Evaluation of apoptosis imaging biomarkers in a genetic model of cell death

被引：9

作者：

Vassileva, Vessela ^{[1
]}

Stribbling, Stephen M. ^{[1
]}

Barnes, Chris ^{[1
]}

Carroll, Laurence ^{[1
]}

Braga, Marta ^{[1
]}

Abrahams, Joel ^{[1
]}

Heinzmann, Kathrin ^{[1
]}

Haegeman, Caroline ^{[1
]}

MacFarlane, Marion ^{[2
]}

Simpson, Kathryn L. ^{[3
]}

Dive, Caroline ^{[3
]}

Honeychurch, Jamie ^{[4
]}

Illidge, Timothy M. ^{[4
]}

Aboagye, Eric O. ^{[1
]}

机构：

[1] Imperial Coll London, Canc Imaging Ctr, Dept Surg & Canc, Fac Med, Hammersmith Hosp Campus,Du Cane Rd, London W12 0NN, England

[2] MRC, Toxicol Unit, Hodgkin Bldg,Lancaster Rd, Leicester LE1 9HN, Leics, England

[3] Univ Manchester, Clin & Expt Pharmacol Grp, Canc Res UK Manchester Inst, Alderley Pk, Macclesfield SK10 4TG, Cheshire, England

[4] Christie Hosp, Manchester Canc Res Ctr, Natl Inst Hlth Res Biomed Res Ctr, Targeted Therapy Grp,Div Canc Sci,Manchester Acad, Manchester, Lancs, England

来源：

EJNMMI RESEARCH | 2019年 / 9卷 / 1期

关键词：

Apoptosis; Caspases; Molecular imaging; F-18-ICMT-11; PET; Radiotracer; Death-switch; FLOW-CYTOMETRIC DETECTION; INDUCED TUMOR APOPTOSIS; PHOSPHATIDYLSERINE EXPRESSION; PET; CASPASE-3; CANCER; BIODISTRIBUTION; RADIOSYNTHESIS; ACTIVATION; INHIBITORS;

D O I：

10.1186/s13550-019-0487-8

中图分类号：

R8 [特种医学]; R445 [影像诊断学];

学科分类号：

1002 ; 100207 ; 1009 ;

摘要：

PurposeWe have previously developed the caspase-based radiotracer, F-18-ICMT-11, for PET imaging to monitor treatment response. We further validated F-18-ICMT-11 specificity in a murine melanoma death-switch tumour model with conditional activation of caspase-3 induced by doxycycline.MethodsCaspase-3/7 activity and cellular uptake of F-18-ICMT-11, F-18-ML-10 and F-18-FDG were assessed in B16ova and B16ovaRevC3 cells after death-switch induction.Death-switch induction was confirmed in vivo in xenograft tumours, and F-18-ICMT-11 and F-18-ML-10 biodistribution was assessed by ex vivo gamma counting of select tissues. PET imaging was performed with F-18-ICMT-11, F-18-ML-10 and F-18-FDG. Caspase-3 activation was confirmed by immunohistochemistry.ResultsSignificantly increased caspase-3/7 activity was observed only in B16ovaRevC3 cells after death-switch induction, accompanied by significantly increased F-18-ICMT-11 (p<0.001) and F-18-ML-10 (p<0.05) and decreased F-18-FDG (p<0.001) uptake compared with controls.B16ova and B16ovaRevC3 tumours had similar growth in vivo; however, B16ovaRevC3 growth was significantly reduced with death-switch induction (p<0.01). Biodistribution studies showed significantly increased F-18-ICMT-11 tumour uptake following death-switch induction (p<0.01), but not for F-18-ML-10. Tumour uptake of F-18-ICMT-11 was higher than that of F-18-ML-10 after death-switch induction. PET imaging studies showed that F-18-ICMT-11 can be used to detect apoptosis after death-switch induction, which was accompanied by significantly increased expression of cleaved caspase-3. F-18-FDG signal decreased in tumours after death-switch induction.ConclusionsWe demonstrate that F-18-ICMT-11 can be used to detect caspase-3 activation in a death-switch tumour model, independent of the confounding effects of cancer therapeutics, thus confirming its specificity and supporting the development of this radiotracer for clinical use to monitor tumour apoptosis and therapy response.

引用

页数：13

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