- 作者：YanLing Zhang ; Xin Chen ; PeiRong Ren ; Zhou Su ; HongYing Cao ; Jie Zhou ; XiaoYan Zou ; ShaoZhi Fu ; Sheng Lin ; Juan Fan ; Bo Yang ; XiaoYang Sun ; Yan Zhou ; Yue Chen ; LingLin Yang ; JingBo Wu
- 刊名：International Journal of Radiation Oncology*Biology*Physics
- 出版年：2013
- 出版时间：1 October, 2013
- 年：2013
- 卷：87
- 期：2
- 页码：356-362
- 全文大小：2829 K
Purpose
To investigate the in?vivo chronomodulated radiosensitizing effect of topotecan (TPT) on human nasopharyngeal carcinoma (NPC) and its possible mechanisms.Methods and Materials
Xenografted BALB/c (nu/nu) NPC mice were synchronized with an alternation of 12 hours of light from 0 to 12 hours after light onset (HALO) and 12 hours of darkness to establish a unified biological rhythm. Chronomodulated radiosensitization of TPT was investigated by analysis of tumor regrowth delay (TGD), pimonidazole hydrochloride, histone H2AX phosphorylation, (¦Ã-H2AX) topoisomerase I (Top I), cell cycle, and apoptosis after treatment with (1) TPT (10 mg/kg) alone; (2) radiation therapy alone (RT); and (3) TPT+RT at 3, 9, 15, and 21 HALO. The tumor-loaded mice without any treatment were used as controls.
Results
The TPT+RT combination was more effective than TPT or RT as single agents. The TPT+RT combination at 15 HALO was best (TGD = 58.0 ¡À 3.6 days), and TPT+RT at 3 HALO was worst (TGD = 35.0 ¡À 1.5 days) among the 4 TPT+RT groups (P<.05). Immunohistochemistry analysis revealed a significantly increased histone H2AX phosphorylation expression and decreased pimonidazole hydrochloride expression in the TPT+RT group at the same time point. The results suggested that the level of tumor hypoxia and DNA damage varied in a time-dependent manner. The expression of Top I in the TPT+RT group was also significantly different from the control tumors at 15 HALO (P<.05). Cell apoptosis index was increased and the proportion of cells in S phase was decreased (P<.05) with the highest value in 15 HALO and the lowest in 3 HALO.
Conclusions
This study suggested that TPT combined with chronoradiotherapy could enhance the radiosensitivity of xenografted NPC. The TPT+RT group at 15 HALO had the best therapeutic effect. The chronomodulated radiosensitization mechanisms of TPT might be related to circadian rhythm of tumor hypoxia, cell cycle redistribution, DNA damage, and expression of Top I.