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.
