Abstract
Circadian clocks gate cellular proliferation and, thereby, therapeutically target availability within proliferative pathways. This temporal coordination occurs within both cancerous and noncancerous proliferating tissues. The timing within the circadian cycle of the administration of drugs targeting proliferative pathways necessarily impacts the amount of damage done to proliferating tissues and cancers. Concurrently measuring target levels and associated key pathway components in normal and malignant tissues around the circadian clock provides a path toward a fuller understanding of the temporal relationships among the physiologic processes governing the therapeutic index of antiproliferative anticancer therapies. The temporal ordering among these relationships, paramount to determining causation, is less well understood using two- or three-dimensional representations. We have created multidimensional multimedia depictions of the temporal unfolding of putatively causative and the resultant therapeutic effects of a drug that specifically targets these ordered processes at specific times of the day. The systems and methods used to create these depictions are provided, as well as three example supplementary movies.
Highlights
We have previously described the chain of events linking cancer cell clock proteins, cancer cell DNA synthesis, proliferation, TS activity (TSA), and
We have shown that despite the fact that cancers often exhibit deregulated cellular proliferation, cancers maintain high amplitude circadian rhythms in their growth, DNA synthesis, and mitosis
The time of day was recorded as Hours After Lights On (HALO)
Summary
Circadian organization of living organisms is ubiquitous. Within these organisms, circadian rhythms in synthetic, metabolic, and proliferative functions characterize all organs, tissues, and cells. Circadian rhythms in synthetic, metabolic, and proliferative functions characterize all organs, tissues, and cells This temporal organization is endogenous and conferred at all levels of biological integration. The mammalian central circadian clock, residing in the suprachiasmatic nuclei (SCN), sets circadian clocks throughout the body through autonomic nervous connections, SCN-orchestrated endocrine secretions, and complex SCN-influenced neurobiological behavior patterns such as human nightly sleep and daily activity [1,2,3]. Each cell in the body resonates with its own circadian orientation, determined by the relationship between the central time keepers’ and its own molecular circadian clockwork [4,5,6]
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