ABSTRACT
Phenotyping of 1,200 'healthy' adults from the UK has been performed through the investigation of diverse classes of hydrophilic and lipophilic metabolites present in serum by applying a series of chromatography-mass spectrometry platforms. These data were made robust to instrumental drift by numerical correction; this was prerequisite to allow detection of subtle metabolic differences. The variation in observed metabolite relative concentrations between the 1,200 subjects ranged from less than 5 % to more than 200 %. Variations in metabolites could be related to differences in gender, age, BMI, blood pressure, and smoking. Investigations suggest that a sample size of 600 subjects is both necessary and sufficient for robust analysis of these data. Overall, this is a large scale and non-targeted chromatographic MS-based metabolomics study, using samples from over 1,000 individuals, to provide a comprehensive measurement of their serum metabolomes. This work provides an important baseline or reference dataset for understanding the 'normal' relative concentrations and variation in the human serum metabolome. These may be related to our increasing knowledge of the human metabolic network map. Information on the Husermet study is available at http://www.husermet.org/. Importantly, all of the data are made freely available at MetaboLights (http://www.ebi.ac.uk/metabolights/).
ABSTRACT
BACKGROUND: 4-(N-(S-glutathionylacetyl)amino) phenylarsenoxide (GSAO) is a water-soluble mitochondrial toxin that binds to adenine nucleotide translocase in the inner mitochondrial membrane, thereby targeting cell proliferation. This phase 1 study investigated safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and pharmacokinetics (PK) of GSAO as a daily 1-h infusion for 5 days a week for 2 weeks in every three. Pharmacodynamics of GSAO was evaluated by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and circulating markers of angiogenesis. METHODS: Patients with advanced solid tumours received GSAO in a dose-escalation trial according to a standard '3 + 3' design that was guided by toxicity and, for the final dose escalation, by arsenic PK data. RESULTS: A total of 34 patients were treated with GSAO across 9 dose levels (1.3-44.0 mg/m(2)). Treatment was well tolerated with few adverse events. An additional three patients were enrolled at the 12.4 mg/m(2) dose level following a DLT of derangement of liver function tests (grade 4). At the 44.0 mg/m(2) dose level, two out of three patients had DLTs (reversible encephalopathy; paroxysmal atrial fibrillation). CONCLUSIONS: The MTD of GSAO was 22.0 mg/m(2)/day. There was no biomarker evidence from DCE-MRI or circulating markers of angiogenesis of an anti-vascular effect of GSAO.