The Chronomodulated Radiosensitization By Cmna On Nasopharyngeal Carcinoma In Vivo

Objective: To investigate effect on tumor growth and the expressions of HIF-1α,γ-H2AX and apoptosis proteins after the chronomodulated radiosensitization by CMNa on human nasopharyngeal carcinoma(NPC) in nude mice, and to disclose the mechanism of chronomodulated radiosensitization on nasopharyngeal carcinoma.Methods: 130 Balb/c mice were synchronized with an alternative lighting regimen with 12 hours for light and 12 hours for dark at least 3 weeks. Human nasopharyngeal poorly differentiated squamous cell carcinoma(CNE-II) cells were implanted into the right lateral thigh of each mouse. Three weeks after transplantation, 112 nude mice xenografts were divided into 3 groups: radiotherapy(RT) group, RT+CMNa group and control group. Each group was divided into 4 subgroups at four time points of 3HALO, 9HALO, 15HALO, 21HALO. CMNa (20mg/kg) were injected introperitoneally one hour before four time points in RT+CMNa group. RT group and RT+CMNa group were given radiotherapy which dose of 10Gy at four time points. Half of nude mice were exceuted 24 hours after radiotherapy. The remaining mice were determined regrowth delay time (TGD), and the growth curve was drawn. The expressions of HIF-1α,γ-H2AX and apoptosis proteins were detected by immunohistochemistry and were analyzed by Image-Pro Plus(IPP) software. Data were analyzed by completely randomized single-factor variance analysis method. Results: The processing factors have different inhibition for NPC xenografts in nude mice. According to TGD, RT+CMNa group obtained the best inhibitory action of tumor. In this group, TGD had statistical difference between 15HALO and 3HALO (P<0.05). According to immunehistochemical results, the expressions HIF-1α,γ-H2AX and apoptosis proteins have circadian rhythm. At the same time point, the expressions of HIF-1α,γ-H2AX and apoptosis proteins had significant difference between RT+CMNa group and RT group (P<0.05). The expression of HIF-1αin RT+CMNa group and RT group: 3HALO>9HALO>21HALO>15HALO. There were statistical difference between 15HALO and 3HALO (P<0.05). The expression ofγ-H2AX in RT+CMNa group and RT group: 15HALO>21HALO>9HALO>3HALO. There were statistical difference between 15HALO and 3HALO (P<0.05). The expression of apoptosis proteins in RT+CMNa group and RT group: 15HALO>21HALO>9HALO>3HALO. There were statistical difference among 15HALO, 3HALO and 9HALO (P<0.05).Conclusion: This study showed that CMNa combined with chronomodulated radiotherapy could obviously enhance the radiosentivity of NPC xenografts, and RT+CMNa group at 15HALO can get the greatest efficacy. The chronomodulated radiosensitization by CMNa have circadian rhythm. Inhibitory effect on tumor and the results of immunohistochemistry have good consistency. Its mechanism might be related to the expression of HIF-1α, the injury of DNA double strands and apoptosis.