Phase I study of epigenetic modulation with 5-azacytidine and valproic acid in patients with advanced cancers. Clin Cancer Res 2008 Oct 01;14(19):6296-301
Date
10/03/2008Pubmed ID
18829512Pubmed Central ID
PMC2582814DOI
10.1158/1078-0432.CCR-08-1247Scopus ID
2-s2.0-58149174109 (requires institutional sign-in at Scopus site) 150 CitationsAbstract
PURPOSE: 5-Azacytidine (5-AZA) is a DNA-hypomethylating agent. Valproic acid is a histone deacetylase inhibitor. Combining hypomethylating agents and histone deacetylase inhibitors produces synergistic anticancer activity in vitro and in vivo. On the basis of this evidence, we conducted a phase I study of the combination of 5-AZA and valproic acid in patients with advanced cancers.
EXPERIMENTAL DESIGN: 5-AZA was administered s.c. daily for 10 days. Valproic acid was given orally daily with a goal to titrate to plasma levels of 75 to 100 mug/mL (therapeutic for seizures). Cycles were 28 days long. 5-AZA was started at 20 mg/m(2) and escalated using an adaptive algorithm based on the toxicity profile in the prior cohort (6 + 6 design). Peripheral blood mononuclear cell global DNA methylation and histone H3 acetylation were estimated with the long interspersed nucleotide elements pyrosequencing assay and Western blots, respectively, on days 1 and 10 of each cycle when patients agreed to provide them.
RESULTS: Fifty-five patients were enrolled. Median age was 60 years (range, 12-77 years). The maximum tolerated dose was 75 mg/m(2) of 5-AZA in combination with valproic acid. Dose-limiting toxicities were neutropenic fever and thrombocytopenia, which occurred at a dose of 94 mg/m(2) of 5-AZA. Stable disease lasting 4 to 12 months (median, 6 months) was observed in 14 patients (25%). A significant decrease in global DNA methylation and induction of histone acetylation were observed.
CONCLUSION: The combination of 5-AZA and valproic acid is safe at doses up to 75 mg/m(2) for 5-AZA in patients with advanced malignancies.
Author List
Braiteh F, Soriano AO, Garcia-Manero G, Hong D, Johnson MM, Silva Lde P, Yang H, Alexander S, Wolff J, Kurzrock RAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Aged
Antineoplastic Combined Chemotherapy Protocols
Azacitidine
Child
Cohort Studies
CpG Islands
DNA Methylation
Drug Synergism
Epigenesis, Genetic
Female
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms
Valproic Acid
