Approaching Sites of Action of Temozolomide for Pharmacological and Clinical Studies in Glioblastoma
Abstract
:1. Introduction
2. Understanding and Monitoring Temozolomide Fate and Biochemical Action
2.1. Absorption, Distribution, Metabolism, and Excretion of Temozolomide
2.2. Chemical Action of Temozolomide
2.3. Biological Action of Temozolomide
2.4. Retrieval of the Intended Anatomical Site of Action of Temozolomide
3. Analytical Workflows to Quantify the Intended Chemical Action of Temozolomide in Glioblastoma
3.1. Sampling of the Intended Cellular Site of Action
3.2. Sample Processing for Intended Sites of Action of Temozolomide
3.2.1. Retrieval of Unbound Temozolomide at the Intended Anatomical Site of Action
3.2.2. Retrieval of the Intended Modified Molecular Site of Action: Methylated Guanines
Retrieval of Deoxyribonucleosides
Retrieval of Purines
3.3. Analysis
3.3.1. LC-MS/MS
3.3.2. MALDI-MS
3.3.3. Quantification Approaches: Development and Validation
Quantification of Temozolomide
Quantification of Methylated Guanines and Guanosines
4. Biological Models to Study the Action of TMZ at SOAs
5. Considerations for the Analysis of Alternative Sites of Action
6. Measurement of the Biological Action of Temozolomide
6.1. Genomics and Transcriptomics
6.2. Proteomics
7. Applications
8. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Param. | Description |
---|---|
P1 | Dose of therapeutic compound |
P2 | Unbound drug concentration in plasma (drug free fraction) |
P3 | Localization of the drug’s cellular SOA (e.g., intravascular or interstitial compartment) |
P4 | Expression and activity of transporters at the cellular SOA |
P5 | Unbound and bound drug concentration on or in the cellular SOA |
P6 | Abundance of the molecular SOA and number of available specific binding sites |
P7 | Chemical interaction between the drug and its molecular SOA |
P8 | Alternative (off-)site binding |
P9 | Concentration of drug metabolites in the cellular SOA |
P10 | Expression and function of drug metabolizing enzymes and other clearance mechanisms |
Sample Type | Targeted Compound | Sample Preparation | Enzymatic Digestion (Specificity Indication) | Analytical Method | Quantification Strategy | Quality Parameters | Ref. |
---|---|---|---|---|---|---|---|
Tissue (mice dosed with TMZ) | TMZ | Low pH conditions/Tissue homogeneization/Protein precipitation | n.a. | LC-MS/MS 4 min LC gradient MRM (QqQ) | Tissue homogenate spiked with TMZ and theophylline (IS) for CALs and QCs | Partial validation (assay precision, accuracy, recovery, linearity, specificty, and matrix effect) [7,46,47,48] | [45] |
Cells (cell lines and patient cells exposed with decitabine) | Decitabine (5-aza-2′-deoxycyti dine) incorporated in DNA | Cell lysis/Protein digestion (proteinase K)/DNA extraction/RNA removal (RNase)/DNA denaturing and hydrolysis/IS spiking/Deproteination/ Evaporation/Reconstitu tion | DNA hydrolysis: DNase I (DNA phosphodiester bonds) NPI (RNA and ssDNA phosphodiester bonds) PDE I (phosphodiester bonds) ALP (removal of 5′-phosphate) | LC-MS/MS MRM (Q-Trap) |
| Partial validation (assay precision, accuracy, recovery, linearity, and matrix effect) [7,46,47,48] | [42] |
DNA (from calf thymus) Liver tissues (from rat exposed to MNU) | N7- and O6-methyl-2′-deoxy guanosine | DNA: DNA methylation by MNU in buffer/DNA precipitation. Tissues: Homogeneization and cell lysis/RNA digestion/Protein digestion (protease K)/DNA precipitation. All samples: DNA hydrolysis/ultrafiltration (<30,000 g/mol) | All samples (DNA hydrolysis): NP1 ALP | LC-UV-MS/MS 23-min gradient MRM (QqQ) | LC mobile phase spiked with N7- and O6-methyl-2′-deoxyguanosines, and [2H3]-N7- and [2H3]-O6-methyl-2′-deoxyguanosines (IS) for CALs | Stability experiments at −20 °C, room temperature, and 37 °C using N7- and O6-methyl-2′-deoxyguanosine solutions in Tris buffer. Recovery: DNA hydrolysates spiked with standards at different concentrations before and after ultrafiltration compared to standards in water without processing. | [49] |
