Topoisomerase II-alpha is a target of common chemotherapeutic agents such as doxorubicin and etoposide, which induce DNA damage by altering the activity of this enzyme. We took rectal biopsies at 4-hour intervals over a 24-hour period (seven total) from each of 10 healthy volunteers and examined immunoperoxidase-stained coded anti-topoisomerase II-alpha-stained sections. A significant circadian periodicity was seen in the number of rectal crypt epithelial cell nuclei that were stained (P =.01). Mean peak staining was at 7:23 a.m. +/- 45 minutes, and the mean rate of change (difference between peak and trough expression) was 40%. Topoisomerase II-alpha expression in rectal epithelium has a significant circadian variation similar to that of tritiated thymidine incorporation. Although direct confirmation is needed, giving topoisomerase II-targeted chemotherapeutic agents at the proper time of day might reduce their mucositis side effects.
[Show abstract][Hide abstract] ABSTRACT: The hypothalamic suprachiasmatic nuclei (SCN) are our principal circadian oscillator, coordinating daily cycles of physiology and behaviour that adapt us to the world. Local versions of the SCN clockwork are also active in peripheral, non-neural tissues, driving the tissue-specific cycles of gene expression that underpin circadian organization. These local oscillators are tuned to each other, and to solar time, by neuroendocrine and metabolic cues that depend on the SCN. The discovery of these local circadian clocks forces a re-appraisal of established models of circadian biology. It also presents new avenues for therapeutic intervention in conditions where disturbance of circadian gene expression is an important cause of morbidity.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Our understanding of the biological basis for mucosal barrier injury (mucositis) induced by cancer therapy with radiation or drugs continues to evolve. A patient's mucosal response to cancer therapy appears to be controlled by both global (i.e. gender, underlying systemic disease, race) and tissue specific (i.e. epithelial type, intrinsic endocrine system, local microbial environment, function) factors. CONCLUSION: Interactions of these elements, coupled with underlying genetic influences, most likely govern the risk, course and severity of regimen-related mucosal injury.
Supportive Care Cancer 07/2006; 14(6):516-8. DOI:10.1007/s00520-006-0058-1 · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sleep is a necessary behavior for physiological allostasis that is common to all vertebrates. Allostasis refers to the set
of intertwined neuroendocrine-immune processes of bodily adaptation to stressful challenges during the wake cycle. The summative
effects of these challenges, the allostatic load, signifies the total cost of wear and tear to the body. A finely regulated
neuroimmunology of the sleep component of the circadian patterns is critical to the physiological repair mechanism required
in allostasis (Solomon and Moos 1964; Solomon 1987; Sterling and Eyer 1988; Chrousos and Gold 1992; Kiecolt-Glaser, McGuire,
Robles, and Glaser 2002; Irwin 2002; McEwen and Wingfield 2003; Schulkin 2003; Chiappelli and Cajulis 2004; Chiappelli et
al. in press-c).
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