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A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors

2007; Elsevier BV; Volume: 18; Issue: 9 Linguagem: Inglês

10.1093/annonc/mdm204

1569-8041

Myrna Candelaria, Dolores Gallardo‐Rincón, Claudia Arce, Lucely Cetina, José Luis Aguilar-Ponce, Óscar Arrieta, Aurora González‐Fierro, Alma Chávez‐Blanco, Erik de la Cruz-Hernandez, Maria Fernanda Vieira Cunha Camargo, Catalina Trejo‐Becerril, Enrique Pérez‐Cárdenas, Carlos Pérez‐Plasencia, Lucía Taja‐Chayeb, Talía Wegman-Ostrosky, Alma Luísa Revilla Vázquez, Alfonso Dueñas‐González,

Pharmacological Effects and Toxicity Studies

Epigenetic aberrations lead to chemotherapy resistance; hence, their reversal by inhibitors of DNA methylation and histone deacetylases may overcome it.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.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.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).