Temporal and spatial evolution of therapy-induced tumor apoptosis detected by caspase-3-selective molecular imaging

摘要

Purpose: Induction of apoptosis in tumors is considered a desired goal of anticancer therapy. We investigated whether the dynamic temporal and spatial evolution of apoptosis in response to cytotoxic and mechanism-based therapeutics could be detected noninvasively by the caspase-3 radiotracer [ 18F]ICMT-11 and positron emission tomography (PET). Experimental Design: The effects of a single dose of the alkylating agent cyclophosphamide (CPA or 4-hydroperoxycyclophosphamide), or the mechanism-based small molecule SMAC mimetic birinapant on caspase-3 activation was assessed in vitro and by [18F]ICMT-11-PET in mice bearing 38C13 B-cell lymphoma, HCT116 colon carcinoma, or MDA-MB-231 breast adenocarcinoma tumors. Ex vivo analysis of caspase-3 was compared to the in vivo PET imaging data. Results: Drug treatment increased the mean [18F]ICMT-11 tumor uptake with a peak at 24 hours for CPA (40 mg/kg; AUC40-60: 8.04±1.33 and 16.05±3.35 %ID/mL×min at baseline and 24 hours, respectively) and 6 hours for birinapant (15 mg/kg;AUC40-60: 20.29±0.82 and 31.07±5.66 %ID/mL×min, at baseline and 6 hours, respectively). Voxel-based spatiotemporal analysis of tumor-intrinsic heterogeneity suggested that discrete pockets of caspase-3 activation could be detected by [ 18F]ICMT-11. Increased tumor [18F]ICMT- 11 uptake was associated with caspase-3 activation measured ex vivo, and early radiotracer uptake predicted apoptosis, distinct from the glucose metabolism with [ 18F]fluorodeoxyglucose-PET, which depicted continuous loss of cell viability. Conclusion: The proapoptotic effects of CPA and birinapant resulted in a time-dependent increase in [18F]ICMT-11 uptake detected by PET. [18F]ICMT-11-PET holds promise as a noninvasive pharmacodynamic biomarker of caspase-3-associated apoptosis in tumors.