ABSTRACT
Increased angiogenesis and vascular endothelial growth factor (VEGF) levels contribute to higher metastasis and mortality in uveal melanoma (UM), an aggressive malignancy of the eye in adults. (±)-MRJF22, a prodrug of the sigma (σ) ligand haloperidol metabolite II conjugated with the histone deacetylase (HDAC) inhibitor valproic acid, has previously demonstrated a promising antiangiogenic activity. Herein, the asymmetric synthesis of (R)-(+)-MRJF22 and (S)-(-)-MRJF22 was performed to investigate their contribution to (±)-MRJF22 antiangiogenic effects in human retinal endothelial cells (HREC) and to assess their therapeutic potential in primary human uveal melanoma (UM) 92-1 cell line. While both enantiomers displayed almost identical capabilities to reduce cell viability than the racemic mixture, (S)-(-)-MRJF22 exhibited the highest antimigratory effects in endothelial and tumor cells. Given the fundamental contribution of cell motility to cancer progression, (S)-(-)-MRJF22 may represent a promising candidate for novel antimetastatic therapy in patients with UM.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Butyrophenones/pharmacology , Melanoma/drug therapy , Pentanoic Acids/pharmacology , Piperidines/pharmacology , Prodrugs/pharmacology , Uveal Neoplasms/drug therapy , Valerates/pharmacology , Angiogenesis Inhibitors/chemical synthesis , Butyrophenones/chemical synthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Pentanoic Acids/chemical synthesis , Piperidines/cerebrospinal fluid , Prodrugs/chemical synthesis , Stereoisomerism , Valerates/cerebrospinal fluidABSTRACT
Clinical and metabolic changes in the central nervous system are described in a patient with biotinidase deficiency before and after biotin treatment. Lactate, pyruvate and 3-hydroxyisovaleric acid as metabolic disease markers were measured in blood, cerebrospinal fluid and brain tissue by biochemical analyses or localized magnetic resonance proton spectroscopy. The patient improved markedly with biotin treatment. Nevertheless, neurological sequelae and abnormal intracerebral lactate concentrations persisted despite normalized metabolic disease markers in extracerebral fluids. Therefore, localized in vivo measurements of intracerebral metabolites may be a valuable tool for elucidating the pathogenesis of biotinidase deficiency.
Subject(s)
Amidohydrolases/deficiency , Biotin/therapeutic use , Brain/physiopathology , Biotinidase , Brain/pathology , Electroencephalography , Humans , Infant , Lactic Acid/blood , Lactic Acid/cerebrospinal fluid , Lactic Acid/metabolism , Magnetic Resonance Imaging , Male , Pyruvic Acid/blood , Pyruvic Acid/cerebrospinal fluid , Pyruvic Acid/metabolism , Seizures/etiology , Valerates/blood , Valerates/cerebrospinal fluid , Valerates/metabolismABSTRACT
This study describes a standardized method for recording single-pulse 1H-nuclear magnetic resonance (1H-NMR) spectra from cerebrospinal fluid (CSF). Quantitative data for alanine, valine, threonine, and lactic acid correlated well with data obtained with conventional techniques. The pH of the samples is important for the reproducibility of the chemical shift of resonances, and should be standardized to improve recognition and assignment of resonances. A database of resonances from various metabolites is presented. Fifty compounds could be identified in CSF, 15 of which had not been observed earlier in NMR studies of CSF. We describe for the first time in the literature, to our knowledge, 3-hydroxyisovaleric acid as a regular component of many CSF samples. As examples of the diagnostic power of the technique, spectra are shown of CSF from patients with three different inborn errors of metabolism. We found high concentrations of N-acetylaspartic acid, citric acid, and succinic acid in CSF from a patient with Canavan disease. This is indirect evidence for the existence of a carrier mechanism that is shared by these di- and tricarboxylic acids.
