Amirghahari Nazanin, Harrison Lynn, Smith Melanie, Rong Xiaohua, Naumann Ilka, Ampil Fred, Shi Runhua, Glass Jonathan, Nathan Cherie Ann O
Department of Otolaryngology/Head and Neck Surgery, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
Int J Radiat Oncol Biol Phys. 2003 Dec 1;57(5):1405-12. doi: 10.1016/s0360-3016(03)01577-3.
Cyclooxygenase-2 (COX-2) protein is frequently elevated in squamous cell carcinoma of the head and neck (HNSCC). The aim of this study was to determine if COX-2 inhibitors have radiosensitizing effects in HNSCC and understand the mechanism by which this occurs.
The radiosensitizing effects of a selective COX-2 inhibitor, NS398, on a HNSCC cell line HEp3, were determined using clonogenic survival assay. Cells were pretreated with the dose of NS398 at which 50% growth inhibition occurred (IC(50)) and then irradiated. COX-2 protein and mRNA were then determined in the presence and absence of NS398.
NS398 significantly decreased (p < 0.0001) the calculated survival fraction (SF) for all radiation doses (0.79 to 0.41 at 2 Gy). A significant increase in COX-2 protein of 2.8 fold for 2 Gy and 3.5 fold for 6 Gy was noted 48 h after radiation. Interestingly, the upregulation of COX-2 protein with radiation was suppressed when cells were pretreated with NS398. Quantitative reverse transcriptase polymerase chain reaction showed no significant corresponding increase in COX-2 mRNA at 48 h with ionizing radiation.
The radiosensitizing effect of NS398 could be due to inhibition of radiation-induced COX-2 upregulation by this drug. NS398, known as an inhibitor of COX-2 enzyme activity, down-regulated COX-2 protein expression, which may indicate that NS398 can act upstream of COX-2, and this change appears to be post-transcriptional.
环氧化酶-2（COX-2）蛋白在头颈部鳞状细胞癌（HNSCC）中常呈高表达。本研究旨在确定COX-2抑制剂对头颈部鳞状细胞癌是否具有放射增敏作用，并了解其发生机制。
采用克隆形成存活试验，测定选择性COX-2抑制剂NS398对头颈部鳞状细胞癌细胞系HEp3的放射增敏作用。细胞先用出现50%生长抑制时的NS398剂量（IC50）进行预处理，然后进行照射。随后在有或无NS398的情况下测定COX-2蛋白和mRNA。
NS398显著降低了所有辐射剂量（2 Gy时从0.79降至0.41）下计算出的存活分数（SF）（p < 0.0001）。辐射后48小时，2 Gy时COX-2蛋白显著增加2.8倍，6 Gy时增加3.5倍。有趣的是，当细胞用NS398预处理时，辐射诱导的COX-2蛋白上调受到抑制。定量逆转录聚合酶链反应显示，电离辐射48小时后COX-2 mRNA无相应显著增加。
NS398的放射增敏作用可能是由于该药物抑制了辐射诱导的COX-2上调。NS398作为COX-2酶活性抑制剂，下调了COX-2蛋白表达，这可能表明NS398可作用于COX-2的上游，且这种变化似乎是转录后水平的。
