title: A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors.
abstract: BACKGROUND
  Epigenetic aberrations lead to chemotherapy resistance; hence, their reversal by inhibitors of DNA methylation and histone deacetylases may overcome it.
  
  
  METHODS
  Phase II, single-arm study of hydralazine and magnesium valproate added to the same schedule of chemotherapy on which patients were progressing. Schedules comprised cisplatin, carboplatin, paclitaxel, vinorelbine, gemcitabine, pemetrexed, topotecan, doxorubicin, cyclophosphamide, and anastrozole. Patients received hydralazine at 182 mg for rapid, or 83 mg for slow, acetylators, and magnesium valproate at 40 mg/kg, beginning a week before chemotherapy. Response, toxicity, DNA methylation, histone deacetylase activity, plasma valproic acid, and hydralazine levels were evaluated.
  
  
  RESULTS
  Seventeen patients were evaluable for toxicity and 15 for response. Primary sites included cervix (3), breast (3), lung (1), testis (1), and ovarian (7) carcinomas. A clinical benefit was observed in 12 (80%) patients: four PR, and eight SD. The most significant toxicity was hematologic. Reduction in global DNA methylation, histone deacetylase activity, and promoter demethylation were observed.
  
  
  CONCLUSIONS
  The clinical benefit noted with the epigenetic agents hydralazine and valproate in this selected patient population progressing to chemotherapy' and re-challenged with the same chemotherapy schedule after initiating hydralazine and valproate' lends support to the epigenetic-driven tumor-cell chemoresistance hypothesis (ClinicalTrials.gov Identifier: NCT00404508).
authors.affiliation: Division de Investigación Clinica, Instituto Nacional de Cancerologia, Mexico City, Mexico.
authors.forename: M
authors.initials: M
authors.lastname: Candelaria
authors.forename: D
authors.initials: D
authors.lastname: Gallardo-Rincón
authors.forename: C
authors.initials: C
authors.lastname: Arce
authors.forename: L
authors.initials: L
authors.lastname: Cetina
authors.forename: J L
authors.initials: JL
authors.lastname: Aguilar-Ponce
authors.forename: O
authors.initials: O
authors.lastname: Arrieta
authors.forename: A
authors.initials: A
authors.lastname: González-Fierro
authors.forename: A
authors.initials: A
authors.lastname: Chávez-Blanco
authors.forename: E
authors.initials: E
authors.lastname: de la Cruz-Hernández
authors.forename: M F
authors.initials: MF
authors.lastname: Camargo
authors.forename: C
authors.initials: C
authors.lastname: Trejo-Becerril
authors.forename: E
authors.initials: E
authors.lastname: Pérez-Cárdenas
authors.forename: C
authors.initials: C
authors.lastname: Pérez-Plasencia
authors.forename: L
authors.initials: L
authors.lastname: Taja-Chayeb
authors.forename: T
authors.initials: T
authors.lastname: Wegman-Ostrosky
authors.forename: A
authors.initials: A
authors.lastname: Revilla-Vazquez
authors.forename: A
authors.initials: A
authors.lastname: Dueñas-González
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D005260:Female; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006830:Hydralazine / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D014635:Valproic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood
chemical_list: D006830:Hydralazine; D014635:Valproic Acid; D006655:Histone Deacetylases