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Preclinical Assessment of Carboplatin Treatment Efficacy in Lung Cancer by (18)F-ICMT-11-Positron Emission Tomography
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 techni...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950258/ https://www.ncbi.nlm.nih.gov/pubmed/24618809 http://dx.doi.org/10.1371/journal.pone.0091694 |
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author | Witney, Timothy H. Fortt, Robin R. Aboagye, Eric O. |
author_facet | Witney, Timothy H. Fortt, Robin R. Aboagye, Eric O. |
author_sort | Witney, Timothy H. |
collection | PubMed |
description | 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. (18)F-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 48h 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. |
format | Online Article Text |
id | pubmed-3950258 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-39502582014-03-12 Preclinical Assessment of Carboplatin Treatment Efficacy in Lung Cancer by (18)F-ICMT-11-Positron Emission Tomography Witney, Timothy H. Fortt, Robin R. Aboagye, Eric O. PLoS One Research Article 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. (18)F-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 48h 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. Public Library of Science 2014-03-11 /pmc/articles/PMC3950258/ /pubmed/24618809 http://dx.doi.org/10.1371/journal.pone.0091694 Text en © 2014 Witney et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Witney, Timothy H. Fortt, Robin R. Aboagye, Eric O. Preclinical Assessment of Carboplatin Treatment Efficacy in Lung Cancer by (18)F-ICMT-11-Positron Emission Tomography |
title | Preclinical Assessment of Carboplatin Treatment Efficacy in Lung Cancer by (18)F-ICMT-11-Positron Emission Tomography |
title_full | Preclinical Assessment of Carboplatin Treatment Efficacy in Lung Cancer by (18)F-ICMT-11-Positron Emission Tomography |
title_fullStr | Preclinical Assessment of Carboplatin Treatment Efficacy in Lung Cancer by (18)F-ICMT-11-Positron Emission Tomography |
title_full_unstemmed | Preclinical Assessment of Carboplatin Treatment Efficacy in Lung Cancer by (18)F-ICMT-11-Positron Emission Tomography |
title_short | Preclinical Assessment of Carboplatin Treatment Efficacy in Lung Cancer by (18)F-ICMT-11-Positron Emission Tomography |
title_sort | preclinical assessment of carboplatin treatment efficacy in lung cancer by (18)f-icmt-11-positron emission tomography |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950258/ https://www.ncbi.nlm.nih.gov/pubmed/24618809 http://dx.doi.org/10.1371/journal.pone.0091694 |
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