Circadian Rhythm of Irinotecan Tolerability in Mice

• Published in: Chronobiology international Vol. 21; no. 4-5; pp. 613 - 630
• Main Authors: Filipski, Elisabeth, Lemaigre, Guy, Liu, Xu-Hui, Méry-Mignard, Dominique, Mahjoubi, Mondher, Lévi, Francis
• Format: Journal Article
• Language: English
• Published: England Informa UK Ltd 2004; Taylor & Francis
• Subjects: Agranulocytosis - chemically induced; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - toxicity; Bone Marrow Cells - drug effects; Bone Marrow Cells - pathology; Camptothecin; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - toxicity; Cell Cycle - drug effects; Chronopharmacology; Chronotherapy; Circadian Rhythm - physiology; Circadian rhythms; CPT-11; Drug Tolerance; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - toxicity; Intestines - drug effects; Intestines - pathology; Irinotecan; Leukopenia - chemically induced; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Photoperiod; Topoisomerase I Inhibitors; Toxicity; Weight Loss - drug effects
• ISSN: 0742-0528; 1525-6073
• DOI: 10.1081/CBI-120040183

The toxicity of irinotecan (CPT-11), a topoisomerase-I inhibitor largely used in cancer patients, was investigated as a function of the circadian time of its administration in mice, with mortality, body weight loss, leukopenia, neutropenia, intestinal lesions, and bone marrow cell cycle phase distribution as end points. Four experiments were performed on a total of 773 male mice standardized with 12 h light 12 h darkness. Irinotecan was administered daily for 4 or 10 consecutive days (D1-4 and D1-10, respectively, in different experiments) at one of six circadian stages expressed in hours after light onset (HALO). The survival curves differed significantly as a function of the dosage and circadian time of drug administration by the D1-10 schedule, with 70% survival at 7 or 11 HALO and 51% at 19 or 23 HALO ( p = 0.039 from log rank test). CPT-11 administration at 19 or 23 HALO resulted in (1) greatest mean body weight loss at nadir; (2) most severe colic and bone marrow lesions and or slowest recovery; and (3) deepest neutropenia nadir and or slowest hematologic recovery. These circadian treatment time-related differences were statistically validated. The bone marrow cell cycle data revealed a four to eight-fold larger G2-M phase arrest following irinotecan administration at 19 or 23 HALO in comparison to the other times of drug administration, apparently representative of the repair of more extensive DNA damage ( p < 0.001 from ANOVA) when the medication was given at these circadian times. Overall, CPT-11 was better tolerated by mice treated during the light (animals' rest) span. The results support the administration of CPT-11 to cancer patients in the second half of the night, during sleep, in order to improve drug tolerability.