Tietz Ole, Wuest Melinda, Marshall Alison, Glubrecht Darryl, Hamann Ingrit, Wang Monica, Bergman Cody, Way Jenilee D, Wuest Frank
Department of Oncology, University of Alberta, 11560- University Avenue, Edmonton, AB, T6G 1Z2, Canada.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
EJNMMI Res. 2016 Dec;6(1):37. doi: 10.1186/s13550-016-0192-9. Epub 2016 Apr 26.
Cyclooxygenase-2 (COX-2) is the inducible isoform of the cyclooxygenase enzyme family. COX-2 is involved in tumor development and progression, and frequent overexpression of COX-2 in a variety of human cancers has made COX-2 an important drug target for cancer treatment. Non-invasive imaging of COX-2 expression in cancer would be useful for assessing COX-2-mediated effects on chemoprevention and radiosensitization using COX-2 inhibitors as an emerging class of anti-cancer drugs, especially for colorectal cancer. Herein, we describe the radiopharmacological analysis of [(18)F]Pyricoxib, a novel radiolabeled COX-2 inhibitor, for specific PET imaging of COX-2 in colorectal cancer.
Uptake of [(18)F]Pyricoxib was assessed in human colorectal cancer cell lines HCA-7 (COX-2 positive) and HCT-116 (COX-2 negative). Standard COX-2 inhibitors were used to test for specificity of [(18)F]Pyricoxib for COX-2 binding in vitro and in vivo. PET imaging, biodistribution, and radiometabolite analyses were included into radiopharmacological evaluation of [(18)F]Pyricoxib.
Radiotracer uptake in COX-2 positive HCA-7 cells was significantly higher than in COX-2 negative HCT-116 cells (P < 0.05). COX-2 inhibitors, celecoxib, rofecoxib, and SC58125, blocked uptake of [(18)F]Pyricoxib in HCA-7 cells in a concentration-dependent manner. The radiotracer was slowly metabolized in mice, with approximately 60 % of intact compound after 2 h post-injection. Selective COX-2-mediated tumor uptake of [(18)F]Pyricoxib in HCA-7 xenografts was confirmed in vivo. Celecoxib (100 mg/kg) selectively blocked tumor uptake by 16 % (PET image analysis; P < 0.05) and by 51 % (biodistribution studies; P < 0.01).
The novel PET radiotracer [(18)F]Pyricoxib displays a promising radiopharmacological profile to study COX-2 expression in cancer in vivo.
环氧合酶-2（COX-2）是环氧合酶家族的诱导型同工酶。COX-2参与肿瘤的发生和发展，其在多种人类癌症中频繁过度表达，这使得COX-2成为癌症治疗的重要药物靶点。对癌症中COX-2表达进行无创成像，对于评估使用COX-2抑制剂作为一类新兴抗癌药物在化学预防和放射增敏方面COX-2介导的作用将是有用的，尤其是对于结直肠癌。在此，我们描述了新型放射性标记的COX-2抑制剂[（18）F]吡罗昔布用于结直肠癌中COX-2特异性PET成像的放射药理学分析。
在人结直肠癌细胞系HCA-7（COX-2阳性）和HCT-116（COX-2阴性）中评估[（18）F]吡罗昔布的摄取。使用标准COX-2抑制剂在体外和体内测试[（18）F]吡罗昔布与COX-2结合的特异性。PET成像、生物分布和放射性代谢物分析纳入了对[（18）F]吡罗昔布的放射药理学评估。
COX-2阳性的HCA-7细胞中放射性示踪剂的摄取显著高于COX-2阴性的HCT-116细胞（P < 0.05）。COX-2抑制剂塞来昔布、罗非昔布和SC58125以浓度依赖的方式阻断HCA-7细胞中[（18）F]吡罗昔布的摄取。放射性示踪剂在小鼠体内代谢缓慢，注射后2小时约60%为完整化合物。在体内证实了[（18）F]吡罗昔布在HCA-7异种移植瘤中由COX-2介导的选择性肿瘤摄取。塞来昔布（100 mg/kg）选择性地使肿瘤摄取降低16%（PET图像分析；P < 0.05）和51%（生物分布研究；P < 0.01）。
新型PET放射性示踪剂[（18）F]吡罗昔布显示出有前景的放射药理学特征，可用于在体内研究癌症中的COX-2表达。