DNA (from salmon testis) exposed to MNU and MMS | N7- and O6-methylguanines | DNA methylation by MNU or MMS in buffer/DNA precipitation and isolation/DNA depurination by simultaneous heat-induced hydrolysis (90% FA, 85 °C for 60 min) | n.a. | LC-MS/MS 8-min gradient MRM (QqQ) | Water with 5% FA spiked with N7- and O6-methylguanines, and [2H3]-N7- and [2H3]-O6-methylguanine (IS) for CALs and QCs. | Partial validation (assay precision, accuracy, linearity) [7,46,47,48] Stability experiments: Freeze-and-thaw and 45-day stabilities at −20 °C. Recovery: control DNA acidic hydrolytes spiked with QC concentrations of N7- and O6-methylguanines and reated IS, compared to QC samples (standards and IS spiked in water with 5% FA). | [50] |
DNA (from calf thymus) exposed to MMS | N7- and O6-methylguanines, and N3-methyladenines | DNA methylation by MMS in buffer/DNA precipitation/DNA depurination by simultaneous heat-induced and acidic hydrolysis (0.1 M HCl, 80 °C for 30 min) | n.a. | LC-MS/MS 4-min gradient MRM (QqQ) | Water/MeOH/TFA 97:3:0.1 (v/v/v) spiked with N7- and O6-methylguanines, and N3-methyladenine, and 15N5-N7-methylguanine (IS), d3-O6-methylguanine (IS), and d3- N3- methyladenine (IS) for CALs and QCs. | Partial validation (assay accuracy and linearity) [7,46,47,48] Intra- and inter-day precision calculated between replicates of untreated DNA spiked with unlabeled standard mixture of fixed concentrations. Recovery: untreated DNA spiked with unlabeled standard mixtures of three different concentrations. Matrix effect: comparison of IS areas between CALs and DNA samples. | [51] |
DNA (from calf thymus) exposed to cisplatin | 1,2 guanine-guanine intrastrand cisplatin adducts (CP-d(GpG)) | DNA hydrolysis/SPE (SCX and C18) or HPLC clean-up | DNAase I NP1 ALP | LC-MS/MS 22-min gradient SRM (QqQ) | Preparation of a CP-d(GpG) analyte standard in 10 mM ammonium acetate and of a 15N10-CP-d(GpG) IS in 10 mM ammonium acetate with 0.1% glacial acetic acid for CALs. | Linearity: one calibration curve. Interday- and interpreparation-precisions: four replicates of CP-d(GpG) at different concentrations. Recovery: analyte standard processed with or without clean-up method. | [52] |
DNA (from human placenta) exposed to FA | Hydroxymethyl deoxynuclosides | DNA incubation with FA/DNA precipitation/DNA hydrolysis | DNAse I PDE ALP | LC-UV | Creation of standard hydroxymethyldeoxydeoxynuclosides by exposition of deoxynucleosides with FA. Calibration curves built without IS normalization. | n.a | [53] |
Oligonucleotides (synthetic) exposed to cisplatin | Guanine-guanine (GG), guanine-adenine (GA), and adenine-guanine (AG) adducts with cisplatin adducts (cis-Pt(NH3)2) | Oligonucleotide incubation with cysplatin/Separation of unreacted and cisplatin derived oligonucleotides/DNA hydrolysis | PDE I or PDE II | LC-UV | n.a. | n.a. | [54] |
Urine (from human) | O6-carboxymethyl guanine, O6-carboxymethyl-2′-deoxyguanosine, O6-methylguanine and O6-methyl-2′-deoxy guanosine | DNA depurination by simultaneous heat-induced and acidic hydrolysis (0.1 M FA, 70 °C for 1 h)/SPE (C18) clean-up | n.a. | LC-MS/MS 23-min gradient SRM (QqQ) | Synthetic urine spiked with serial dilutions of O6-carboxymethylgua nine, O6-carboxymethyl-2′-deoxyguano sine, O6-methylguanine (control) and O6-methyl-2′-deoxyguanosine (control) and fixed concentrations of tubercidin (IS) for CALs and QCs. | Partial validation (assay linearity, intra-and inter-day accuracy and precision) [7,46,47,48] | [55] |
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Fresnais, M.; Turcan, S.; Theile, D.; Ungermann, J.; Abou Zeed, Y.; Lindner, J.R.; Breitkopf, M.; Burhenne, J.; Haefeli, W.E.; Longuespée, R. Approaching Sites of Action of Temozolomide for Pharmacological and Clinical Studies in Glioblastoma. Biomedicines 2022, 10, 1. https://doi.org/10.3390/biomedicines10010001
Fresnais M, Turcan S, Theile D, Ungermann J, Abou Zeed Y, Lindner JR, Breitkopf M, Burhenne J, Haefeli WE, Longuespée R. Approaching Sites of Action of Temozolomide for Pharmacological and Clinical Studies in Glioblastoma. Biomedicines. 2022; 10(1):1. https://doi.org/10.3390/biomedicines10010001
Chicago/Turabian StyleFresnais, Margaux, Sevin Turcan, Dirk Theile, Johannes Ungermann, Yasmin Abou Zeed, Joshua Raoul Lindner, Marius Breitkopf, Jürgen Burhenne, Walter E. Haefeli, and Rémi Longuespée. 2022. "Approaching Sites of Action of Temozolomide for Pharmacological and Clinical Studies in Glioblastoma" Biomedicines 10, no. 1: 1. https://doi.org/10.3390/biomedicines10010001