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. ? ? ?
