title: Time dependency of hematopoietic growth factor coupled to chronotoxicity of carboplatin.
abstract: A growing body of data suggests that cancer therapy may be improved and toxicity reduced by administration of antineoplastic agents and cytokines at carefully selected times of the day. The time-dependent effects of each of the drugs have been documented, but not their mutual time dependencies. In the present studies we sought to determine the best time for granulocyte colony-stimulating factor (G-CSF) administration after carboplatin treatment. Carboplatin was injected in different groups of ICR mice at four different circadian stages for 5 consecutive days. Mice were synchronized with an alternation of 12 h of light (from 6:00 a.m. to 6:00 p.m.) and 12 h of darkness. After the last injection, peripheral WBCs of three mice from each group were counted every 4 h over a 24-h period. Bone marrow toxicity was estimated with the mean 24-h WBC count. The most severe leukopenia occurred in the group injected at 3:00 p.m. - 9 h after light onset. The second set of experiments evaluated the time-dependent effect of G-CSF when singly injected or given after carboplatin injections for 5 days only at 3:00 p.m. G-CSF was injected into various groups on days 8 and 9 at the same four different circadian stages. On the 10th day after the first injection, peripheral WBCs of three mice from each group were counted every 4 h over a 24-h period. Time-dependent effects were observed when G-CSF was injected as a single agent. When G-CSF was given at various times to the group with the most severe carboplatin-induced leukopenia, peripheral WBC count recovery was monitored at all injection times; it reached its highest level (exceeding even that of the control) when G-CSF was injected at 3:00 a.m. Dosing times of both chemotherapy and growth factor are relevant for optimization of carboplatin's hematologic tolerability.
authors.affiliation: Department of Human Genetics, Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: I G
authors.initials: IG
authors.lastname: Ron
authors.forename: L
authors.initials: L
authors.lastname: Peleg
authors.forename: S
authors.initials: S
authors.lastname: Rienstein
authors.forename: A
authors.initials: A
authors.lastname: Dotan
authors.forename: A
authors.initials: A
authors.lastname: Ticher
authors.forename: S
authors.initials: S
authors.lastname: Wolfson
authors.forename: I E
authors.initials: IE
authors.lastname: Ashkenazi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D016190:Carboplatin / Q000633:toxicity*; D019454:Chronotherapy; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D016298:Hematopoietic Cell Growth Factors / Q000378:metabolism*; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D016298:Hematopoietic Cell Growth Factors; D016179:Granulocyte Colony-Stimulating Factor; D016190:Carboplatin