Abstract
Background In vivo imaging using Annexin A5-based radioligands is a powerful technique for visualizing massive cell death, but has been less successful in monitoring the modest cell death typically seen in solid tumors after chemotherapy. Here we combined dynamic positron emission tomography (PET) imaging using Annexin A5 with a serum-based apoptosis marker, for improved sensitivity and specificity in assessment of chemotherapy-induced cell death in a solid tumor model.Methodology/Principal FindingsModest cell death was induced by doxorubicin in a mouse xenograft model with human FaDu head and neck cancer cells. PET imaging was based on 11C-labeled Sel-tagged Annexin A5 ([11C]-AnxA5-ST) and a size-matched control. 2-deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) was utilized as a tracer of tissue metabolism. Serum biomarkers for cell death were ccK18 and K18 (M30 Apoptosense® and M65). Apoptosis in tissue sections was verified ex vivo for validation. Both PET imaging using [11C]-AnxA5-ST and serum ccK18/K18 levels revealed treatment-induced cell death, with ccK18 displaying the highest detection sensitivity. [18F]-FDG uptake was not affected by this treatment in this tumor model. [11C]-AnxA5-ST gave robust imaging readouts at one hour and its short half-life made it possible to perform paired scans in the same animal in one imaging session.Conclusions/SignificanceThe combined use of dynamic PET with [11C]-AnxA5-ST, showing specific increases in tumor binding potential upon therapy, with ccK18/K18 serum measurements, as highly sensitive markers for cell death, enabled effective assessment of modest therapy-induced cell death in this mouse xenograft model of solid human tumors.
Highlights
Therapy must be individually optimized if outcomes for cancer patients are to be improved [1]
We subsequently evaluated the use of these two ligands for positron emission tomography (PET) imaging in a xenograft tumor model, without or with chemotherapy that induces modest cell death
We propose that the combined use of serum biomarkers for apoptosis together with dynamic PET imaging using [11C]Annexin A5 (AnxA5)-ST, preferably compared with a size-matched control ligand provides a sensitive technique for detecting, localizing and assessing the extent of cell death induced by chemotherapeutics even in this modestly responsive xenograft model of human solid tumors
Summary
Therapy must be individually optimized if outcomes for cancer patients are to be improved [1]. We investigated whether positron emission tomography (PET) imaging of cell death in combination with analyses of serum markers could provide a strategy for assessing cell death which is more effective than using either of these techniques alone. AnxA5-based imaging techniques can have difficulty detecting modest responses to therapy such as those often seen clinically in solid tumors. We subsequently evaluated the use of these two ligands for PET imaging in a xenograft tumor model, without or with chemotherapy that induces modest cell death. We combined dynamic positron emission tomography (PET) imaging using Annexin A5 with a serum-based apoptosis marker, for improved sensitivity and specificity in assessment of chemotherapy-induced cell death in a solid tumor model
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