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Annals of Oncology 2007 18(9):1529-1538; doi:10.1093/annonc/mdm204
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© 2007 European Society for Medical Oncology

miscellaneous tumors

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

M Candelaria2, D Gallardo-Rincón3, C Arce2, L Cetina2, JL Aguilar-Ponce3, Ó Arrieta3, A González-Fierro1, A Chávez-Blanco1, E de la Cruz-Hernández1, MF Camargo1, C Trejo-Becerril1, E Pérez-Cárdenas1, C Pérez-Plasencia1, L Taja-Chayeb1, T Wegman-Ostrosky2, A Revilla-Vazquez and A Dueñas-González1,*

1 Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas (IIB), Universidad Nacional Autonóma de Mexico (UNAM), Instituto Nacional de Cancerología, Mexico City
2 Division de Investigación Clinica, Instituto Nacional de Cancerologia, Mexico City
3 División de Medicina, Instituto Nacional de Cancerologia, Mexico City, Mexico

* Correspondence to: Dr A. Dueñas-González, Dirección de Investigación, Instituto Nacional de Cancerología, San Fernando 22, Tlalpan, 14080 México, D.F., México. Tel: +52-55-56280486; Fax: +52-55-55734662; E-mail: alfonso_duenasg{at}yahoo.com

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

Patients and 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 [ClinicalTrials.gov] ).

Key words: epigenetic therapy, hydralazine, magnesium valproate, phase II, refractory, solid tumors

Received for publication February 28, 2007. Revision received April 18, 2007. Accepted for publication April 19, 2007.


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