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PMID: 17183730 Published · epublish English Clinical Trial Journal Article Research Support, Non-U.S. Gov't

A proof-of-principle study of epigenetic therapy added to neoadjuvant doxorubicin cyclophosphamide for locally advanced breast cancer.

PloS one ·Vol. 1 ·2006-12-20 ·Pages e98

Arce C, Pérez-Plasencia C, González-Fierro A, de la Cruz-Hernández E, Revilla-Vázquez A, Chávez-Blanco A, Trejo-Becerril C, Pérez-Cárdenas E, Taja-Chayeb L, Bargallo E, Villarreal P, Ramírez T, Vela T, Candelaria M, Camargo MF, Robles E, Dueñas-González A

Abstract

Aberrant 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. This 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. 16 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. Hydralazine 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.

MeSH Terms
Adult Aged Antineoplastic Combined Chemotherapy Protocols/administration & dosage Breast Neoplasms/drug therapy,genetics,pathology Cyclophosphamide/administration & dosage DNA Methylation/drug effects Doxorubicin/administration & dosage Epigenesis, Genetic/drug effects Female Gene Expression/drug effects Histone Deacetylase Inhibitors/administration & dosage Humans Hydralazine/administration & dosage Middle Aged Neoadjuvant Therapy Valproic Acid/administration & dosage
Chemicals
Histone Deacetylase Inhibitors Hydralazine Valproic Acid Doxorubicin Cyclophosphamide
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Arce Claudia
Division de Investigación Clinica, Instituto Nacional de Cancerología (ICAN), Mexico City, Mexico.
Pérez-Plasencia Carlos
González-Fierro Aurora
de la Cruz-Hernández Erick
Revilla-Vázquez Alma
Chávez-Blanco Alma
Trejo-Becerril Catalina
Pérez-Cárdenas Enrique
Taja-Chayeb Lucia
Bargallo Enrique
Villarreal Patricia
Ramírez Teresa
Vela Teresa
Candelaria Myrna
Camargo Maria F
Robles Elizabeth
Dueñas-González Alfonso
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0000098
Published
2006-12-20
Epub
2006-00-20
Pages
e98
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC1762324
Subset
IM
Databases
ClinicalTrials.gov
NCT00395655
External Links
PubMed source DOI: 10.1371/journal.pone.0000098 PMC Full Text View journal details
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