title: Persistent twenty-four hour changes in liver and bone marrow despite suprachiasmatic nuclei ablation in mice.
abstract: 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 B6D2F(1) 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.
authors.affiliation: INSERM E 0354 "Cancer chronotherapeutics" (Université Paris XI Paul Brousse Hospital, 94800 Villejuif, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Filipski
authors.forename: Verdun M
authors.initials: VM
authors.lastname: King
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Etienne
authors.forename: XiaoMei
authors.initials: X
authors.lastname: Li
authors.forename: Bruno
authors.initials: B
authors.lastname: Claustrat
authors.forename: Teresa G
authors.initials: TG
authors.lastname: Granda
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
authors.forename: Michael H
authors.initials: MH
authors.lastname: Hastings
authors.forename: Francis
authors.initials: F
authors.lastname: Lévi
mesh_terms: D000758:Anesthesia; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001772:Blood Cell Count; D001831:Body Temperature / Q000502:physiology; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D002453:Cell Cycle / Q000502:physiology; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D003345:Corticosterone / Q000097:blood; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009944:Organoplatinum Compounds / Q000633:toxicity; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013493:Suprachiasmatic Nucleus / Q000502:physiology*
chemical_list: D000963:Antimetabolites; D009944:Organoplatinum Compounds; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D005978:Glutathione; D005472:Fluorouracil; D003345:Corticosterone