Circadian variation of topoisomerase II-alpha in human rectal crypt epithelium: implications for reduction of toxicity of chemotherapy.
ABSTRACT 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.
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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.Nature reviews Neuroscience 09/2003; 4(8):649-61. DOI:10.1038/nrn1177 · 31.38 Impact Factor
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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 · 2.50 Impact Factor
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ABSTRACT: Genotoxic stress induced by anticancer drugs can lead to apoptosis of both angiogenic endothelial cells (ECs) and proliferating tumor cells. However, growth factors such as basic fibroblast growth factor (bFGF) and vascular endothelial cell growth factor (VEGF) present within the tumor microenvironment can promote chemoresistance by suppressing apoptotic mechanisms in these cells. Here, we have identified apoptosis signal-regulating kinase 1 (ASK1), a proapoptotic member of the MAP3K family, as a target of bFGF-mediated survival signaling in ECs. Evidence is provided that ASK1 is required for EC apoptosis in response to the genotoxic chemotherapeutic agent doxorubicin, and that bFGF, but not VEGF, neutralizes the death-promoting activity of ASK1. Specifically, bFGF stimulation promotes the formation of a Raf-1/ASK1 complex at the mitochondria, inhibits ASK1 kinase activity, and protects ECs from genotoxic stress. Mutation of the Raf-1 activation domain (SS338/9AA) not only prevents Raf-1/ASK1 complex formation but abolishes bFGF-mediated EC protection from genotoxic stress. In line with these observations, bFGF, but not VEGF, neutralizes the antiangiogenic effects of doxorubicin in vivo. These findings reveal a new pathway of EC survival signaling and define a molecular mechanism for chemoresistance induced by bFGF.Cancer Research 04/2007; 67(6):2766-72. DOI:10.1158/0008-5472.CAN-06-3648 · 9.28 Impact Factor