Abstract
Temozolomide (TMZ), together with bulk resection and focal radiotherapy, is currently a standard of care for glioblastoma. Absorption, distribution, metabolism, and excretion (ADME) parameters, together with the mode of action of TMZ, make its biochemical and biological action difficult to understand. Accurate understanding of the mode of action of TMZ and the monitoring of TMZ at its anatomical, cellular, and molecular sites of action (SOAs) would greatly benefit precision medicine and the development of novel therapeutic approaches in combination with TMZ. In the present perspective article, we summarize the known ADME parameters and modes of action of TMZ, and we review the possible methodological options to monitor TMZ at its SOAs. We focus our descriptions of methodologies on mass spectrometry-based approaches, and all related considerations are taken into account regarding the avoidance of artifacts in mass spectrometric analysis during sampling, sample preparation, and the evaluation of results. Finally, we provide an overview of potential applications for precision medicine and drug development.
Highlights
IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
Separation methods based on chemical properties (LC or ion mobility) or mass spectrometry (MS)/MS fragmentation, rather than the intact mass, are necessary to discriminate between MS signals from N7- and O6-methylguanines for further specific quantification
Approaching the site of action (SOA) of drugs in clinical pharmacological investigations would have a great impact in precision medicine, during clinical trials, and for patient monitoring
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Expression and function of drug metabolizing enzymes and other clearance mechanisms Mass spectrometric methods such as liquid chromatography–tandem mass spectrometry (LC-MS/MS) and desorption/ionization (DI) methods such as matrix-assisted laser desorption ionization (MALDI) are commonly used to quantify drugs at their SOA [6]. Results from LC-MS/MS provide strong support for the development of alternative MS-based approaches, e.g., on-surface imaging and/or profiling using MALDI-MS. In this perspective article, we focus on LC-MS/MS and MALDIbased approaches, as well as their interplay, to detect TMZ and its effects at its SOAs, as well as analytical workflows suitable for this purpose
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