title: Preclinical assessment of carboplatin treatment efficacy in lung cancer by 18F-ICMT-11-positron emission tomography.
abstract: Tumour response to therapy is assessed primarily in the clinic by monitoring reductions in tumour size. However, this approach lacks sensitivity since in many cases several weeks may elapse before there is evidence of tumour shrinkage. There is therefore a need to develop non-invasive imaging techniques for monitoring tumour treatment response in the clinic. Here, we assessed the pre-clinical utility of (18)F-ICMT-11 positron emission tomography--a method for detecting caspase 3/7 activation--in non-small cell lung cancer (NSCLC). (18)F-ICMT-11 uptake was compared to molecular biochemical measures of cell death in PC9 and A549 NSCLC cells following treatment with carboplatin in vitro and in vivo. Carboplatin-induced apoptosis in the ERCC1 low/mutant EGFR PC9 cells was characterised by time and dose-related increased caspase-3/7 activation, poly-ADP-ribose polymerase cleavage and Annexin V staining. 18F-ICMT-11 uptake was consequently increased up to 14-fold at 200 µM carboplatin compared to vehicle treated cells (P<0.01). In contrast, necrosis was the predominant death mechanism in ERCC1 high/wt EGFR A549 cells and no change in (18)F-ICMT-11 uptake was detected. In vivo, histological analysis of PC9 tumour xenografts indicated high pre-therapy necrosis. A 4.6-fold increase in cleaved caspase-3/7 was measured in non-necrotic regions of PC9 tumours at 48 h post carboplatin therapy. Average PET-derived tumour (18)F-ICMT-11 uptake was insensitive to changes in apoptosis in the presence of substantial pre-existing necrosis. PET-based voxel intensity sorting however, identified intra-tumoural regions of high (18)F-ICMT-11 uptake, enabling accurate assessment of apoptosis and therefore therapy response. In A549 tumours that lacked high pre-therapy necrosis, carboplatin induced growth inhibition that was only minimally associated with apoptosis and thus not detectable by (18)F-ICMT-11 PET.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Witney
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: R
authors.initials: R
authors.lastname: Fortt
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Robin R
authors.initials: RR
authors.lastname: Fortt
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis; D001386:Azides / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007211:Indoles / Q000378:metabolism; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000188:drug therapy; D049268:Positron-Emission Tomography; D023041:Xenograft Model Antitumor Assays
chemical_list: C571272:(18)F-ICMT11; D000970:Antineoplastic Agents; D001386:Azides; D007211:Indoles; D016190:Carboplatin; D053148:Caspase 3; D053179:Caspase 7