Synergistic Effect of Combination Topotecan and Chronomodulated Radiation Therapy on Xenografted Human Nasopharyngeal Carcinoma

• Published in: International journal of radiation oncology, biology, physics Vol. 87; no. 2; pp. 356 - 362
• Main Authors: Zhang, YanLing, MD, Chen, Xin, MD, Ren, PeiRong, MD, Su, Zhou, MD, Cao, HongYing, MD, Zhou, Jie, MD, Zou, XiaoYan, MD, Fu, ShaoZhi, PhD, Lin, Sheng, PhD, Fan, Juan, MD, Yang, Bo, BD, Sun, XiaoYang, BD, Zhou, Yan, BD, Chen, Yue, PhD, Yang, LingLin, PhD, Wu, JingBo, MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2013
• Subjects: Animals; ANOXIA; APOPTOSIS; Carcinoma; CARCINOMAS; Cell Hypoxia; Chronotherapy - methods; Combined Modality Therapy - methods; CONTROL; DNA Damage; DNA Topoisomerases, Type I - metabolism; Dose-Response Relationship, Radiation; Hematology, Oncology and Palliative Medicine; Histones - metabolism; Humans; IN VIVO; Male; MICE; Mice, Inbred BALB C; Mice, Nude; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms - metabolism; Nasopharyngeal Neoplasms - prevention & control; Nasopharyngeal Neoplasms - radiotherapy; Neoplasm Recurrence, Local - prevention & control; Nitroimidazoles - metabolism; Phosphorylation; Radiation Tolerance - drug effects; Radiation-Sensitizing Agents - pharmacology; Radiology; RADIOLOGY AND NUCLEAR MEDICINE; RADIOSENSITIVITY; RADIOTHERAPY; Time Factors; Topoisomerase I Inhibitors - pharmacology; Topotecan - pharmacology; Transplantation, Heterologous
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/j.ijrobp.2013.05.047

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, (γ-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 ± 3.6 days), and TPT+RT at 3 HALO was worst (TGD = 35.0 ± 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.