Chronobiological Principles to Maximize Efficacy of Alt*

描述（由申请人提供）：时间疗法包括使用定时输注或多通道可编程泵使化疗药物递送适应昼夜节律。肿瘤反应、宿主耐受性和药物药理学的节律性变化已经被评估，已经用几种标准化疗药物进行了评估，以确定一天中使用特定治疗药物的最佳时间。在临床试验中对这种治疗方法的疗效进行了评估，结果表明，计时疗法的毒性明显低于大剂量或恒速输注。我们建议将这些令人兴奋的时间生物学结果与化疗一起转化为替代饮食疗法的使用。我们将重点关注两种人类前列腺癌异种移植模型的使用，一种雄激素敏感（LNCaP）和一种雄激素不敏感（PC-3）。使用这两个模型系统，我们将评估三种结构和机制不同的膳食制剂的时间疗法（AIM #1），维生素D3，姜黄素和硒（亚硒酸钠形式），这些药物已经单独或作为辅助剂进行了临床前和临床试验，而不考虑昼夜节律。小鼠将在光起（HALOs）和肿瘤生长（曲线下面积= AUC）监测6-12周后的不同小时内分别服用这三种营养剂。此外，所有三种药物的肿瘤和正常组织生物分布（AIM #2）将在用于治疗剂量的相同halo下进行研究。这些生物分布研究将为肿瘤和正常组织摄取与毒性和抗肿瘤反应的相关性提供一种方法。从机制上讲，每种药物都有调节细胞周期动力学、增殖和凋亡的报道。我们将启动机制研究，以解决与这些药物的时间疗法相关的关键靶蛋白的昼夜节律变化（AIM #3）。这项工作的结果将有助于(a)未来用于治疗和化学预防的其他膳食制剂的时间生物学研究，以及(b)将结果转化为临床试验。

DESCRIPTION (provided by applicant): Chronotherapy consists of the adaptation of chemotherapeutic drug delivery to circadian rhythms using timed infusions or multichannel programmable pumps. Rhythmic changes in tumor response, host tolerance, and drug pharmacology have been evaluated have been evaluated with several standard chemotherapeutic agents to determine the optimal time of day to dose with a particular therapeutic agent. The efficacy of the treatment approach has been evaluated in clinical trials and results have shown that chronotherapy is significantly less toxic and more effective than bolus dosing or constant rate infusion. We propose to translate these exciting chronobiological results with chemotherapy to the use of alterative dietary therapeutics. We will focus on the use of two human prostatic cancer xenograft models, one androgen sensitive (LNCaP) and one androgen-insensitive (PC-3). Using these two model systems, we will evaluate chronotherapy (AIM #1) of three structurally and mechanistically distinct dietary agents, vitamin D3, curcumin and selenium (in the sodium selenite form) that have undergone preclinical and clinical trials alone or as adjuvants without consideration to circadian rhythms. Mice will be dosed with each of the three nutritional agents at different Hours After Light Onset (HALOs) and tumor growth (area under the curve = AUC) monitored over 6-12 weeks. In addition, tumor and normal tissue biodistribution (AIM #2) of all three agents will be studied at the same HALOs as used for therapeutic dosing. These biodistribution studies will provide a method for the correlation of tumor and normal tissue uptake with both toxicity and anti-tumor responses. Mechanistically, each agent has been reported to modulate cell cycle kinetics, proliferation and apoptosis. We will initiate mechanistic studies to address circadian changes in key target proteins involved in chronotherapy with these agents (AIM #3). The results of this work will lend itself to (a) future chronobiological studies of other dietary agents for both therapy and chemoprevention and (b) translation of results into clinical trials.