Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study

Chávez‐Blanco, Alma; Segura-Pacheco, Blanca; Pérez-Cárdenas, Enrique; Taja‐Chayeb, Lucía; Cetina, Lucely; Candelaria, Myrna; Cantú, David; González-Fierro, Aurora; Garcı́a-López, Patricia; Zambrano, Pilar; Pérez‐Plasencia, Carlos; Cabrera, Gustavo; Trejo-Becerril, Catalina; Ángeles, Enrique; Dueñas‐González, Alfonso

doi:10.1186/1476-4598-4-22

Cited by 116 publications

(38 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Several other groups (Imai et al 2003;Roh et al 2004;Watanabe et al 2005) have reported growth inhibition and sensitization to Fas-mediated cell death of human osteosarcoma cells by HDAC inhibitors, FR901228 and TSA, but not inhibition of soluble Fas secretion. Importantly, our results showed that VPA exerted its eVects at concentrations which are attainable in sera of patients administered with VPA orally without serious side eVects (Johannessen and Johannessen 2003;Chavez-Blanco et al 2005;Allen et al 2006;Ueshima et al 2008). These results indicate the possibility that VPA may be applicable to the treatment of osteosarcomas.…”

Section: Discussionmentioning

confidence: 57%

Sodium valproate, a histone deacetylase inhibitor, decreases the secretion of soluble Fas by human osteosarcoma cells and increases their sensitivity to Fas-mediated cell death

Yamanegi

Yamane

Hara

et al. 2008

J Cancer Res Clin Oncol

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 57%

Sodium valproate, a histone deacetylase inhibitor, decreases the secretion of soluble Fas by human osteosarcoma cells and increases their sensitivity to Fas-mediated cell death

Yamanegi

Yamane

Hara

et al. 2008

J Cancer Res Clin Oncol

View full text Add to dashboard Cite

show abstract

“…Plasma levels progressively decreased until the end of treatment. However, the mean value in the lowest (four-cycle) determination was >75 µg/mL, which is an effective concentration [28].…”

Section: Discussionmentioning

confidence: 82%

“…Assays were performed using the colorimetric HDAC activity assay from BioVision (BioVision Research Products, Mountain View, CA, USA) according to manufacturer instructions, as described [28].…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer

et al. 2006

Self Cite

View full text Add to dashboard Cite

BackgroundAberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy.MethodologyThis was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655). After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day –7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate.Main Findings16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1–2. Five (31%) patients had clinical CR and eight (50%) PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6%) had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5mC content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively.ConclusionsHydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the efficacy of chemotherapy. A randomized phase III study is ongoing to support the efficacy of so-called epigenetic or transcriptional cancer therapy.

show abstract

“…Although active in reinducing H3 and H4 acetylation in tumour cells, the clinical efficacy seems limited [103].…”

Section: Short Chain Fatty Acidsmentioning

confidence: 99%

Histone Deacetylase Inhibitors: Molecular and Biological Activity as a Premise to Clinical Application

Santini¹,

Gozzini²,

Ferrari

2007

CDM

125

View full text Add to dashboard Cite

Epigenetic modifications are reversible chromatin rearrangements that in normal cells modulate gene expression, without changing DNA sequence. Alterations of this equilibrium, mainly affecting the two interdependent mechanisms of DNA methylation and histone acetylation, are frequently involved in the genesis of cancer. The histone code, regulating gene expression, is constituted by the combination of different acetylated lysine residues of histones. In neoplastic cells, the abundance of deacetylated histones is usually associated with DNA hypermethylation and gene silencing. Several compounds, known to have in vitro antineoplastic activity, have been eventually shown to act as histone deacetylase inhibitors. Thus, HDAC inhibitors have been successfully introduced in clinical trials as antitumour agents. They are classified according to their chemical structures and are endowed with different specificity and affinity for the HDACs of classes 1, 2, 4. Among HDAC inhibitors, the most potent are the hydroxamic acid derivatives, like SAHA, which has been recently approved for therapy of cutaneous T-cell lymphomas. Other classes of HDAC inhibitors are short chain fatty acids (SCFA), benzamides, epoxyketone and non-epoxyketone containing cyclic tetrapeptides, and hybrid molecules. SCFA, although widely used (especially valproic acid) and clinically efficacious, have weak HDAC inhibition constants. Benzamides, like MS-275, and cyclic peptides, like depsipeptide, have been studied in numerous clinical trials and demonstrated low toxicity and activity in solid and haematological neoplasms. HDAC inhibitors are also potent radiation sensitizers. Their future in oncology may thus be based on their activity as single agents and on their synergy with the hypomethylating drugs and with chemo- and radiotherapeutics.

show abstract

Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study

Cited by 116 publications

References 43 publications

Sodium valproate, a histone deacetylase inhibitor, decreases the secretion of soluble Fas by human osteosarcoma cells and increases their sensitivity to Fas-mediated cell death

Sodium valproate, a histone deacetylase inhibitor, decreases the secretion of soluble Fas by human osteosarcoma cells and increases their sensitivity to Fas-mediated cell death

A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer

Histone Deacetylase Inhibitors: Molecular and Biological Activity as a Premise to Clinical Application

Contact Info

Product

Resources

About