Edmonds Christine E, Makvandi Mehran, Lieberman Brian P, Xu Kuiying, Zeng Chenbo, Li Shihong, Hou Catherine, Lee Hsiaoju, Greenberg Roger A, Mankoff David A, Mach Robert H
Department of Radiology, Perelman School of Medicine, University of Pennsylvania 231 S. 34th Street, Philadelphia, PA 19104, USA.
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania 231 S. 34th Street, Philadelphia, PA 19104, USA.
Am J Nucl Med Mol Imaging. 2016 Jan 28;6(1):94-101. eCollection 2016.
The nuclear enzyme PARP1 plays a central role in sensing DNA damage and facilitating repair. Tumors with BRCA1/2 mutations are highly dependent on PARP1 as an alternative mechanism for DNA repair, and PARP inhibitors generate synthetic lethality in tumors with BRCA mutations, resulting in cell cycle arrest and apoptosis. Zhou et al. recently synthesized an (18)F-labeled PARP1 inhibitor ([(18)F]FluorThanatrace) for PET, and demonstrated high specific tracer uptake in a xenograft model of breast cancer [1]. In the current study, we characterize the level of baseline PARP expression and activity across multiple human breast cancer cell lines, including a BRCA1 mutant line. PARP expression and activity, as measured by levels of PAR and PARP1, is correlated with in vitro [(18)F]FluorThanatrace binding as well as tracer uptake on PET in a xenograft model of breast cancer. Radiotracer uptake in genetically-engineered mouse fibroblasts indicates [(18)F]FluorThanatrace is selective for PARP1 versus other PARP enzymes. This motivates further studies of [(18)F]FluorThanatrace as an in vivo measure of PARP1 expression and activity in patients who would benefit from PARP inhibitor therapy.
核酶聚（ADP-核糖）聚合酶1（PARP1）在感知DNA损伤和促进修复过程中发挥核心作用。携带BRCA1/2突变的肿瘤高度依赖PARP1作为DNA修复的替代机制，PARP抑制剂在携带BRCA突变的肿瘤中产生合成致死性，导致细胞周期停滞和凋亡。周等人最近合成了一种用于正电子发射断层扫描（PET）的（18）F标记的PARP1抑制剂（[(18)F]FluorThanatrace），并在乳腺癌异种移植模型中证明了其对示踪剂的高特异性摄取[1]。在本研究中，我们对多种人类乳腺癌细胞系（包括一种BRCA1突变细胞系）的PARP基线表达水平和活性进行了表征。通过聚（ADP-核糖）（PAR）和PARP1水平测量的PARP表达和活性，与体外[(18)F]FluorThanatrace结合以及乳腺癌异种移植模型中PET上的示踪剂摄取相关。在基因工程小鼠成纤维细胞中的放射性示踪剂摄取表明，[(18)F]FluorThanatrace对PARP1具有相对于其他PARP酶的选择性。这促使人们进一步研究[(18)F]FluorThanatrace作为体内测量PARP1表达和活性的方法，用于那些将从PARP抑制剂治疗中受益的患者。
