Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating phase I clinical trial

Abstract

Altered histone deacetylase (HDAC) activity has been identified in several types of cancer. This study was designed to determine the safety and maximum tolerated dose (MTD) of valproic acid (VPA) as an HDAC inhibitor in cancer patients. Twenty-six pre-treated patients with progressing solid tumours were enrolled in dose-escalating three-patient cohorts, starting at a dose of VPA 30 mg kg À1 day À1 . VPA was administered as an 1-h infusion daily for 5 consecutive days in a 21-day cycle. Neurocognitive impairment dominated the toxicity profile, with grade 3 or 4 neurological side effects occurring in 8 out of 26 patients. No grade 3 or 4 haematological toxicity was observed. The MTD of infusional VPA was 60 mg kg À1 day À1 . Biomonitoring of peripheral blood lymphocytes demonstrated the induction of histone hyperacetylation in the majority of patients and downmodulation of HDAC2. Pharmacokinetic studies showed increased mean and maximum serum VPA concentrations 4120 and 4250 mg l À1 , respectively, in the 90 and 120 mg kg À1 cohorts, correlating well with the incidence of dose-limiting toxicity (DLT). Neurotoxicity was the main DLT of infusional VPA, doses up to 60 mg kg À1 day À1 for 5 consecutive days are well tolerated and show detectable biological activity. Further investigations are warranted to evaluate the effectivity of VPA alone and in combination with other cytotoxic drugs.

Using iPSC‐derived human DA neurons from opioid‐dependent subjects to study dopamine dynamics

“…1981), which is comparable to our tested concentration (0.6 mM) and this and higher doses are well tolerated (Atmaca et al. 2007). In summary, taken together, the data support the feasibility of testing VPA for future drug addiction treatment.…”

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

“…27 Section immunostaining was performed using primary antibody against Wilim's Tumor-1 or LC3B (Abcam) as previously described. 28 Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) Assay TUNEL assay was performed by using an In Situ Cell Death Detection kit (Roche, Basel, Switzerland) according to the manufacturer's instructions. At least 100 glomeruli were examined.…”

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis

“…36 Gene expression profiling allowed us to study a large number of genes and to analyze global pathways rather than single targets. Among the 27 367 probe sets considered as present, 60% were significantly modulated and 14% were differentially expressed, with a fold change of 1.5 (increase or decrease) after VPA treatment for 4 h. These rates indicate the broad effects of VPA on transcriptome modulation at a well-tolerated concentration: 57% of probe sets were upregulated, but VPA could also downregulate 43% of them, probably through indirect mechanisms.…”

“…VPA is currently being tested alone or in combination with other agents mostly in hematological malignancies, 24 but there is increasing interest in testing on solid tumors. 23,25,36,39 Resistance to chemotherapy is a major problem in leukemia treatment, and despite the efficiency of fludarabine in the induction of clinical responses in CLL, resistance to this drug has been well documented. 40,41 Furthermore, new drugs in clinical trials with powerful apoptotic potential (for example, flavopiridol) can cause many side effects such as anemia, thrombocytopenia, infections, diarrhea and fatigue.…”