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1 Cancer Chronotherapeutics, INSERM E0354 (Universite Paris XI), Paul Brousse Hopital, Villejuif, France
2 Department of Anatomy, University of Cambridge, Cambridge, United Kingdom
3 Oncopharmacology Unit Centre Antoine Lacassagne, Nice, Cedex, France
4 Service Radiopharmacie et Radioanalyse, Hopital Neurocardiologique, Lyon, France
5 Division of Neurobiology, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
* To whom correspondence should be addressed. E-mail: levi-f{at}vjf.inserm.fr.
Rest-activity or cortisol rhythms can be altered in cancer patients, a condition which 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 6 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 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 non sinusoidal. Liver DPD mRNA expression and bone marrow cell cycle phase distribution displayed similar 24-h sinusoidal patterns in sham and in SCN(-) mice. These results support the existence of another light-dark entrainable pacemaker which 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.
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