Establishment of cellular models for investigating of cancer chronotherapy

癌症的时间疗法改善了癌症的治疗。抗癌药物的给药时间对肿瘤化疗的疗效和毒副反应有重要影响。但迄今为止，还没有阐明癌症时间疗法的确切机制。为了阐明时间疗法治疗肿瘤的分子基础，我们一直在尝试建立一个时间疗法的细胞模型系统。伊立替康是一种靶向拓扑异构酶I并抑制其酶活性的药物。已知伊立替康相关因子如拓扑异构酶I、ABCB 1和UGTA 1的基因以昼夜节律方式振荡。我们克隆了拓扑异构酶I、ABCB 1和UGTA 1的启动子区，并利用Nakajima等建立的荧光素酶系统构建了报告基因。这些报告基因的应用将有助于了解肿瘤细胞中时钟基因和伊立替康相关因子的协同作用以及对伊立替康治疗的反应。

Chronotherapy for cancer has improved therapy for cancer. Dosing time of anticancer drugs is appeared to be influencing to effectiveness and toxicity of chemotherapy for cancer. But no precise mechanisms of cancer chronotherapy are elucidated, so far. To clarify the molecular basis of chronotheray for cancer, we have been trying to establish a cell model system for chronotherapy. Irinotecan is an agent for targeting topoisomerase I and inhibit its enzymatic activity. It is known that genes of irinotecan related factors, such as topoisomerase I, ABCB1 and UGTA1 are oscillated in circadian manner. We cloned promoter region of topoisomerase I, ABCB1 and UGTA1 and constructed reporters using multicolor luciferase system, established by Nakajima et al. The application of these reporters to this study will be helpful to understand the coordination of clock genes and irinotecan related factors in cancer cells and the reactions to the treatment of iriotecan.