甘氨双唑钠下调ATM信号通路对喉癌细胞放射增敏的机制研究

Laryngeal cancer is one of the high morbidity and mortality of malignant tumors in China. Radiotherapy is an important treatment of laryngeal cancer, but there are some limitations in this treatment: radiation doses can not be escalated enough to kill most of the tumor cells because of radiation-induced tissue damage; the tumor cells far away from vascular bed are less sensitive to radiation due to hypoxia. Therefore, the radiosensitizer has a very important position and a promising prospect for application in the radiotherapy of laryngeal cancer.Sodium glycididazole is an efficient radiosensitizer of low toxicities ,which was developed independently by scientists of China. Our previous studies suggest that sodium glycididazole has an significant radiosensitizing effect on laryngeal cancer. However,the radiosensitization mechanism of signal transduction pathways of sodium glycididazole is rarely reported currently both at home and abroad. It is of urgent need to investigate its radiosensitization mechanism of signal transduction pathways.The radiosensitization mechanism of how sodium glycididazole down-regulation ATM signal transduction pathway, which will affect the cell cycle checkpoint, will be investigated with lots of experimental techniques, such as RT-PCR, Western Blotting, flow cytometry ,RNAi,etc.This study will provide new perspectives(singal transduction pathways) revealing the radiosensitizing mechanism of sodium glycididazole.

喉癌是我国一种发病率和致死率较高的恶性肿瘤，放疗是治疗喉癌的重要手段，但放疗在喉癌的治疗中也存在一些局限：由于放射性组织损害而导致放疗剂量无法提高到足以杀灭绝大部分肿瘤细胞的程度；生长在肿瘤血管床较远隔的瘤细胞由于低氧状态而放射敏感性降低。因此，放射增敏剂在喉癌的放疗中就具有十分重要的地位和发展前景。甘氨双唑钠是我国自主开发的一种高效、低毒的放射增敏剂。本课题组前期的研究提示，甘氨双唑钠对喉癌有明显的放射增敏作用，然而，目前国内外关于甘氨双唑钠放射增敏的信号传导通路机制的研究尚无报道，迫切需要对其放射增敏的信号传导机制进行研究。本项目运用RT-PCR、Western Blotting、流式细胞术和RNAi等技术试图从信号传导通路方面，研究甘氨双唑钠是如何通过下调ATM信号传导通路来调节细胞周期检验点，从而实现放射增敏的。本课题将从崭新的角度-信号传导通路方面揭示甘氨双唑钠的放射增敏机制。

喉癌是临床常见的恶性肿瘤，发病率和致死率均较高，居头颈部恶性肿瘤之首。甘氨双唑钠是一种硝基咪唑类化合物，对某些肿瘤有放疗增敏作用，但其在喉癌中的作用尚不清楚。有研究显示，ATM基因与肿瘤细胞的放射敏感性相关。通过本项目的研究，我们发现，经甘氨双唑钠干预再接受放射，喉癌细胞Hep-2的ATM表达水平明显下降；甘氨双唑钠影响喉癌细胞细胞周期的分布而增加其放射敏感性。通过体内、体外实验研究提示，甘氨双唑钠主要是通过抑制DNA放射损伤的修复，增加G2/M期细胞比例而减少G1期细胞比例，促进肿瘤细胞凋亡来实现放射增敏作用的。进一步的深入研究发现，甘氨双唑钠主要是通过调节ATM信号传导通路的相关下游分子来实现放射增敏作用。此外，在人体研究中，甘氨双唑钠对局部晚期喉癌有明显的放疗增敏作用，可以延长患者的无进展生存期，且患者耐受性好。总之，本项目率先初步阐明了甘氨双唑钠对喉癌放射增敏作用的具体作用机制，并且进一步证实了ATM基因与放射敏感性的密切关系，为日后肿瘤放射敏感性或放射抵抗的研究提供参考，为甘氨双唑钠在国内外的推广应用提供证据支持。