Chronochemoprevention of Prostate Cancer

描述(由申请人提供)：昼夜节律是基因表达和相关细胞功能中规则的、自我维持的振荡。这些节律变化中的许多都发生在太阳日的过程中。生物钟的要素对肿瘤的发生和/或进展、肿瘤治疗和药物毒性都有影响。虽然已经有许多临床前和临床研究讨论了对广泛的已确立的疾病状态进行昼夜节律治疗的时间安排，但很少有人注意到它对疾病预防的潜在影响。绿茶中发现的硒和多酚等饮食制剂对前列腺癌具有化学预防作用。此R21申请是根据PA-04-053：癌症护理辅助方法项目提交的。它阐述了营养剂的昼夜节律给药时间如何影响前列腺癌的预防。我们将使用特征良好的TRAMP鼠前列腺癌模型来评估在四个不同的昼夜节律时间之一给药的化学预防效果。这些营养剂将在3Halo(光照开始后数小时)、9Halo、15Halo或21Halo给药，对应于小鼠的早期休息、中期休息、早期活动或晚期活动阶段。疾病进展将通过为该模型建立的标准来监测，即在16、22和28周时对前列腺背外侧进行组织学分析(H&E、增殖细胞核抗原、TUNEL染色)，以及在12和16周龄时检测IGF-1和IGFBP3的血清分析(用印度墨水法)。为了评估昼夜节律对这两种药物的药代动力学/药效学(PK/PD)的影响，将进行生物分布研究。这些药物的放射性标记形式已经可用，并将用于在上述时间预防治疗研究中使用的相同的四个HALO时间点进行这些研究。这些PK/PD研究将提供更多关于这些药物从前列腺、血液和其他组织中的吸收、吸收和清除的数据。此外，这些研究将评估昼夜节律对这些参数的影响，并将为与时辰预防治疗研究的相关性提供有价值的数据。这项提议的第三个目标将导致建立一个组织银行，由残留的前列腺、关键器官的正常组织以及血液组成。这将为未来对选定生物标记物的相关研究以及相关的基因组和蛋白质组研究奠定基础。总体而言，这些已成功应用于癌症化疗的时间生物学原理应用于癌症预防的拟议研究，将增加对化学预防的理解，并具有降低前列腺癌发病率和负担的真正潜力。

DESCRIPTION (provided by applicant): Circadian rhythms are regular, self-sustained oscillations in gene expression and associated cellular functions. Many of these rhythmic changes occur over the course of a solar day. Elements of the circadian clock impact on tumor onset and/or progression, tumor therapy and drug toxicity. While there have been many preclinical and clinical studies addressing circadian timing of treatment for a wide range of established disease states, little attention has been paid to its potential impact on disease prevention. Dietary agents such as selenium and polyphenols found in green tea have chemopreventive activity for prostate cancer. This R21 application is being submitted in response to PA-04-053: Projects in Complementary Approaches to Cancer Care. It addresses how circadian timing of administration of nutritional agents can impact on prostate cancer prevention. We will use the well-characterized TRAMP mouse prostate cancer model to assess the chemopreventive effect of dosing at one of four different circadian times. These nutritional agents will be given at either 3 HALO (Hours After Light Onset), 9 HALO, 15 HALO, or 21 HALO, corresponding to the early-rest, mid-rest, early-activity, or late-activity phases of the mouse. Disease progression will be monitored by established criteria for this model, namely, histological analysis of the dorsolateral prostate (H&E, PCNA, TUNEL staining) at 16, 22, and 28 weeks and presence of lymph node and lung metastasis (by the india ink method) as well as serum assays for IGF-1 and IGFBP3 at 12 and 16 weeks of age. To assess circadian influences on the pharmacokinetics/pharmacodynamics (PK/PD) of these two agents, biodistribution studies will be performed. Radiolabeled forms of these agents are available and will be utilized to conduct these studies at the same four HALO time points that will be used in the chronopreventive therapy studies described above. These PK/PD studies will provide additional data about the absorption, uptake and clearance of these agents from prostate, blood and other tissues. Also, these studies will assess circadian influences on these parameters and will provide valuable data for correlation with the chronopreventive therapy studies. The third aim of this proposal will result in the establishment of a tissue bank consisting of residual prostate, normal tissues from critical organs, as well as blood. This will allow for future correlative studies of selected biomarkers as well as correlative genomic and proteomic studies. Overall, these proposed studies on the application of chronobiological principles, which have already been utilized successfully in cancer chemotherapy, to cancer prevention will add to the understanding of chemoprevention and hold real potential for reducing the incidence and burden of prostate cancer.