Azizzadeh B, Yip H T, Blackwell K E, Horvath S, Calcaterra T C, Buga G M, Ignarro L J, Wang M B
Division of Head and Neck Surgery, Department of Molecular and Medical Pharmacology, University of California Los Angeles School of Medicine, Los Angeles, California 90095-1624, USA.
Laryngoscope. 2001 Nov;111(11 Pt 1):1896-900. doi: 10.1097/00005537-200111000-00004.
To test whether nitric oxide (NO) enhances the cytotoxicity of cisplatin in a head and neck squamous cell carcinoma (HNSCC) cell line.
Cisplatin is one of the most frequently used chemotherapeutic agents in the treatment of HNSCC. NO has been shown to play an important role in regulating tumor growth. Previous studies demonstrate that NO can enhance the cytotoxicity of cisplatin in Chinese hamster lung fibroblasts. In this report, we examined the in vitro interaction of NO and cisplatin in a HNSCC cell line.
CCL23 cells were pretreated with three different NO donors: PAPA/NO (t 1/2 = 15 min), DPTA/NO (t 1/2 = 3 h), and DETA/NO (t 1/2 = 20 h). The cells were rinsed and exposed for 6 hours to a culture medium containing cisplatin. Cell survival and LD50 of cisplatin were calculated with and without NO pretreatment.
PAPA/NO and DPTA/NO did not show any cytotoxic activity and did not change the LD50 of cisplatin. DETA/NO when used alone resulted in 25.6% cell death at its peak dose (100 microM). Pretreatment with DETA/NO resulted in almost a threefold reduction of the LD50 of cisplatin (6.8 vs. 2.4 microg/mL). Pretreatment with DETA/NO sensitized the HNSCC cells to subsequent cisplatin activity (two-sided P =.00016).
Pretreatment of HNSCC cells with long-acting NO donors enhances cisplatin activity. Short- and medium-acting NO donors do not exert a toxic effect and do not augment the activity of cisplatin. NO agonists should be considered in the future as a possible adjunct to cisplatin in the treatment of HNSCC. Further studies with animal models are necessary to further clarify this relationship.
检测一氧化氮（NO）是否能增强顺铂对人头颈部鳞状细胞癌（HNSCC）细胞系的细胞毒性。
顺铂是治疗HNSCC最常用的化疗药物之一。NO已被证明在调节肿瘤生长中起重要作用。先前的研究表明，NO可增强顺铂对中国仓鼠肺成纤维细胞的细胞毒性。在本报告中，我们检测了NO与顺铂在HNSCC细胞系中的体外相互作用。
用三种不同的NO供体预处理CCL23细胞：PAPA/NO（半衰期=15分钟）、DPTA/NO（半衰期=3小时）和DETA/NO（半衰期=20小时）。冲洗细胞后，将其暴露于含顺铂的培养基中6小时。计算有无NO预处理时顺铂的细胞存活率和半数致死剂量（LD50）。
PAPA/NO和DPTA/NO未显示任何细胞毒性活性，也未改变顺铂的LD50。单独使用DETA/NO时，在其峰值剂量（100微摩尔）时导致25.6%的细胞死亡。用DETA/NO预处理导致顺铂的LD50几乎降低了三倍（6.8对2.4微克/毫升）。用DETA/NO预处理使HNSCC细胞对随后的顺铂活性敏感（双侧P=0.00016）。
用长效NO供体预处理HNSCC细胞可增强顺铂活性。短效和中效NO供体不产生毒性作用，也不增强顺铂的活性。未来，NO激动剂应被视为顺铂治疗HNSCC的一种可能辅助药物。需要进一步用动物模型进行研究以进一步阐明这种关系。
