RÉSUMÉ
Developing rational targeted cancer drugs requires the implementation of pharmacodynamic (PD), preferably non-invasive, biomarkers to aid response assessment and patient follow-up. Magnetic resonance spectroscopy (MRS) allows the non-invasive study of tumour metabolism. We describe the MRS-detectable PD biomarkers resulting from the action of targeted therapeutics, and discuss their biological significance and future translation into clinical use.
Sujet(s)
Antinéoplasiques/pharmacologie , Systèmes de délivrance de médicaments , Surveillance des médicaments/méthodes , Spectroscopie par résonance magnétique/méthodes , Tumeurs/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Inhibiteurs de l'angiogenèse/pharmacologie , Inhibiteurs de l'angiogenèse/usage thérapeutique , Animaux , Antinéoplasiques/usage thérapeutique , Marqueurs biologiques , Choline/métabolisme , Métabolisme énergétique/effets des médicaments et des substances chimiques , Antienzymes/pharmacologie , Antienzymes/usage thérapeutique , Histone deacetylases/métabolisme , Humains , Protéines tumorales/antagonistes et inhibiteurs , Protéines tumorales/métabolisme , Tumeurs/traitement médicamenteux , Phospholipides/métabolisme , Protein kinases/métabolisme , , Cellules cancéreuses en culture/effets des médicaments et des substances chimiques , Cellules cancéreuses en culture/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
Magnetic resonance spectroscopy is increasingly used as a non-invasive method to investigate apoptosis. Apoptosis was induced in Jurkat T-cells by Fas mAb. (1)H magnetic resonance spectra of live cells showed an increase in methylene signal as well as methylene/methyl ratio of fatty acid side chains at 5 and 24 h following induction of apoptosis. To explain this observation, (1)H magnetic resonance spectra of cell extracts were investigated. These demonstrated a 70.0+/-7.0%, 114.0+/-8.0% and 90.0+/-5.0% increase in the concentration of triacylglycerols following 3, 5 and 7 h of Fas mAb treatment (P<0.05). Confocal microscopy images of cells stained with the lipophilic dye Nile Red demonstrated the presence of lipid droplets in the cell cytoplasm. Quantification of the stained lipids by flow cytometry showed a good correlation with the magnetic resonance results (P > or =0.05 at 3, 5 and 7 h). (31)P magnetic resonance spectra showed a drop in phosphatidylcholine content of apoptosing cells, indicating that alteration in phosphatidylcholine metabolism could be the source of triacylglycerol accumulation during apoptosis. In summary, apoptosis is associated with an early accumulation of mobile triacylglycerols mostly in the form of cytoplasmic lipid droplets. This is reflected in an increase in the methylene/methyl ratio which could be detected by magnetic resonance spectroscopy.