Development, validation, and clinical application of a high-performance liquid chromatography-tandem mass spectrometry assay for the quantification of total intracellular β-decitabine nucleotides and genomic DNA incorporated β-decitabine and 5-methyl-2’-deoxycytidine

Publication date: Available online 3 October 2018Source: Journal of Pharmaceutical and Biomedical AnalysisAuthor(s): Jeroen Roosendaal, Hilde Rosing, Luc Lucas, Aram Oganesian, Jan H.M. Schellens, Jos H. BeijnenAbstractDNA hypermethylation is an epigenetic event that is commonly found in malignant cells and is used as a therapeutic target for β-decitabine (β-DEC) containing hypomethylating agents (eg Dacogen® and guadecitabine). β-DEC requires cellular uptake and intracellular metabolic activation to β-DEC triphosphate before it can get incorporated into the DNA. Once incorporated in the DNA, β-DEC can exert its hypomethylating effect by trapping DNA methyltransferases (DNMTs), resulting in reduced 5-methyl-2’-deoxycytidine (5mdC) DNA content. β-DEC DNA incorporation and its effect on DNA methylation, however, have not yet been investigated in patients treated with β-DEC containing therapies. For this reason, we developed and validated a sensitive and selective LC-MS/MS method to determine total intracellular β-DEC nucleotide (β-DEC-XP) concentrations, as well as to quantify β-DEC and 5mdC DNA incorporation relative to 2’-deoxycytidine (2dC) DNA content. The assay was successfully validated according to FDA and EMA guidelines in a linear range from 0.5-100 ng/mL (β-DEC), 50-10,000 ng/mL (2dC), and 5-1,000 ng/mL (5mdC) in peripheral blood mononuclear cell (PBMC) lysate. An additional ca...
Source: Journal of Pharmaceutical and Biomedical Analysis - Category: Drugs & Pharmacology Source Type: research

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