Clinical and Biological Effects of Valproic Acid as a Histone Deacetylase Inhibitor on Tumor and Surrogate Tissues: Phase I/II Trial of Valproic acid and Epirubicin/FEC

Abstract

Purpose: The aim was to study the biological and molecular effects of the histone deacetylase (HDAC) inhibitor, valproic acid, in patients with solid tumor malignancies. Experimental Design: A phase I dose escalation of valproic acid given on days 1to 3 followed by epirubicin (day 3) was followed by a dose expansion of valproic acid combined with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC100). Pharmacodynamic and pharmacokinetic studies entailed valproic acid and epirubicin plasma levels and their interaction, the effects of valproic acid on histone acetylation in peripheral blood mononuclear cells (PBMC) and tumor cells at baseline and day 3, and baseline expression of HDAC2 and HDAC6 as therapeutic targets. Results: Forty-four patients were enrolled in the phase I part, with a disease-specific cohort expansion of 15 breast cancer patients (median age, 55 years; range, 28-66 years) receiving 120 mg/kg/day valproic acid followed by FEC100. Partial responses were seen in 9 of 41 (22%) patients during the phase I part. Objective responses were seen in 9 of 14 (64%) evaluable patients at the dose expansion with a median number of 6 administered cycles. Predominant toxicities were valproic acid^associated somnolence and epirubicin-induced myelosuppression. Valproic acid plasma levels were associated with short-term, reversible depletion of WBC and neutrophils within 48 hours. Histone acetylation in tumor samples and in PBMCs correlated with valproic acid levels and was further linked to baseline HDAC2 but not to HDAC6 expression. Conclusion: Valproic acid is a clinically relevant HDAC inhibitor, and PBMCs may serve as a surrogate for tumor histone acetylation in solid tumor malignancies. HDAC2 should be further considered as a relevant therapeutic target.

Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker

“…Slides were simultaneously counterstained with anti-pan histone 3 (Upstate Biotechnology; polyclonal, or BD Biosciences, San Jose, CA, USA; monoclonal, 1 : 200) for 1 h. Respective proteins were then developed with anti-rabbit Alexa-Fluor 546 and anti-mouse Alexa-Fluor 488 (Molecular Probes, Eugene, OR, USA) and bisbenzimide (0.5 mg ml À1 ) for 1 h. All pre-and post-treatment PBMC and tumour samples were evaluated by immunofluorescence confocal microscopy. Resultant images were analysed as previously described (Marchion et al, 2005a, c;Munster et al, 2009). All PBMC samples were processed for western blot analysis, and membranes were probed with the respective antibodies as outlined for immunofluorescence staining: anti-acetylated histone H4 or H3, topo IIa, topo IIb, HP-1, HDAC2, and HDAC6 (all rabbit polyclonal, Upstate Biotechnology).…”

Analysis of the genomic response of human prostate cancer cells to histone deacetylase inhibitors

“…Valproic acid (VPA) in combination with epirubicin/FEC (5-fluorouracil, epirubicin, cyclophosphamide) resulted in an objective response in 64% of patients with solid advanced malignancies. 3 Combination therapy with the HDACi magnesium valproate and DNA demethylating agent hydralazine resensitized 80% of cancer patients to chemotherapy on which they had previously progressed. 4 This combination was successfully added to doxorubicin and cyclophosphamide therapy in breast cancer patients as well.…”

Enhanced suppression of proliferation and migration in highly-metastatic lung cancer cells by combination of valproic acid and coumarin-3-carboxylic acid and its molecular mechanisms of action

“…Valproic acid not only suppressed some tumor growth and metastasis, but also induced tumor differentiation in vitro and in vivo (Blaheta and Cinatl 2002). Valproic acid inhibited the in vitro and in vivo cancer cell growth of melanoma (Landreville et al 2012), urinary bladder cancer (Byun et al 2009;Ozawa et al 2010), breast cancer (Munster et al 2009), and prostate cancer (Chou et al 2011). Recently, the combination of valproic acid with other anticancer agents has been considered as a useful and necessary strategy to inhibit tumor growth and progression (Byun et al 2009;Munster et al 2009;Ozawa et al 2010;Chou et al 2011).…”