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Am J Physiol Regul Integr Comp Physiol 287: R844-R851, 2004. First published June 24, 2004; doi:10.1152/ajpregu.00085.2004
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SLEEP AND TEMPERATURE REGULATION

Persistent twenty-four hour changes in liver and bone marrow despite suprachiasmatic nuclei ablation in mice

Elisabeth Filipski,1 Verdun M. King,2 Marie-Christine Etienne,3 XiaoMei Li,1 Bruno Claustrat,4 Teresa G. Granda,1 Gérard Milano,3 Michael H. Hastings,5 and Francis Lévi1

1Institut National de la Santé et de la Recherche Médicale E 0354 "Cancer chronotherapeutics" (Université Paris XI), Paul Brousse Hospital, 94800 Villejuif; 3Oncopharmacology Unit Centre Antoine Lacassagne, 06189 Nice, Cedex 2; and 4Service Radiopharmacie et Radioanalyse, Hôpital Neurocardiologique, 69003 Lyon, France; and 2Department of Anatomy, University of Cambridge, Cambridge CB2 3DY; and 5Medical Research Council Laboratory of Molecular Biology, Division of Neurobiology, Cambridge CB2 2QH, United Kingdom

Submitted 9 February 2004 ; accepted in final form 16 June 2004

Rest-activity or cortisol rhythms can be altered in cancer patients, a condition that may impair the benefits from a timed delivery of anticancer treatments. In rodents, the circadian pattern in rest-activity is suppressed by the destruction of the suprachiasmatic nuclei (SCN) in the hypothalamus. We sought whether such ablation would result in a similar alteration of cellular rhythms known to be relevant for anticancer drug chronopharmacology. The SCN of 77 B6D2F1 mice synchronized with 12 h of light and 12 h of darkness were destroyed by electrocoagulation [SCN(–)], while 34 animals were sham operated. Activity and body temperature were recorded by telemetry. Blood and organs were sampled at one of six circadian times for determinations of serum corticosterone concentration, blood leukocyte count, reduced glutathione (GSH), and dihydropyrimidine dehydrogenase (DPD) mRNA expression in liver and cell cycle phase distribution of bone marrow cells. Sham-operated mice displayed significant 24-h rhythms in rest-activity and body temperature, whereas such rhythms were found in none and in 15% of the SCN(–) mice, respectively. SCN lesions markedly altered the rhythmic patterns in serum corticosterone and liver GSH, which became nonsinusoidal. Liver DPD mRNA expression and bone marrow cell cycle phase distribution displayed similar 24-h sinusoidal patterns in sham-operated and SCN(–) mice. These results support the existence of another light-dark entrainable pacemaker that can coordinate cellular functions in peripheral organs. They suggest that the delivery of anticancer treatments at an optimal time of day may still be beneficial, despite suppressed rest-activity or cortisol rhythms.

circadian coordination; cancer chronotherapeutics; cortisol; cell cycle; dihydropyrimidine dehydrogenase


Address for reprint requests and other correspondence: F. Lévi, INSERM E 0354 "Cancer chronotherapeutics" (Université Paris XI), Paul Brousse Hospital, 94800 Villejuif, France (E-mail: levi-f{at}vjf.inserm.fr)




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