title: Time-of-Day Dictates Transcriptional Inflammatory Responses to Cytotoxic Chemotherapy.
abstract: Many cytotoxic chemotherapeutics elicit a proinflammatory response which is often associated with chemotherapy-induced behavioral alterations. The immune system is under circadian influence; time-of-day may alter inflammatory responses to chemotherapeutics. We tested this hypothesis by administering cyclophosphamide and doxorubicin (Cyclo/Dox), a common treatment for breast cancer, to female BALB/c mice near the beginning of the light or dark phase. Mice were injected intravenously with Cyclo/Dox or the vehicle two hours after lights on (zeitgeber time (ZT2), or two hours after lights off (ZT14). Tissue was collected 1, 3, 9, and 24 hours later. Mice injected with Cyclo/Dox at ZT2 lost more body mass than mice injected at ZT14. Cyclo/Dox injected at ZT2 increased the expression of several pro-inflammatory genes within the spleen; this was not evident among mice treated at ZT14. Transcription of enzymes within the liver responsible for converting Cyclo/Dox into their toxic metabolites increased among mice injected at ZT2; furthermore, transcription of these enzymes correlated with splenic pro-inflammatory gene expression when treatment occurred at ZT2 but not ZT14. The pattern was reversed in the brain; pro-inflammatory gene expression increased among mice injected at ZT14. These data suggest that inflammatory responses to chemotherapy depend on time-of-day and are tissue specific.
authors.affiliation: Department of Neuroscience, Neuroscience Research Institute, and Behavioral Neuroendocrinology Group, The Ohio State University, Wexner Medical Center, Columbus, OH 43210 USA.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Borniger
authors.affiliation: Department of Neuroscience, Neuroscience Research Institute, and Behavioral Neuroendocrinology Group, The Ohio State University, Wexner Medical Center, Columbus, OH 43210 USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Walker Ii
authors.affiliation: Department of Neuroscience, Neuroscience Research Institute, and Behavioral Neuroendocrinology Group, The Ohio State University, Wexner Medical Center, Columbus, OH 43210 USA.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Gaudier-Diaz
authors.affiliation: Department of Neuroscience, Neuroscience Research Institute, and Behavioral Neuroendocrinology Group, The Ohio State University, Wexner Medical Center, Columbus, OH 43210 USA.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Stegman
authors.affiliation: Department of Neuroscience, Neuroscience Research Institute, and Behavioral Neuroendocrinology Group, The Ohio State University, Wexner Medical Center, Columbus, OH 43210 USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, Neuroscience Research Institute, and Behavioral Neuroendocrinology Group, The Ohio State University, Wexner Medical Center, Columbus, OH 43210 USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hollyfield
authors.affiliation: Department of Neuroscience, Neuroscience Research Institute, and Behavioral Neuroendocrinology Group, The Ohio State University, Wexner Medical Center, Columbus, OH 43210 USA.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Nelson
authors.affiliation: Department of Neuroscience, Neuroscience Research Institute, and Behavioral Neuroendocrinology Group, The Ohio State University, Wexner Medical Center, Columbus, OH 43210 USA.
authors.forename: A Courtney
authors.initials: AC
authors.lastname: DeVries
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000633:toxicity*; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000633:toxicity*; D002940:Circadian Rhythm; D003520:Cyclophosphamide / Q000378:metabolism / Q000633:toxicity; D016207:Cytokines / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism / Q000633:toxicity; D064420:Drug-Related Side Effects and Adverse Reactions / Q000150:complications / Q000378:metabolism*; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008807:Mice, Inbred BALB C; D017440:Photoperiod; D013154:Spleen / Q000187:drug effects / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D016207:Cytokines; D018836:Inflammation Mediators; D004317:Doxorubicin; D003520:Cyclophosphamide