title: Temporal and spatial evolution of therapy-induced tumor apoptosis detected by caspase-3-selective molecular imaging.
abstract: OBJECTIVE
  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 [(18)F]ICMT-11 and positron emission tomography (PET).
  
  
  METHODS
  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 [(18)F]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 [(18)F]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 [(18)F]ICMT-11. Increased tumor [(18)F]ICMT-11 uptake was associated with caspase-3 activation measured ex vivo, and early radiotracer uptake predicted apoptosis, distinct from the glucose metabolism with [(18)F]fluorodeoxyglucose-PET, which depicted continuous loss of cell viability.
  
  
  CONCLUSIONS
  The proapoptotic effects of CPA and birinapant resulted in a time-dependent increase in [(18)F]ICMT-11 uptake detected by PET. [(18)F]ICMT-11-PET holds promise as a noninvasive pharmacodynamic biomarker of caspase-3-associated apoptosis in tumors.
authors.affiliation: Department of Surgery and Cancer, Imperial College London Faculty of Medicine, Comprehensive Cancer Imaging Centre, Hammersmith Hospital, London, United Kingdom.
authors.forename: Quang-Dé
authors.initials: QD
authors.lastname: Nguyen
authors.forename: Ioannis
authors.initials: I
authors.lastname: Lavdas
authors.forename: James
authors.initials: J
authors.lastname: Gubbins
authors.forename: Graham
authors.initials: G
authors.lastname: Smith
authors.forename: Robin
authors.initials: R
authors.lastname: Fortt
authors.forename: Laurence S
authors.initials: LS
authors.lastname: Carroll
authors.forename: Martin A
authors.initials: MA
authors.lastname: Graham
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001386:Azides; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D003520:Cyclophosphamide / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D016393:Lymphoma, B-Cell / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D023041:Xenograft Model Antitumor Assays
chemical_list: C571272:(18)F-ICMT11; D018906:Antineoplastic Agents, Alkylating; D001386:Azides; D004151:Dipeptides; D007211:Indoles; D019275:Radiopharmaceuticals; C582429:birinapant; D003520:Cyclophosphamide; C505407:CASP3 protein, human; D053148:Caspase 3