which HDAC inhibition occurs. We initiated a minimum effective pharmacologic dose study of Depsipeptide, targeting an in vivo dose at which acetylation of histone proteins H3 and H4 increased by 100% or more in vitro. Ten patients with CLL and 10 patients with AML were treated with 13 mg/m(2) Depsipeptide intravenously days 1, 8, and 15 of therapy. Neither life-threatening toxicities nor cardiac toxicities were noted, although the majority of patients experienced progressive fatigue, nausea, and other constitutional symptoms that prevented repeated dosing. Several patients had evidence of antitumor activity following treatment, but no partial or complete responses were noted by National Cancer Institute criteria. HDAC inhibition and histone acetylation increases of at least 100% were noted, as well as increases in p21 promoter H4 acetylation, p21 protein, and 1D10 antigen expression. We conclude that Depsipeptide effectively inhibits HDAC in vivo in patients with CLL and AML, but its use in the current schedule of administration is limited by progressive constitutional symptoms. Future studies with Depsipeptide should examine alternative administration schedules.
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a phase 1 and pharmacodynamic study of Depsipeptide fk228 in chronic lymphocytic leukemia and acute myeloid leukemia
Blood, 2004Co-Authors: John C Byrd, Mark R. Parthun, Jim J. Xiao, Amy R. Sklenar, Melanie E. Davis, Guido Marcucci, Rebecca B. Klisovic, Mollie E Moran, David M Lucas, Beth FischerAbstract:Preclinical studies with the histone deacetylase (HDAC) inhibitor Depsipeptide (FK228) in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) have demonstrated that it effectively induces apoptosis at concentrations at which HDAC inhibition occurs. We initiated a minimum effective pharmacologic dose study of Depsipeptide, targeting an in vivo dose at which acetylation of histone proteins H3 and H4 increased by 100% or more in vitro. Ten patients with CLL and 10 patients with AML were treated with 13 mg/m2 Depsipeptide intravenously days 1, 8, and 15 of therapy. Neither life-threatening toxicities nor cardiac toxicities were noted, although the majority of patients experienced progressive fatigue, nausea, and other constitutional symptoms that prevented repeated dosing. Several patients had evidence of antitumor activity following treatment, but no partial or complete responses were noted by National Cancer Institute criteria. HDAC inhibition and histone acetylation increases of at least 100% were noted, as well as increases in p21 promoter H4 acetylation, p21 protein, and [1D10][1] antigen expression. We conclude that Depsipeptide effectively inhibits HDAC in vivo in patients with CLL and AML, but its use in the current schedule of administration is limited by progressive constitutional symptoms. Future studies with Depsipeptide should examine alternative administration schedules. [1]: /lookup/external-ref?link_type=PDB&access_num=1D10&atom=%2Fbloodjournal%2F105%2F3%2F959.atom
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Depsipeptide fr901228 induces histone acetylation and inhibition of histone deacetylase in chronic lymphocytic leukemia cells concurrent with activation of caspase 8 mediated apoptosis and down regulation of c flip protein
Blood, 2003Co-Authors: Jennifer L Aron, Mark R. Parthun, Melanie E. Davis, Guido Marcucci, Shinichi Kitada, Andrew P Mone, Tiansheng Shen, Timothy Murphy, Joseph Wickham, Chris KanakryAbstract:Depsipeptide is in clinical trials for chronic lymphocytic leukemia (CLL) on the basis of earlier observations demonstrating selective in vitro activity in CLL. We sought to determine the relationship of histone H3 and H4 acetylation, inhibition of histone deacetylase, and apoptosis observed in CLL cells to justify a pharmacodynamic end point in these clinical trials. We demonstrate that in vitro Depsipeptide induces histone H3 and H4 acetylation and histone deacetylase enzyme inhibition at concentrations corresponding to the LC50 (concentration producing 50% cell death) for cultured CLL cells (0.038 μM Depsipeptide). The changes in histone acetylation are lysine specific, involving H4 K5, H4 K12, and H3 K9, and to a lesser extent H4 K8, but not H4 K16 or H3 K14. Depsipeptide-induced apoptosis is caspase dependent, selectively involving the tumor necrosis factor (TNF) receptor (extrinsic pathway) initiating caspase 8 and effector caspase 3. Activation of caspase 8 was accompanied by the down-regulation of cellular FLICE-inhibitory protein (c-FLIP, I-FLICE) without evidence of Fas (CD95) up-regulation. Changes in other apoptotic proteins, including Bcl-2, Bax, Mcl-1, and X-linked inhibitor of apoptosis (XIAP), were not observed. Our results demonstrate a relationship between target enzyme inhibition of histone deacetylase, histone H3 and H4 acetylation, and apoptosis involving the TNF-receptor pathway of apoptosis that is not used by other therapeutic agents in CLL. These data suggest use of histone H3 and H4 acetylation, inhibition of histone deacetylase, and down-regulation of FLIP as pharmacodynamic end points for further evaluation of this drug in patients.