The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all‐trans retinoic acid in patients with acute myeloid leukemia

@article{Kuendgen2006TheHD,
  title={The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all‐trans retinoic acid in patients with acute myeloid leukemia},
  author={A. Kuendgen and Mathias Schmid and Richard F. Schlenk and Sabine Knipp and Barbara Hildebrandt and Christian Steidl and Ulrich Germing and Rainer Haas and Hartmut Dōhner and Norbert Gattermann},
  journal={Cancer},
  year={2006},
  volume={106}
}
Valproic acid (VPA) inhibits histone deacetylase activity and, synergizing with all‐trans retinoic acid (ATRA), achieves differentiation induction of myeloid blast cells in vitro. 
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Will histone deacetylase inhibitors require combination with other agents to fulfil their therapeutic potential?
TLDR
This review highlights the promising data for their combination with a wide range of established and novel anticancer agents and discusses the mechanisms that underpin these interactions.
Valproic acid combined with 13-cis retinoic acid and 1,25-dihydroxyvitamin D3 in the treatment of patients with myelodysplastic syndromes.
TLDR
In the present study, VPA in combination with two differentiating agents, 13-cis retinoic acid and 1,25-dihydroxyvitamin D3, was given to 19 previously untreated patients with MDS or CMML and three patients responded to treatment.
Effect of histone deacetylase inhibitor valproic acid on progenitor cells of acute myeloid leukemia.
TLDR
Here, VPA maintains a significantly higher proportion of CD34+ LPC and colony forming units compared to control cultures in six AML samples, but selectively reduces leukemic cell numbers in another AML sample with expression of AML1/ETO.
Histone Deacetylase Inhibitors and Demethylating Agents: Clinical Development of Histone Deacetylase Inhibitors for Cancer Therapy
TLDR
Clinical data gathered to date, combination therapies designed to increase efficacy, and toxicities attributed to this new class of agents are discussed.
Histone deacetylase inhibitors for the treatment of breast cancer: recent trial data
TLDR
The role of histone deacetylase inhibitors in the treatment of breast cancer as single agents as well as in combination with chemotherapeutic, hormonal, and targeted agents is reviewed.
Valproic acid for the treatment of myeloid malignancies
TLDR
In this report, the authors reviewed the in vitro and in vivo data obtained with VPA, and they considered possible combination regimens aimed at improving therapeutic efficacy.
Histone deacetylase inhibition in the treatment of acute myeloid leukemia: the effects of valproic acid on leukemic cells, and the clinical and experimental evidence for combining valproic acid with other antileukemic agents
TLDR
It is concluded that disease-stabilizing treatment including VPA should be considered especially in unfit patients, because the possibility of improving normal blood values has been documented in several studies and the risk of clinically relevant toxicity is minimal.
Phase I trial of ATRA-IV and depakote in patients with advanced solid tumor malignancies
TLDR
A phase I two-step dose escalation trial of the liposomal ATRA analog ATRA-IV and divalproex sodium (Depakote) and the histone deacetylase inhibitor valproic acid in hematologic malignancies.
Valproic Acid and All-Trans Retinoic Acid: Meta-Analysis of a Palliative Treatment Regimen in AML and MDS Patients
TLDR
21 patients with de novo/secondary AML and 1 patient with myelodysplastic syndrome with ATRA and VPA were treated and 4 patients revealed hematological improvement and another 4 patients experienced a reduction in transfusion dependency.
Analysis of the interplay between all-trans retinoic acid and histone deacetylase inhibitors in leukemic cells
TLDR
It is demonstrated that ATRA protects APL cells from cytotoxic effects of SAHA, MS-275, and Marbostat-100, and that the affinity of HDACi for class I HDACs determines whether such drugs can kill naïve and maturated APl cells.
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Valproic acid induces differentiation of carcinoma cells, transformed hematopoietic progenitor cells and leukemic blasts from acute myeloid leukemia patients, and tumor growth and metastasis formation are significantly reduced in animal experiments, suggesting that it might serve as an effective drug for cancer therapy.
Histone Deacetylase Is a Target of Valproic Acid-Mediated Cellular Differentiation
TLDR
VPA and VPA analogs induce differentiation in hematopoietic cell lines in a p21-dependent manner, and the order of potency for induction of differentiation parallels the potencies for inhibition in vitro, supporting the argument that differentiation caused by VPA is mediated through inhibition of HDACs.
Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid.
TLDR
VPA is of therapeutic benefit for patients with MDS, and ATRA may be effective when added later, as it is shown to inhibit histone deacetylase activity and to synergize with all-trans retinoic acid in the differentiation induction of acute myelogenous leukemia (AML) blasts in vitro.
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TLDR
It is shown that AML1/ETO, the commonest AML-associated fusion protein, is an HDAC-dependent repressor of RA signaling, which relates alteration of the RA pathway to myeloid leukemogenesis and underscores the potential of transcriptional/differentiation therapy in AML.
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TLDR
Several classes of HDAC inhibitors induce differentiation and cell death in myeloid and lymphoid model systems and are now in clinical trials for hematologic malignancies.
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TLDR
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TLDR
Several HDAC inhibitors have shown impressive antitumor activity in vivo with remarkably little toxicity in preclinical studies and are currently in phase I clinical trial.
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TLDR
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Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen*
TLDR
It is proposed that inhibition of histone deacetylase provides a mechanism for valproic acid-induced birth defects and could also explain the efficacy of valproIC acid in the treatment of bipolar disorder.
Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells.
TLDR
In conclusion, transcriptional repression mediated by AML1-ETO appears to play a mechanistic role in the t(8;21) AML, and relief of repression using agents such as PB (alone or in combination) may prove to be therapeutically useful.
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