Witney Timothy H, Fortt R, Aboagye Eric O
Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
PLoS One. 2014 Mar 11;9(3):e91694. doi: 10.1371/journal.pone.0091694. eCollection 2014.
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.
在临床上，肿瘤对治疗的反应主要通过监测肿瘤大小的缩小来评估。然而，这种方法缺乏敏感性，因为在许多情况下，可能要过几周才会有肿瘤缩小的迹象。因此，需要开发非侵入性成像技术来在临床上监测肿瘤治疗反应。在此，我们评估了（18）F-ICMT-11正电子发射断层扫描（一种检测半胱天冬酶3/7激活的方法）在非小细胞肺癌（NSCLC）中的临床前效用。在体外和体内用卡铂治疗后，将（18）F-ICMT-11摄取与PC9和A549 NSCLC细胞中细胞死亡的分子生化指标进行了比较。卡铂诱导ERCC1低/突变型EGFR PC9细胞凋亡的特征是半胱天冬酶-3/7激活、聚ADP核糖聚合酶裂解和膜联蛋白V染色随时间和剂量增加。因此，与用赋形剂处理的细胞相比，在200µM卡铂时，18F-ICMT-11摄取增加了高达14倍（P<0.01）。相反，坏死是ERCC1高/野生型EGFR A549细胞中的主要死亡机制，未检测到（18）F-ICMT-11摄取的变化。在体内，PC9肿瘤异种移植的组织学分析表明治疗前坏死程度高。卡铂治疗后48小时，在PC9肿瘤的非坏死区域测得裂解的半胱天冬酶-3/7增加了4.6倍。在存在大量预先存在的坏死的情况下，基于PET的肿瘤（18）F-ICMT-11摄取平均值对凋亡变化不敏感。然而，基于PET的体素强度分选确定了（18）F-ICMT-11摄取高的肿瘤内区域，从而能够准确评估凋亡以及治疗反应。在缺乏高治疗前坏死的A549肿瘤中，卡铂诱导的生长抑制仅与凋亡有最小关联，因此（18）F-ICMT-11 PET无法检测到。
