Chronobiological Principles to Maximize Efficacy of Alt*

描述(申请人提供)：时间疗法包括使用定时输液或多通道可编程泵使化疗药物输送适应昼夜节律。已经用几种标准化疗药物评估了肿瘤反应、宿主耐受性和药物药理学的节律性变化，以确定一天中使用特定治疗药物的最佳时间。这种治疗方法的疗效已经在临床试验中进行了评估，结果表明，计时疗法的毒性明显低于团注或恒速滴注，而且更有效。我们建议将这些令人兴奋的时间生物学结果与化疗转化为使用替代饮食疗法。我们将重点介绍两种人前列腺癌异种移植模型的应用，一种是雄激素敏感的(LNCaP)，另一种是雄激素不敏感的(PC-3)。使用这两个模型系统，我们将评估三种结构和机械上不同的饮食制剂，维生素D3，姜黄素和硒(亚硒酸钠形式)的时辰疗法(AIM#1)，这些制剂已经单独进行了临床前和临床试验，或者作为佐剂而不考虑昼夜节律。在6-12周内监测小鼠的肿瘤生长(曲线下面积=AUC)，在光照开始后的不同时间给小鼠服用这三种营养剂(光晕)。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光环下进行研究。这些生物分布研究将为肿瘤和正常组织的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，据报道，每种药物都能调节细胞周期动力学、增殖和凋亡。我们将启动机制研究，以解决这些药物在计时治疗中涉及的关键目标蛋白的昼夜变化(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饮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.