Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias

Gojo, Ivana; Jiemjit, Anchalee; Trepel, Jane B.; Sparreboom, Alex; Figg, William D.; Rollins, Sandra; Tidwell, Michael; Greer, Jacqueline M.; Chung, Eun Joo; Lee, Min-Jung; Gore, Steven D.; Sausville, Edward A.; Zwiebel, James A.; Karp, Judith E.

doi:10.1182/blood-2006-05-021873

Cited by 267 publications

(164 citation statements)

References 49 publications

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“…Consistent with this hypothesis, several clinical trials showed reduced toxicity with selective HDAC inhibitors relative to the pan-HDAC inhibitors. For example, hematological toxicities, anemia, and QT prolongation were absent or reduced in clinical trials with class I selective inhibitors entinostat and mocetinostat, 16,17 as compared with pan inhibitors such as SAHA. 18 In addition to their possible use as more effective clinical drugs, isoformselective HDAC inhibitors would be useful chemical tools to study HDAC cell biology.…”

Section: Introductionmentioning

confidence: 99%

Development of an ELISA-Based HDAC Activity Assay for Characterization of Isoform-Selective Inhibitors

2015

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Histone deacetylase (HDAC) proteins are promising targets for cancer treatment, with several HDAC inhibitors used clinically as anticancer drugs. Most HDAC inhibitors nonspecifically interact with all or many of the 11 HDAC isoforms. Isoform-selective HDAC inhibitors would be useful tools to dissect the individual functions of HDAC proteins in cancer formation, in addition to potentially displaying effective anticancer properties. We report here a robust HDAC activity assay for screening selective HDAC inhibitors, which is inspired by the traditional enzyme-linked immunosorbent assay (ELISA). The key feature of the ELISA-based HDAC activity assay is use of mammalian cell-derived HDAC isoforms instead of recombinant proteins. Importantly, the assay was validated with several known HDAC inhibitors. The ELISAbased HDAC activity assay will facilitate the characterization of isoform-selective HDAC inhibitors against mammalian cell-derived HDAC proteins, which will enhance HDAC-centered cancer research and provide a foundation for anticancer drug development.

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Section: Introductionmentioning

confidence: 99%

Development of an ELISA-Based HDAC Activity Assay for Characterization of Isoform-Selective Inhibitors

2015

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“…Thus, it can be used as a tool to discern between relative contributions of these HDACs to cancer types. In addition, MS-275 has been evaluated in Phase I/II clinical trials to treat acute leukemias and solid tumors (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Potentiation of reactive oxygen species is a marker for synergistic cytotoxicity of MS-275 and 5-azacytidine in leukemic cells

Gao¹,

Mobley²,

Miller³

et al. 2008

Leukemia Research

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Epigenetic modifiers are currently in clinical use for various tumor types. Recently, numerous studies supporting the combination of histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors have emerged, encouraging early clinical trials of these agents together. Here we show that MS-275, an HDACi, and 5-azacytidine, a methyltransferase inhibitor, display synergistic cytotoxicity and apoptosis in AML and ALL cells. Intracellular production of reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, is a novel marker for this synergism in ALL cells. These data suggest that assessment of oxidative stress can serve as a marker of the concerted action of MS-275 and 5-azacytidine.

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“…Vorinostat as well as other HDACI such as Entinostat (MS-275) (Gojo et al, 2007) and MGCD0103 (Kell, 2007) -both of them in clinical trials (Kell, 2007;Tomillero & Moral, 2010) -have been shown to exert proapoptotic effects on pancreatic tumor cells and to chemosensitize them to gemcitabine (Arnold et al, 2007;Iwahashi et al, 2011;Sung et al, 2011). These drugs are now being tested in phase I-II trials recruiting advanced pancreatic cancer patients.…”

Section: Histone Deacetylase (Hdacs)mentioning

confidence: 99%

New Targets for Therapy in Pancreatic Cancer

Tinari¹,

Tursi²,

Grassadonia³

et al. 2012

Pancreatic Cancer - Molecular Mechanism and Targets

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Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias

Abstract: MS-275 is

Cited by 267 publications

References 49 publications

Development of an ELISA-Based HDAC Activity Assay for Characterization of Isoform-Selective Inhibitors

Development of an ELISA-Based HDAC Activity Assay for Characterization of Isoform-Selective Inhibitors

Potentiation of reactive oxygen species is a marker for synergistic cytotoxicity of MS-275 and 5-azacytidine in leukemic cells

New Targets for Therapy in Pancreatic Cancer

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