Dorow Donna S, Cullinane Carleen, Conus Nelly, Roselt Peter, Binns David, McCarthy Timothy J, McArthur Grant A, Hicks Rodney J
Centre for Molecular Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Eur J Nucl Med Mol Imaging. 2006 Apr;33(4):441-52. doi: 10.1007/s00259-005-0039-5. Epub 2006 Feb 1.
This study was designed as "proof of concept" for a drug development model utilising multi-tracer serial small animal PET imaging to characterise tumour responses to molecularly targeted therapy.
Mice bearing subcutaneous A431 human squamous carcinoma xenografts (n=6-8) were treated with the pan-Erb-B inhibitor CI-1033 or vehicle and imaged serially (days 0, 3 and 6 or 7) with [(18)F]fluorodeoxyglucose, [(18)F]fluoro-L: -thymidine, [(18)F]fluoro-azoazomycinarabinoside or [(18)F]fluoromisonidazole. Separate cohorts (n=3) were treated identically and tumours were assessed ex vivo for markers of glucose metabolism, proliferation and hypoxia.
During the study period, mean uptake of all PET tracers generally increased for control tumours compared to baseline. In contrast, tracer uptake into CI-1033-treated tumours decreased by 20-60% during treatment. Expression of the glucose transporter Glut-1 and cell cycle markers was unchanged or increased in control tumours and generally decreased with CI-1033 treatment, compared to baseline. Thymidine kinase activity was reduced in all tumours compared to baseline at day 3 but was sevenfold higher in control versus CI-1033-treated tumours by day 6 of treatment. Uptake of the hypoxia marker pimonidazole was stable in control tumours but was severely reduced following 7 days of CI-1033 treatment.
CI-1033 treatment significantly affects tumour metabolism, proliferation and hypoxia as determined by PET. The PET findings correlated well with ex vivo biomarkers for each of the cellular processes studied. These results confirm the utility of small animal PET for evaluation of the effectiveness of molecularly targeted therapies and simultaneously definition of specific cellular processes involved in the therapeutic response.
本研究旨在作为一种药物开发模型的“概念验证”，该模型利用多示踪剂系列小动物正电子发射断层扫描（PET）成像来表征肿瘤对分子靶向治疗的反应。
将携带皮下A431人鳞状细胞癌异种移植瘤的小鼠（n = 6 - 8）用泛Erb - B抑制剂CI - 1033或赋形剂处理，并分别在第0、3和6或7天用[（18）F]氟脱氧葡萄糖、[（18）F]氟 - L - 胸腺嘧啶核苷、[（18）F]氟偶氮霉素阿拉伯糖苷或[（18）F]氟米索硝唑进行系列成像。另外的队列（n = 3）接受相同处理，对肿瘤进行体外葡萄糖代谢、增殖和缺氧标志物评估。
在研究期间，与基线相比，对照肿瘤的所有PET示踪剂平均摄取量总体增加。相反，CI - 1033处理的肿瘤在治疗期间示踪剂摄取量下降了20% - 60%。与基线相比，对照肿瘤中葡萄糖转运蛋白Glut - 1和细胞周期标志物的表达未改变或增加，而CI - 1033处理后通常下降。与基线相比，所有肿瘤的胸苷激酶活性在第3天降低，但在治疗第6天时，对照肿瘤比CI - 1033处理的肿瘤高7倍。缺氧标志物匹莫硝唑的摄取在对照肿瘤中稳定，但在CI - 1033治疗7天后严重降低。
PET检测显示CI - 1033治疗显著影响肿瘤代谢、增殖和缺氧。PET结果与所研究的每个细胞过程的体外生物标志物密切相关。这些结果证实了小动物PET在评估分子靶向治疗有效性以及同时确定治疗反应中涉及的特定细胞过程方面的实用性。
